Magellan Rx Report - Fall 2022

Contributors

Caroline

M.Sc., FAPM, CPHQ

CMO, Magellan Health, Magellan Rx Management

Steve Cutts, Pharm.D.

SVP, Market General Manager, MRx Specialty

Haita Makanji, Pharm.D.

VP, Clinical Strategy and Innovation, Specialty

Amy E. Edquist

Senior Manager, Marketing

Joe Tavares

SVP, Sales and Business Development, Specialty Carole Kallas

Project Manager

Brian MacDonald, Pharm.D. Director, Specialty Clinical Strategy

Erin Ventura, Pharm.D. Manager, Specialty Clinical Programs

Brian Kinsella, Esq.

Senior Legal Counsel

Alina Young Associate Legal Counsel

Lilly Ackley

VP, Corporate Communications

Editorial Advisory Board

Mona M. Chitre, Pharm.D., CGP

Chief Pharmacy Officer & VP Clinical Analytics, Strategy & Innovation, Excellus BlueCross BlueShield

Dennis Bourdette, M.D., FAAN, FANA

Chair and Roy and Eulalia Swank Family Research Professor, Department of Neurology, Oregon Health & Science University

Yousaf Ali, M.D., FACR

Chief, Division of Rheumatology, Mount Sinai West; Professor of Medicine, Icahn School of Medicine at Mount Sinai

Steven L. D’Amato, B.S.Pharm.

Executive Director, New England Cancer Specialists

Joseph Mikhael, M.D., M.Ed., FRCPC, FACP

Chief Medical Officer, International Myeloma Foundation

Natalie Tate, Pharm.D., MBA, BCPS

VP, Pharmacy Management, BlueCross BlueShield of Tennessee

Steve Marciniak, R.Ph.

Director II, Medical Benefit Drug Management, BlueCross BlueShield of Michigan

Saira A. Jan, M.S., Pharm.D.

Director of Pharmacy Strategy and Clinical Integration, Horizon BlueCross BlueShield of New Jersey

Dear Managed Care Colleagues,

Welcome to our fall 2022 issue of the Magellan Rx Report! So many exciting advances have occurred this year. So far, the FDA has approved 24 novel drugs, with more anticipated through the end of the year. The healthcare industry continues to face and meet challenges associated with the COVID-19 pandemic as well as the monkeypox health emergency, while continuing to advance treatment and management across chronic and terminal conditions. As always, Magellan Rx Management aims to keep our readers informed on the latest managed care trends and treatment updates.

Our cover story (page 22) focuses on two eye diseases, agerelated macular degeneration and diabetic macular edema. The aging of the American population and the high prevalence of diabetes will continue to drive the need for treatment. This update includes an outline of recent approvals in the category and highlights how biosimilars entering the space will impact pricing and payer management.

In this issue, we also highlight the expansive pipeline of gene therapies for rare diseases (page 17), including a new gene therapy approval for beta thalassemia, as well as the changing management and reimbursement landscape for payers and manufacturers alike. We also discuss how the introduction of adalimumab biosimilars will impact the rheumatoid arthritis category for all stakeholders (page 4) and discuss potential payer management strategies for the rheumatoid arthritis pipeline.

Other topics in this issue include an update on hereditary transthyretin amyloidosis (page 35), a dive into the treatment challenges associated with metastatic bladder cancer (page 13), and a spotlight on a new product to treat acute myeloid leukemia (page 40). As always, the issue is rounded out with our pipeline update (page 45) and managed care newsstand (page 2).

To learn more about Magellan Rx Management and our support for payer initiatives of the future, please feel free to contact us at MagellanRxReport@magellanhealth.com. As always, we value any feedback you may have. I hope you enjoy the report!

Sincerely,

Caroline Carney, M.D., M.Sc., FAPM, CPHQ

Chief Medical Officer

Magellan Health & Magellan Rx Management

SUBSCRIBE TODAY!

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MANAGED CARE NEWSSTAND

Biden-Harris Administration Announces Actions to Address Youth Mental Health Crisis

In late July, the Biden-Harris administration announced two new actions to strengthen school-based mental health services and address the youth mental health crisis:

• Awarding the first of nearly $300 million that the president secured through the FY2022 bipartisan omnibus agreement to expand access to mental health services in schools.

• Encouraging governors to invest more in school-based mental health services. In a letter sent to governors across the country, the departments of Education and Health and Human Services highlight federal resources available to states and schools to invest in mental health services for students.

These actions build upon earlier investments and announcements designed to expand access to mental health services for youth.

CMS Releases Guidance on Mental Health

In August, several new resources and guidance documents were released by the Centers for Medicaid and Medicare Services (CMS) on mental health and children’s mental health. In particular, the CMS Informational Bulletin described leveraging Medicaid and the Children’s Health Insurance Program (CHIP) to deliver

behavioral health services for children and youth, and guidance on payment for Medicaid school-based services.

CMS Releases Informational Bulletin on Beneficiary Protections and Medicaid Drug Coverage

The Center for Medicaid and CHIP Services (CMCS) released a CMCS Informational Bulletin concerning beneficiary protections and Medicaid drug coverage, particularly under Value-Based Purchasing (VBP) arrangements. This bulletin reminds states and stakeholders of the existing federal beneficiary protections in statute and regulation that must be followed when providing Medicaid pharmacy benefits, especially when states enter into novel payment arrangements with drug manufacturers, such as VBP arrangements.

CMS Releases Information on Expiration of PHE-Related Flexibilities

In September, CMS released information to help prepare providers and health plans for the expiration of certain regulatory flexibilities put in place during the COVID-19 public health emergency (PHE). During the pandemic, CMS has used a combination of methods, including expanded Section 1135 emergency authority waivers, new guidance, regulatory change, and enforcement discretion to promote rapid healthcare industry stakeholder treatment and response capabilities. CMS published the following materials to inform stakeholders on the eventual termination of several flexibilities at the end of the PHE, including Medicare telehealth flexibilities (which expire 151 days after the end of the PHE):

• Creating a Roadmap for the End of the COVID-19 Public Health Emergency: Outlines the position of CMS leadership

on PHE flexibilities that have been largely successful and will remain in place postPHE end, as well as flexibilities that will no longer be necessary at that time. Of note, CMS lauds the value of telehealth services to the health and well-being of Americans yet maintains that expansion of telehealth use, including matters related to Medicare payment of telehealth services is an example of required congressional change.

• Fact sheets for providers and plans on COVID-19 PHE waivers and flexibilities: Describes in detail both current flexibilities and policies as well as the impact to the flexibility or policy when the PHE concludes. Specific fact sheets include information on the impact of the PHE end of Medicare payment rates for COVID-19 vaccines and treatment, prior authorization waivers, and other flexibilities relating to the operation of Medicare Advantage and Part D plans.

• Healthcare System Resiliency: A fact sheet on CMS strategic actions to plan for the end of the PHE and improve aspects of the U.S. healthcare system to promote long-term preparedness. CMS notes that it is evaluating PHE blanket waivers and flexibilities in three concurrent phases, including assessing the need for continuing certain waivers post-PHE, assessing which flexibilities would be most useful in a future PHE, and collaborating with federal partners and industry stakeholders to advance equitable, high-quality, value-based care to ensure the system is adequately prepared for future emergencies.

CMS Releases Proposed Rule Streamlining Medicaid and CHIP Eligibility and Enrollment

CMS recently released a notice of proposed

rule-making (NPRM) that would overhaul eligibility and enrollment processes for Medicaid, CHIP, and Basic Health Programs (BHPs).

Provisions of the proposed rule would standardize state eligibility and enrollment policies, such as limiting renewals to once every 12 months, allowing applicants 30 days to respond to information requests, requiring prepopulated renewal forms, and establishing consistent renewal processes across states. CMS also proposes process improvements that would increase enrollment and retention for people aged 65 and older or for individuals who receive coverage based on blindness or a disability.

For CHIP, the proposed rule would allow people to remain enrolled or re-enroll without a lockout period for failure to pay premiums, remove the option for waiting periods, and prohibit lifetime and annual benefit limits. The NPRM also proposes national standards for recordkeeping,

including eligibility information and documentation, retention requirements, application and renewal processing timelines, and requirements to maintain information in electronic data formats.

CMS Releases RFI on Medicare Advantage Program

In July, CMS released a request for information (RFI) on the Medicare Advantage program. The RFI specifically seeks information on the following topics:

• Advance Health Equity.

• Drive Innovation to Promote PersonCentered Care.

• Support Affordability and Sustainability.

• Engage Partners.

HHS Issues New Proposed Antidiscrimination Regulation

The Biden administration has proposed significant changes to federal antidiscrimination rules that apply to entities receiving federal healthcare funds, including payments under Medicare and Medicaid. The proposed changes broaden the definition of protections included in the provision.

House Passes Telehealth Legislation

In July, the U.S. House of Representatives overwhelmingly passed legislation that would extend many current flexibilities under the Medicare program around payment for telehealth through the end of 2024. The bill would allow Medicare and federally qualified health centers — including rural health clinics — to continue covering telehealth visits from patients’ homes, as well as audio-only telehealth under Medicare. The measure would also extend a waiver permitting mental health

patients to avoid having to go to in-person visits. The bill now moves to the Senate, where it appears to have the needed votes for passage, but it faces an uncertain future as a result of several factors including the packed legislative calendar.

President Biden Signs Inflation Reduction Act

The U.S. Senate and House of Representatives passed the Inflation Reduction Act (IRA) of 2022 that includes prescription drug reform, insulin price caps in Medicare, and climate and tax changes, along with a three-year extension of the American Rescue Plan Act (ARPA), which includes enhanced advanced premium tax credits (APTCs). Biden signed the bill into law in August. This new law contains several impactful provisions including the following:

Rebate rule moratorium: Extends the statuary moratorium on the Centers for Medicare and Medicaid Services (CMS) regulation that would eliminate the AntiKickback Statute’s safe-harbor for Part D prescription drug rebates from January 2027 through January 2032.

HHS Drug Negotiation: Allows the federal government to negotiate drug prices with manufacturers with negotiated prices going into effect for a specific number of Part D and B drugs every year until 2026.

Part D Benefit Redesign: Eliminates the Medicare Part D coverage gap phase effective 2025, imposes an annual outof-pocket cap on beneficiary cost-sharing for prescription drugs at $2,000, changes plan liability.

Part D Insulin: Caps out-of-pocket costs at $35 a month for insulin co-pays in Part D, effective 2023.

The Biden-Harris administration announced two new actions to strengthen schoolbased mental health services and address the youth mental health crisis.

Rheumatoid Arthritis:

Biosimilar Update and Management

Pending adalimumab biosimilar launches show promise that lowered costs for RA treatment are on the horizon.

Rheumatoid arthritis (RA) is a chronic, inflammatory disease that affects about 1.5 million people in the U.S.1, 2 RA is an autoimmune disease, meaning it causes the immune system to attack healthy joint tissues. It is estimated that women are two to three times more likely than men to develop RA, suggesting that hormones may play a role in this disorder.1, 2 In the U.S., the lifetime risk of RA is 3.6% for women and 1.7% for men. Symptoms generally begin to present between the ages of 30 to 60 in women and later in life for men.1, 2 While no cause is known, it is believed that a combination of factors lead to the development of the condition.

RA typically occurs in a symmetrical pattern, with joints affected bilaterally.1 Joints in the wrist, hands, and feet are most prone to RA, although the spine, knees, and jaw may also be impacted.1 Symptoms of RA typically include joint pain at rest and when moving; tenderness, swelling, and warmth of the joint; joint stiffness that lasts longer than 30 minutes, typically after waking in the morning or after resting for a long period of time; fatigue; occasional low-grade fever; and loss of appetite.1 In some cases, symptoms may start as mild or moderate inflammation that, if left untreated, can worsen and lead to more joints being affected. Symptoms may worsen during “flares” due to a trigger such as stress, increased activity, or noncompliance with medication or treatment.1

Further potential complications for patients with RA include rheumatoid nodules; anemia; neck pain; and dry eyes and mouth.1 In rare cases, patients with RA may develop vasculitis, pleurisy, or pericarditis.1

Rheumatologists typically diagnose RA based on a combination of factors: a physical exam, review of medical history, blood tests, and imaging tests.3 Blood tests will often examine erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), and antibodies to cyclic citrullinated

Luke Merkel,

peptides (CCP).3 Imaging tests to assess the joints include X-rays, ultrasounds, and MRI scans. Diagnostic criteria for RA generally include inflammatory arthritis in two or more large joints or in smaller joints, positive biomarker tests for RF or CCP antibodies, elevated levels of CRP or an elevated ESR, and symptoms that have lasted more than six weeks. Timely diagnosis and initiation of treatment is crucial to proper disease management.3

Treatment Landscape

Successful treatment for RA will decrease inflammation and pain as well as slowing or stopping further joint damage.1 Available treatments for RA include anti-inflammatory medications, corticosteroids, disease-modifying anti-rheumatic drugs (DMARDs), biologic response modifiers (BRMs), and janus kinase (JAK) inhibitors.1 Studies suggest that early treatment with a combination of medications (as opposed to monotherapy) may be more effective in decreasing or preventing joint damage.1

Typically, if a patient does not respond well to DMARDs, providers may utilize biologic response modifiers, or biologics, which target molecules that cause inflammation. Some biologics indicated and used for RA include etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), and rituximab (Rituxan®).

Pipeline: Rheumatoid Arthritis7

Drug Manufacturer

TNF Inhibitors

Adalimumab Biosimilar Launch and Payer Impact

Starting in early 2023, biosimilar versions of adalimumab are anticipated to launch in the U.S. market, which is likely to impact the treatment landscape for RA as well as other indications of the drug.4 Thus far, the FDA has approved seven biosimilars for adalimumab. A number of factors play into how biosimilars will impact prescribing

adalimumab (SB5 HC)Samsung Bioepis; Organoninjectable

TNF-alpha inhibitorRA; JIA approved (08/15/2022) adalimumab (MSB11022)Fresenius Kabi SC

TNF-alpha inhibitorRA pending (4Q 2022) adalimumab (MYL-1401A)Mylan; Biocon SC

TNF-alpha inhibitorRA phase 3 etanercept (YLB113)Lupin SC

TNF-alpha inhibitorRA phase 3 infliximab (NI-071) Nichi-Iko; Aprogen injectable TNF-alpha inhibitorRA phase 3 Interleukins

olokizumab R-Pharm; UCB SC IL-6R antagonist RA phase 3 tocilizumab (BAT1806) Bio-Thera Solutions/Biogen IV IL-6R antagonist RA phase 3 tocilizumab (MSB11456)Fresenius Kabi

antagonist

phase 3 Anti-CD20 antibody

rituximab (DRL RI) Dr. Reddy’s; Fresenius KabiIV

Anti-CD20 antibodyRA phase 3 rituximab (SAIT101)Archigen; AstraZenecaIV

Anti-CD20 antibodyRA phase 3 rituximab (MabionCD20®)Mabion injectable Anti-CD20 antibodyRA phase 3 Other

otilimab (GSK3196165 SC)GSK/MorphoSys

Abbreviations: GM-CSF

phase 3

=

A number of factors play into how biosimilars will impact prescribing and management decisions, including clinical data supporting safety and efficacy as well as interchangeability designations.

RHEUMATOID ARTHRITIS

and management decisions, including clinical data supporting safety and efficacy as well as interchangeability designations.4

Providers treating patients with RA are already familiar with biosimilars, as infliximab and rituximab biosimilars have been available for some time; this experience will impact providers’ comfort level in switching or starting patients on adalimumab biosimilars once available.5

Rheumatologists may have a higher degree of confidence in switching patients who responded well to the reference product to a biosimilar designated as interchangeable.4 This designation may also increase utilization of respective biosimilars as they launch. While biosimilars with interchangeable status can be dispensed in place of an originator brand without physician approval, some states have placed restrictions; in many states, providers can request dispensing of the reference drug rather than any biosimilar, regardless of interchangeability.4

Regardless, providers and payers will be tasked with challenging decisions in clinical practice and formulary placement, respectively.4, 5 The approved adalimumab biosimilars vary by concentration, citrate content, needle size, and potential for allergic reactions to latex. Providers and payers will need to consider these factors when determining appropriate biosimilars to utilize.4

Biosimilars can create opportunity for both patients and payers, including increasing access by lowering costs. Particularly where interchangeability exists, the ability for adalimumab biosimilars to compete with the reference drug will hinge largely on pricing and the potential for cost management. As of 2021, a year supply of Humira could cost as much as $84,000; the increased competition in this space may come with the promise of lowered costs.5 In the U.S., data suggests that biosimilars for other rheumatology biologic drugs have created competitive pricing landscapes. Three rituximab biosimilars captured a 55% share of the Rituxan market from the end of 2019 to the first half of 2021, and by the end of that period, one of the biosimilars was offered at a 36% discount of the reference price.5 Overall, the average sales price of infliximab dropped nearly 50% from the end of 2016 to the first half of 2021.5

Rheumatology, specifically RA, has been a challenging and costly management space for payers. Due to the high costs associated with RA treatment, notably biologic drugs, many payers implement utilization management programs. A 2020 IQVIA analysis revealed that 80% of commercially insured patients attempting to fill a new prescription for RA or multiple sclerosis encountered a utilization management restriction, with more than 30% of these patients unable to gain approval for the new treatment.6 This same study found that 60% of new RA patients used cost-sharing assistance to help afford their RA treatment in 2018. The high costs to payers and patients alike in this category may present barriers to accessing treatment.6

The availability of biosimilars in the RA space has had an impact on prices, and the pending launch of adalimumab biosimilars shows some promise that further lowered costs for RA treatment are on the horizon.

The availability of biosimilars in the RA space has had an impact on prices, and the pending launch of adalimumab biosimilars shows some promise that further lowered costs for RA treatment are on the horizon.

Our latest

CLINICAL INSIGHTS Virtual Reality: Coming Soon

Psychedelics: Out Now

magellanrx.com/publications

References

1. National Institute of Arthritis and Musculoskeletal and Skin Diseases. “Rheumatoid Arthritis.” National Institutes of Health, Sept. 2019, https://www.niams.nih.gov/health-topics/rheumatoidarthritis.

2. Vandever, Leslie. “Rheumatoid Arthritis by the Numbers: Facts, Statistics, and You.” Healthline, 21 July 2021, https://www. healthline.com/health/rheumatoid-arthritis/facts-statisticsinfographic.

3. “Rheumatoid Arthritis.” Cleveland Clinic, 18 Feb. 2022, https:// my.clevelandclinic.org/health/diseases/4924-rheumatoidarthritis#diagnosis-and-tests.

4. Hagen, Tony. “Humira, the biosimilars are coming, the biosimilars are coming!” Managed Healthcare, 19 May 2022, https://www. managedhealthcareexecutive.com/view/humira-the-biosimilarsare-coming-the-biosimilars-are-coming-.

5. Hagen, Tony. “Humira Biosimilars Are Hitting the Market in 2023. Finally. But Will Prescriptions Follow?” Managed Healthcare, 7 April 2022, https://www.managedhealthcareexecutive.com/view/ humira-biosimilars-are-hitting-the-market-in-2023-finally-but-willprescriptions-follow-.

6. Migliara, Gabby. “Payers subject 80% of new RA and MS patients to utilization management restrictions.” PhRMA, 22 July 2022, https:// catalyst.phrma.org/payers-subject-80-of-new-ra-and-ms-patientsto-utilization-management-restrictions.

7. “Rheumatoid Arthritis.” IPD Analytics, https://ipdanalytics.com.

30%

in the risk of death vs chemotherapy (N=608; HR=0.70; 95%

0.56, 0.89; P

* The EV-301 trial evaluated PADCEV vs investigator’s-choice chemotherapy in a randomized, multicenter, phase 3 trial of 608 patients with locally advanced or metastatic urothelial cancer who had previously received platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor. Patients were randomized 1:1 to either 1.25 mg/kg of PADCEV via IV infusion over 30 minutes on days 1, 8, and 15 of every 28-day cycle, or docetaxel at 75 mg/m2, paclitaxel at 175 mg/m2, or vinflunine at 320 mg/m2 on day 1 of every 21-day cycle. For both arms, treatment continued until radiographic disease progression or unacceptable toxicity.1,2

† Based on log-rank test. Stratification factors were ECOG PS, region and liver metastasis.1

IMPORTANT SAFETY INFORMATION

BOXED WARNING: SERIOUS SKIN REACTIONS

• PADCEV can cause severe and fatal cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later.

• Closely monitor patients for skin reactions.

• Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions.

• Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.

INDICATION

PADCEV is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who:

• have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or

• are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.

WARNINGS AND PRECAUTIONS

Skin reactions Severe cutaneous adverse reactions, including fatal cases of SJS or TEN, occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later. Skin reactions occurred in 55% of the 680 patients treated with PADCEV in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 33% had pruritus. Grade 3-4 skin reactions occurred in 13% of patients, including maculo-papular rash, rash erythematous, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), dermatitis bullous, dermatitis exfoliative, and palmarplantar erythrodysesthesia. In clinical trials, the median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 6.4). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=59), 24% of patients restarting at the same dose and 16% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 2.6% of patients. Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. Withhold PADCEV and refer for specialized care for suspected SJS or TEN or for severe (Grade 3) skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN, or for Grade 4 or recurrent Grade 3 skin reactions. Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with PADCEV. Patients with baseline hemoglobin A1C ≥8% were excluded from clinical trials. In clinical trials, 14% of the 680 patients treated with PADCEV developed hyperglycemia; 7% of patients developed Grade 3-4 hyperglycemia. The incidence of Grade 3-4

hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. The median time to onset of hyperglycemia was 0.6 months (range: 0.1 to 20.3). Hyperglycemia led to discontinuation of PADCEV in 0.6% of patients. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV. Pneumonitis Severe, life-threatening or fatal pneumonitis occurred in patients treated with PADCEV. In clinical trials, 3.1% of the 680 patients treated with PADCEV had pneumonitis of any grade and 0.7% had Grade 3-4. In clinical trials, the median time to onset of pneumonitis was 2.9 months (range: 0.6 to 6). Monitor patients for signs and symptoms indicative of pneumonitis, such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold PADCEV for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis.

Peripheral neuropathy (PN) occurred in 52% of the 680 patients treated with PADCEV in clinical trials, including 39% with sensory neuropathy, 7% with muscular weakness and 6% with motor neuropathy; 4% experienced Grade 3-4 reactions. PN occurred in patients treated with PADCEV with or without pre-existing PN. The median time to onset of Grade ≥2 PN was 4.6 months (range: 0.1 to 15.8 months). Neuropathy led to treatment discontinuation in 5% of patients. Monitor patients for symptoms of new or worsening peripheral neuropathy and consider dose interruption or dose reduction of PADCEV when PN occurs. Permanently discontinue PADCEV in patients who develop Grade ≥3 PN. Ocular disorders were reported in 40% of the 384 patients treated with PADCEV in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 34% of patients, and blurred vision occurred in 13% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.6 months (range: 0 to 19.1 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.

Infusion site extravasation Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 680 patients, 1.6% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. Two patients (0.3%) developed

PADCEV® SIGNIFICANTLY IMPROVED OS vs CHEMOTHERAPY

In the EV-201‡ trial (Cohort 2)

CR: 22% PR: 28%

‡The EV-201 trial (Cohort 2) was a single-arm, multicenter trial of 89 patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and were cisplatin ineligible. Patients received 1.25 mg/kg of PADCEV via IV infusion over 30 minutes on days 1, 8, and 15 of every 28-day cycle and continued to receive treatment until disease progression or unacceptable toxicity. The major efficacy outcome measures, confirmed ORR and DOR, were assessed by BICR using RECIST v1.1. ORR consisted of confirmed CR and PR. CR was defined as the disappearance of all target and nontarget lesions. PR was defined as a ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Median duration of follow-up was 13.4 months.1,4,5

§Kaplan-Meier estimate of duration of response, defined as the time from first response to date of progression or death due to any cause, was assessed by BICR.4,6

||Based on patients (n=45) with a response by BICR.1

extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

Embryo-fetal toxicity PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.

ADVERSE REACTIONS

Most Common Adverse Reactions, Including Laboratory Abnormalities (≥20%) Rash, aspartate aminotransferase (AST) increased, glucose increased, creatinine increased, fatigue, PN, lymphocytes decreased, alopecia, decreased appetite, hemoglobin decreased, diarrhea, sodium decreased, nausea, pruritus, phosphate decreased, dysgeusia, alanine aminotransferase (ALT) increased, anemia, albumin decreased, neutrophils decreased, urate increased, lipase increased, platelets decreased, weight decreased and dry skin.

EV-301 Study: 296 patients previously treated with a PD-1/L1 inhibitor and platinum-based chemotherapy.

Serious adverse reactions occurred in 47% of patients treated with PADCEV; the most common (≥2%) were urinary tract infection, acute kidney injury (7% each) and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1.0%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis and pelvic abscess (0.3% each). Adverse reactions leading to discontinuation occurred in 17% of patients; the most common (≥2%) were PN (5%) and rash (4%). Adverse reactions leading to dose interruption occurred in 61% of patients; the most common (≥4%) were PN (23%), rash (11%) and fatigue (9%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common (≥2%) were PN (10%), rash (8%), decreased appetite and fatigue (3% each). Clinically relevant adverse reactions (<15%) include vomiting (14%), AST increased (12%), hyperglycemia (10%), ALT increased (9%), pneumonitis (3%) and infusion site extravasation (0.7%). EV-201, Cohort 2 Study: 89 patients previously treated with a PD-1/L1 inhibitor and not eligible for platinum-based chemotherapy.

Serious adverse reactions occurred in 39% of patients treated with PADCEV; the most common (≥3%) were pneumonia, sepsis and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia and

pneumonitis (1.1% each). Adverse reactions leading to discontinuation occurred in 20% of patients; the most common (≥2%) was PN (7%). Adverse reactions leading to dose interruption occurred in 60% of patients; the most common (≥3%) were PN (19%), rash (9%), fatigue (8%), diarrhea (5%), AST increased and hyperglycemia (3% each). Adverse reactions leading to dose reduction occurred in 49% of patients; the most common (≥3%) were PN (19%), rash (11%) and fatigue (7%). Clinically relevant adverse reactions (<15%) include vomiting (13%), AST increased (12%), lipase increased (11%), ALT increased (10%), pneumonitis (4%) and infusion site extravasation (1%).

DRUG INTERACTIONS

Effects of other drugs on PADCEV (Dual P-gp and Strong CYP3A4 Inhibitors)

Concomitant use with a dual P-gp and strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with dual P-gp and strong CYP3A4 inhibitors.

SPECIFIC POPULATIONS

Lactation Advise lactating women not to breastfeed during treatment with PADCEV and for at least 3 weeks after the last dose.

Hepatic impairment Avoid the use of PADCEV in patients with moderate or severe hepatic impairment.

Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including BOXED WARNING, on adjacent pages.

BICR=blinded independent central review; CI=confidence interval; CR=complete response; DOR=duration of response; HR=hazard ratio; IV=intravenous; la=locally advanced; mUC=metastatic urothelial cancer; NE=not evaluable; ORR=objective response rate; OS=overall survival; PD-(L)1=programmed death receptor-1 or programmed deathligand 1; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors.

Table 2. Recommended Dose Reduction Schedule

Dose Level

Starting dose

PADCEV® (enfortumab vedotin-ejfv) for injection, for intravenous use

The following is a brief summary of the full Prescribing Information. Please see the package insert for full prescribing information including BOXED WARNING.

WARNING: SERIOUS SKIN REACTIONS

• PADCEV can cause severe and fatal cutaneous adverse reactions including StevensJohnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later.

• Closely monitor patients for skin reactions.

• Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions.

• Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions

INDICATIONS AND USAGE

PADCEV® is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who:

• have previously received a programmed death receptor-1 (PD-1) or programmed deathligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or

• are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.

DOSAGE AND ADMINISTRATION

Recommended Dosage

The recommended dose of PADCEV is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥ 100 kg) administered as an intravenous infusion over 30 minutes on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.

Dose Modifications

Adverse

Table 1. Dose Modifications

Suspected SJS or TEN

Dose

Immediately withhold, consult a specialist to confirm the diagnosis. If not SJS/TEN, see Grade 3 skin reactions.

Skin Reactions

Confirmed SJS or TEN; Grade 4 or recurrent Grade 3 skin reactions

Grade 3 (severe) skin reactions

Hyperglycemia Blood glucose > 250 mg/dL

Permanently discontinue.

Withhold until Grade ≤ 1, then resume treatment at the same dose level or consider dose reduction by one dose level.

Withhold until elevated blood glucose has improved to ≤ 250 mg/dL, then resume treatment at the same dose level.

Pneumonitis

Grade 2

Withhold until Grade ≤ 1 for persistent or recurrent Grade 2 pneumonitis, consider dose reduction by one dose level.

Grade ≥ 3 Permanently discontinue.

Grade 2

Peripheral Neuropathy

Withhold until Grade ≤ 1, then resume treatment at the same dose level (if first occurrence). For a recurrence, withhold until Grade ≤ 1, then resume treatment reduced by one dose level.

Grade ≥ 3 Permanently discontinue.

Grade 3

Other nonhematologic toxicity

1.25 mg/kg up to 125 mg

First dose reduction 1.0 mg/kg up to 100 mg

Second dose reduction 0.75 mg/kg up to 75 mg

Third dose reduction 0.5 mg/kg up to 50 mg

WARNINGS AND PRECAUTIONS

Skin Reactions

Severe cutaneous adverse reactions, including fatal cases of SJS or TEN occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later.

Skin reactions occurred in 55% of the 680 patients treated with PADCEV in clinical trials. Twenty-three percent (23%) of patients had maculopapular rash and 33% had pruritus. Grade 3-4 skin reactions occurred in 13% of patients, including maculo-papular rash, rash erythematous, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), dermatitis bullous, dermatitis exfoliative, and palmar-plantar erythrodysesthesia. In clinical trials, the median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 6.4 months). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=59), 24% of patients restarting at the same dose and 16% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 2.6% of patients. Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated.

Withhold PADCEV and refer for specialized care for suspected SJS, TEN or for severe (Grade 3) skin reactions.

Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.

Hyperglycemia

Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with PADCEV.

Patients with baseline hemoglobin A1C ≥ 8% were excluded from clinical trials. In clinical trials, 14% of the 680 patients treated with PADCEV developed hyperglycemia; 7% of patients developed Grade 3-4 hyperglycemia. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. The median time to onset of hyperglycemia was 0.6 months (range: 0.1 to 20.3 months). Hyperglycemia led to discontinuation of PADCEV in 0.6% of patients.

Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia.

If blood glucose is elevated (> 250 mg/dL), withhold PADCEV.

Pneumonitis

Severe, life-threatening or fatal pneumonitis occurred in patients treated with PADCEV. In clinical trials, 3.1% of the 680 patients treated with PADCEV had pneumonitis of any grade and 0.7% had Grade 3-4. In clinical trials, the median time to onset of pneumonitis was 2.9 months (range: 0.6 to 6 months).

Monitor patients for signs and symptoms indicative of pneumonitis such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations.

Withhold PADCEV for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis.

Peripheral Neuropathy

Peripheral neuropathy occurred in 52% of the 680 patients treated with PADCEV in clinical trials including 39% with sensory neuropathy, 7% with muscular weakness and 6% with motor neuropathy; 4% experienced Grade 3-4 reactions. Peripheral neuropathy occurred in patients treated with PADCEV with or without preexisting peripheral neuropathy. The median time to onset of Grade ≥ 2 peripheral neuropathy was 4.6 months (range: 0.1 to 15.8 months). Neuropathy led to treatment discontinuation in 5% of patients.

Monitor patients for symptoms of new or worsening peripheral neuropathy and consider dose interruption or dose reduction of PADCEV when peripheral neuropathy occurs. Permanently discontinue PADCEV in patients who develop Grade ≥ 3 peripheral neuropathy.

Ocular Disorders

Withhold until Grade ≤ 1, then resume treatment at the same dose level or consider dose reduction by one dose level.

Grade 4 Permanently discontinue.

Grade 3, or Grade 2 thrombocytopenia

Hematologic toxicity

Grade 4

Withhold until Grade ≤ 1, then resume treatment at the same dose level or consider dose reduction by one dose level.

Withhold until Grade ≤ 1, then reduce dose by one dose level or discontinue treatment.

*Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.

Ocular disorders were reported in 40% of the 384 patients treated with PADCEV in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 34% of patients, and blurred vision occurred in 13% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.6 months (range: 0 to 19.1 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.

Infusion Site Extravasation

Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 680 patients, 1.6% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days

after extravasation and resolved within 1-4 weeks of peak. Two patients (0.3%) developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals, PADCEV can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of enfortumab vedotin-ejfv to pregnant rats during the period of organogenesis caused maternal toxicity, embryo-fetal lethality, structural malformations and skeletal anomalies at maternal exposures approximately similar to the clinical exposures at the recommended human dose of 1.25 mg/kg.

Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with PADCEV and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.

ADVERSE REACTIONS

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to PADCEV as a single agent at 1.25 mg/kg in 680 patients in EV-301, EV-201, EV-101 (NCT02091999), and EV-102 (NCT03070990). Ocular disorders reflect 384 patients in EV-201, EV-101, and EV-102. Among 680 patients receiving PADCEV, 36% were exposed for ≥ 6 months, and 9% were exposed for ≥ 12 months. In this pooled population, the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were rash, aspartate aminotransferase increased, glucose increased, creatinine increased, fatigue, peripheral neuropathy, lymphocytes decreased, alopecia, decreased appetite, hemoglobin decreased, diarrhea, sodium decreased, nausea, pruritus, phosphate decreased, dysgeusia, alanine aminotransferase increased, anemia, albumin decreased, neutrophils decreased, urate increased, lipase increased, platelets decreased, weight decreased and dry skin.

The data described in the following sections reflect exposure to PADCEV from an openlabel, randomized, study (EV-301); and Cohort 1 and Cohort 2 of an open-label, single arm, two cohort study (EV-201). Patients received PADCEV 1.25 mg/kg on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.

Previously Treated Locally Advanced or Metastatic Urothelial Cancer EV-301

The safety of PADCEV was evaluated in EV-301 in patients with locally advanced or metastatic urothelial cancer (n=296) who received at least one dose of PADCEV 1.25 mg/kg and who were previously treated with a PD-1 or PD-L1 inhibitor and a platinum-based chemotherapy. Routine ophthalmologic exams were not conducted in EV-301. The median duration of exposure to PADCEV was 5 months (range: 0.5 to 19.4 months).

Serious adverse reactions occurred in 47% of patients treated with PADCEV. The most common serious adverse reactions (≥ 2%) were urinary tract infection, acute kidney injury (7% each) and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1.0%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis and pelvic abscess (0.3% each).

Adverse reactions leading to discontinuation occurred in 17% of patients; the most common adverse reactions (≥ 2%) leading to discontinuation were peripheral neuropathy (5%) and rash (4%).

Adverse reactions leading to dose interruption occurred in 61% of patients; the most common adverse reactions (≥ 4%) leading to dose interruption were peripheral neuropathy (23%), rash (11%) and fatigue (9%).

Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions (≥ 2%) leading to dose reduction were peripheral neuropathy (10%), rash (8%), decreased appetite (3%) and fatigue (3%).

the most common (

15%) adverse reactions

Adverse Reaction

Gastrointestinal disorders

EV-301.

Eye Disorders

Blood and lymphatic system disorders

Infections and infestations

Vascular disorders

Investigations

blister, blood blister, conjunctivitis, dermatitis, dermatitis bullous, drug eruption, eczema, erythema, erythema multiforme, exfoliative rash, intertrigo, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculopapular, rash papular, rash pruritic, rash vesicular, skin irritation, skin exfoliation, stomatitis.

fatigue, asthenia

3Includes: pyrexia, hyperthermia, hyperpyrexia, body temperature increased

burning sensation, demyelinating polyneuropathy, dysesthesia, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, neurotoxicity, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peroneal nerve palsy, peripheral sensory neuropathy, gait disturbance, polyneuropathy, sensory loss

5Includes: dysgeusia, ageusia, hypogeusia

6Includes: diarrhea, colitis, enterocolitis

7Includes: abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, hepatic pain, abdominal tenderness, gastrointestinal pain

8Includes: myalgia, arthralgia, back pain, bone pain, pain in extremity, musculoskeletal pain, arthritis, neck pain, non-cardiac chest pain, musculoskeletal chest pain, spinal pain, musculoskeletal stiffness, musculoskeletal discomfort

9Includes: blepharitis, conjunctivitis, dry eye, eye irritation, keratitis, keratopathy, lacrimation increased, Meibomian gland dysfunction, ocular discomfort, punctate keratitis

10Includes: urinary tract infection, urinary tract infection bacterial, urinary tract infection enterococcal, streptococcal urinary tract infection, escherichia urinary tract infection, pyelonephritis acute, escherichia pyelonephritis, urinary tract infection fungal, cystitis, urinary tract infection staphylococcal, urinary tract infection pseudomonal

11Includes: hematuria, rectal hemorrhage, gastrointestinal hemorrhage, epistaxis, upper gastrointestinal hemorrhage, tumor hemorrhage, hemoptysis, vaginal hemorrhage, anal hemorrhage, hemorrhagic stroke, urethral hemorrhage, infusion site hemorrhage, conjunctival hemorrhage, hemorrhagic ascites, hemorrhoidal hemorrhage

Clinically relevant adverse reactions (< 15%) include vomiting (14%), aspartate aminotransferase increased (12%), hyperglycemia (10%), alanine aminotransferase increased (9%), dry eye (6%) and infusion site extravasation (0.7%).

EV-201, Cohort 2

The safety of PADCEV was evaluated in EV-201, Cohort 2 in patients with locally advanced or metastatic urothelial cancer (n=89) who received at least one dose of PADCEV 1.25 mg/kg and had prior treatment with a PD-1 or PD-L1 inhibitor and were not eligible for cisplatin-based chemotherapy. The median duration of exposure was 5.98 months (range: 0.3 to 24.6 months).

Serious adverse reactions occurred in 39% of patients treated with PADCEV. The most common serious adverse reactions (≥ 3%) were pneumonia, sepsis and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia and pneumonitis (1.1% each).

Adverse reactions leading to discontinuation occurred in 20% of patients; the most common adverse reaction (≥ 2%) leading to discontinuation was peripheral neuropathy (7%). Adverse reactions leading to dose interruption occurred in 60% of patients; the most common adverse reactions (≥ 3%) leading to dose interruption were peripheral neuropathy (19%), rash (9%), fatigue (8%), diarrhea (5%), aspartate aminotransferase increased (3%) and hyperglycemia (3%).

Adverse reactions leading to dose reduction occurred in 49% of patients; the most common adverse reactions (≥ 3%) leading to dose reduction were peripheral neuropathy (19%), rash (11%) and fatigue (7%).

Table 4 summarizes the All Grades and Grade 3-4 adverse reactions reported in patients in EV-201, Cohort 2.

Adverse Reaction

Skin and subcutaneous tissue disorders

Nervous system disorders

disorders

Blood and lymphatic disorders

Gastrointestinal disorders

Investigations

Eye disorders

1Includes: blister, conjunctivitis, dermatitis bullous, dermatitis exfoliative generalized, eczema, erythema, erythema multiforme, intertrigo, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash vesicular, skin exfoliation, stomatitis

2Includes: demyelinating polyneuropathy, gait disturbance, hypoesthesia, motor dysfunction, muscle atrophy, muscular weakness, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peroneal nerve palsy, peripheral sensory neuropathy

3Includes: dysgeusia, ageusia, hypogeusia

4Includes: fatigue, asthenia

5Includes: diarrhea, colitis, enterocolitis

6Includes: blepharitis, conjunctivitis, dry eye, eye irritation, keratitis, keratopathy, lacrimation increased, limbal stem cell deficiency, Meibomian gland dysfunction, ocular discomfort, punctate keratitis, tear break up time decreased

Clinically relevant adverse reactions (<15%) include vomiting (13%), aspartate aminotransferase increased (12%), alanine aminotransferase increased (10%) and infusion site extravasation (1%).

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the trials described below with the incidence of antibodies in other trials or other enfortumab vedotin-ejfv products may be misleading.

Following administration of PADCEV 1.25 mg/kg; 16/590 (2.7%) patients tested positive for anti-therapeutic antibody (ATA) against enfortumab vedotin-ejfv at one or more postbaseline time points. Due to the limited number of patients with ATA against enfortumab vedotin-ejfv, no conclusions can be drawn concerning a potential effect of immunogenicity on efficacy, safety or pharmacokinetics.

DRUG INTERACTIONS

Effects of Other Drugs on PADCEV

Dual P-gp and Strong CYP3A4 Inhibitors

Concomitant use with dual P-gp and strong CYP3A4 inhibitors may increase unconjugated MMAE exposure which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with dual P-gp and strong CYP3A4 inhibitors.

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

Based on the mechanism of action and findings in animals, PADCEV can cause fetal harm when administered to a pregnant woman. There are no available human data on PADCEV use in pregnant women to inform a drug-associated risk. In an animal reproduction study, administration of enfortumab vedotin-ejfv to pregnant rats during organogenesis caused maternal toxicity, embryo-fetal lethality, structural malformations and skeletal anomalies at maternal exposures approximately similar to the exposures at the recommended human dose of 1.25 mg/kg. Advise patients of the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Lactation

Risk Summary

There are no data on the presence of enfortumab vedotin-ejfv in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with PADCEV and for at least 3 weeks after the last dose.

Females and Males of Reproductive Potential Pregnancy testing

Verify pregnancy status in females of reproductive potential prior to initiating PADCEV treatment.

Contraception Females

PADCEV can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.

Infertility Males

Based on findings from animal studies, PADCEV may impair male fertility.

Pediatric Use Safety and effectiveness of PADCEV in pediatric patients have not been established.

Geriatric Use

Of the 680 patients treated with PADCEV in clinical trials, 440 (65%) were 65 years or older and 168 (25%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Hepatic Impairment

Avoid the use of PADCEV in patients with moderate or severe hepatic impairment (total bilirubin > 1.5 x ULN and AST any). PADCEV has only been studied in a limited number of patients with moderate hepatic impairment (n=3) and has not been evaluated in patients with severe hepatic impairment. In another ADC that contains MMAE, the frequency of ≥ Grade 3 adverse reactions and deaths was greater in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment compared to patients with normal hepatic function. No adjustment in the starting dose is required when administering PADCEV to patients with mild hepatic impairment (total bilirubin 1 to 1.5 × ULN and AST any, or total bilirubin ≤ ULN and AST >ULN).

Renal Impairment

No dose adjustment is required in patients with mild (CrCL > 60-90 mL/min), moderate (CrCL 30-60 mL/min) or severe (CrCL < 30 mL/min) renal impairment.

Manufactured and Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Distributed and Marketed by: Seagen Inc., Bothell, WA 98021; 1-855-4SEAGEN

U.S. License 2124

Revised:

Rx Only

© 2019 Agensys, Inc. and Seagen Inc. PADCEV® and the PADCEV device are trademarks jointly owned by Agensys, Inc. and Seagen Inc.

Astellas

Inc.

Seagen

of

Seagen Inc.

Metastatic Bladder Cancer:

Treatment Challenges and Opportunities

In the population of cisplatin-ineligible mUC patients, there remains a high unmet need. Recent studies for first-line standard of care therapies have not demonstrated significant improvements in OS, PFS, or ORR.

About 10-15% of patients diagnosed with bladder cancer present with metastasis.1 The most common form of bladder cancer is urothelial carcinoma (UC), which accounts for about 95% of all bladder cancer cases.2 Metastatic urothelial carcinoma (mUC) is an aggressive disease with poor prognosis. Less than 8% of patients with mUC survive five years after diagnosis.3 mUC is one of the leading causes of genitourinary cancer-related mortality.1

Treatment Challenges in mUC Population

Lindsay Speicher, JD Project Manager, Specialty Magellan Rx Management

Cisplatin is the established standard of care in the neoadjuvant setting in cases of unresectable or mUC.4 However, about 55% of patients presenting with mUC are determined cisplatin-ineligible;5 these patients have worse outcomes compared to patients who are eligible for cisplatin therapy (8.6 months versus 14.4 months, respectively).5 In the population of cisplatin-ineligible mUC patients, there remains a high unmet need. Recent studies for first-line standard of care therapies have not demonstrated significant improvements in overall survival (OS), progression-free survival (PFS), or overall response rate (ORR).6

While cisplatin-based chemotherapy is the standard first-line treatment for patients with mUC, about half of the patients with mUC are excluded from this treatment due to multiple factors, including, but not limited to, renal dysfunction, neuropathy, or poor performance status.7 In many cases, first-line therapy may be the only therapy these patients are able to receive. An estimated 60% of cisplatin-ineligible patients do not receive first-line therapy, and fewer than half receive second-line treatment.5 About half of the patients who start on platinum-based chemotherapy are eligible to and go on to receive maintenance therapy. Notably, maintenance therapy has only been shown to provide incremental OS when looking at OS outcomes before and after maintenance introduction into the treatment paradigm.8

Pembrolizumab and atezolizumab have been standard first-line therapy options for cisplatinineligible patients with high PD-L1 expression. Immune checkpoint inhibitors such as PD-1 and PD-L1

METASTATIC BLADDER CANCER

are approved for platinum-containing or chemotherapy-ineligible patients with mUC, regardess of PD-L1 expression.4 Antibodydrug conjugates (ADCs) are designed to deliver effective cytotoxic drugs directly and selectively to the cancer cells; two promising ADCs for mUC are enfortumab vedotin, which has recently gained the U.S. Food and Drug Administration (FDA) approval, and sacituzumab govitecan, which is currently being investigated.9

Enfortumab Vedotin-EJFV (PADCEV)

In 2021, the FDA approved enfortumab vedotin-EJFV, a Nectin4-directed antibody and microtubule inhibitor conjugate, for adult patients with locally advanced or mUC who have previously received a PD-1 or PD-L1 inhibitor and platinum containing chemotherapy or who are ineligible for cisplatin-containing

chemotherapy and have previously received one or more prior lines of therapy.10 Enfortumab vedotin-EJFV (EV) was previously approved through the FDA accelerated approval process in 2019 for patients with locally advanced or mUC who have received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.10

Approval was based on results from Trial EV-301, an openlabel, randomized, multicenter trial of 608 patients with locally advanced or mUC who received prior PD-1 or PD-L1 inhibitor and platinum-based chemotherapy.11 Patients were randomized to receive EV 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle or one of the following single-agent chemotherapies: docetaxel, paclitaxel, or vinflunine.11 The primary efficacy end point of the trial was OS, with secondary end points including PFS and ORR.11 Patients in the EV arm had a median OS of 12.9 months, compared to 9.0 months for those receiving chemotherapy.11 Median PFS was higher for patients in the EV arm compared to those receiving chemotherapy (5.6 months versus 3.7 months, respectively).11 The ORR in patients receiving EV was 40.6% compared to 17.9% for patients receiving chemotherapy.11 Common adverse reactions associated with EV treatment included rash, aspartate aminotransferase increase, glucose increase, creatinine increase, fatigue, peripheral neuropathy, lymphocytes decrease, alopecia, decrease in appetite, hemoglobin decrease, diarrhea, sodium decrease, nausea, pruritus, phosphate decrease, dysgeusia, alanine aminotransferase increase, anemia, albumin decrease, neutrophils decrease, urate increase, lipase increase, platelets decrease, weight decrease, and dry skin.10, 11

Other studies have shown the efficacy of EV in treating mUC. In EV-201, the efficacy and safety of EV in the post-immunotherapy setting in cisplatin-ineligible patients with locally advanced or mUC were investigated.12 The primary end point of EV-201 was confirmed ORR; results showed ORR was 52% with 18 of 89 patients achieving a complete response and 28 achieving partial response.12 The phase 3, randomized EV-301 trial showed that EV prolonged median OS by nearly four months and reduced risk of death by 30%. Patient reported outcomes from EV-301 showed that chemotherapy was associated with greater deterioration and variability in quality of life.13 Patients receiving EV reported reduction in pain symptoms when compared to chemotherapy treated patients; however, treatment with EV was associated with increased patient-reported appetite loss.12

There is an ongoing study (KEYNOTE-869) investigating the safety and anti-tumor activity of EV as monotherapy in the first-line setting and with PD-1 inhibitor pembrolizumab and/or chemotherapy in mUC.14

ineligible mUC patients, there remains a high unmet need.

Combination Treatment with Enfortumab VedotinEJFV and Pembrolizumab

There is evidence that a combination of EV and pembrolizumab may provide value for mUC patients who are cisplatin-ineligible.14 Clinical data from an ongoing trial suggests that EV plus pembrolizumab may have the potential to induce greater antitumor activity in locally advanced or mUC compared with either agent alone.14 In February 2020, the combination therapy of EV and pembrolizumab was granted Breakthrough designation for cisplatin-ineligible patients with locally advanced or mUC in the first-line setting.1 The ongoing trial has demonstrated that the combination therapy is encouraging and durable activity with a tolerable and stable safety profile in cisplatin-ineligible patients with locally advanced or mUC in the first-line setting.15

In August 2022, results from the phase 1b/2 EV-103 clinical trial show EV in combination with pembrolizumab as first-line treatment in patients with locally advanced or mUC who are ineligible for cisplatin-based chemotherapy were published.16

Broader Bladder Cancer Pipeline17

Drug Manufacturer

Route of Administration

Results showed that patients treated with the combination enfortumab vedotin plus pembrolizumab regimen had a 73.3% confirmed ORR and a 15.6% complete response rate.16 Median duration of response and overall survival were 25.6 months and 26.1 months, respectively.16

Mechanism of Action Indication Status

ImmunityBio/NantWorks SC; intravesical IL-15 agonist bladder cancer pending (05/23/2023) paclitaxel (ONCOFID-P-B)Fidia

nogapendekin alfa inbakicept (N-803)

intravesical mitotic inhibitor bladder cancer phase 3 mitomycin (UGN-102)UroGen

Bayer oral FGFR inhibitor urothelial cancer phase 3

intravesical cytotoxic agent bladder cancer phase 3 rogaratinib (BAY1163877)

tremelimumab AstraZeneca; MedImmune IV

Abbreviations: FGFR = fibroblast growth factor receptor; IL-15 = interleukin 15; SC = subcutaneous

Payer Impact

A 2020 study of Medicare claims assessed the lifetime economic burden of UC.18 Results showed that stage III UC had the highest cost per patient, driven by intensive care with multi-modal management, including cystectomy and multi-drug chemotherapy.18 Stage IV UC had the lowest cost per patient, which could be due to the less intense therapy.18 However, across all stages, hospitalizations contributed the greatest spend to the lifetime cost. Access to and utilization of treatments that may decreased hospitalizations – in frequency and duration – may play a role in lowering costs.18

Over the years, multiple immune checkpoint inhibitors (ICIs) have received approval as single agents or following chemotherapy in

CTLA-4 inhibitor

urothelial cancer; bladder cancer phase 3

early and late-stage UC. Without definitive cost-effectiveness data, payers are concerned about the added spend for this therapy class. As ICIs tend to have high costs, payers may seek pricing discounts or other management strategies.19 Although UC accounts for only 4% of new cancer cases in the U.S. and the number of mUC cases is even smaller, higher cost treatments tend to be a concern for payers. The population of cisplatin-ineligible mUC patients only accounts for about half of the mUC cases and may require different treatment and management for improved outcomes; due to the small size of this subset of the UC population, these patients may not be a high priority in terms of payer management. However, as the long-term outcomes of ICIs and treatments for mUC continue to be examined, payers may continue to consider and evaluate appropriate access and management of this category.

There is evidence that a combination of enfortumab vedotin and pembrolizumab may provide value for mUC patients who are cisplatinineligible.

METASTATIC BLADDER CANCER

1. Chin, J. L., et al. “Metastatic Bladder Cancer.” Introduction to Cancer Metastasis, p. 177-198, 2017, https://www.sciencedirect.com/ science/article/pii/B9780128040034000104.

2. Markman, Maurie. “Bladder cancer types.” Cancer Treatment Centers of America, 18 May 2022, https://www.cancercenter.com/cancertypes/bladder-cancer/types

3. “Cancer Stat Facts: Bladder Cancer.” National Cancer Institute, National Institutes of Health, https://seer.cancer.gov/statfacts/html/ urinb.html.

4. Einstein, David J., et al. “Treatment Approaches for CisplatinIneligible Patients with Invasive Bladder Cancer.” Current Treatment Options in Oncology, 11 Feb. 2019, https://pubmed.ncbi.nlm. nih.gov/30741358/#:~:text=Pembrolizumab%20and%20 atezolizumab%20offer%20options,L1%20inhibitors%20are%20 eagerly%20awaited.

5. Sonpavde, Guru P., et al. “Real-World Treatment Patterns and Clinical Outcomes with First-Line Therapy in Cisplatin-Eligible and Ineligible Patients with Advanced Urothelial Carcinoma.” Journal of Clinical Oncology, 2022 ASCO Annual Meeting, https://ascopubs.org/doi/ abs/10.1200/JCO.2022.40.16_suppl.4565

6. Bloudek, Lisa, et al. “Systematic Literature Review (SLR) and Network Meta-Analysis (NMA) of First-Line Therapies (1L) for Locally Advanced/Metastatic Urothelial Carcinoma (la/mUC).” Journal of Clinical Oncology, 2022 ASCO Genitourinary Cancers Symposium, https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.6_suppl.570

7. Rosenberg, Jonathan E., et al. “Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/ Programmed Death Ligand 1 Therapy.” Journal of Clinical Oncology, 10 Oct. 2019, https://pubmed.ncbi.nlm.nih.gov/31356140/.

8. Galsky, Matthew, et al. “Benchmarking Maintenance Therapy Survival in First-Line Advanced Urothelial Carcinoma Using Disease Modeling.” Journal of Clinical Oncology, 2022 ASCO Annual Meeting I, https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_ suppl.4575.

9. Park, Inkeun, et al. “Systemic treatment for advanced urothelial cancer: an update on recent clinical trials and current treatment options.” Korean Journal of Internal Medicine, 1 July 2020 , https:// www.kjim.org/journal/view.php?doi=10.3904/kjim.2020.204.

10. U.S. Food & Drug Administration, “FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer.” 9 July 2021, https://www.fda.gov/drugs/ resources-information-approved-drugs/fda-grants-regularapproval-enfortumab-vedotin-ejfv-locally-advanced-or-metastaticurothelial-cancer.

11. Powles, Thomas, et al. “Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma.” New England Journal of Medicine, 25 March 2021, https://www.nejm.org/doi/full/10.1056/ NEJMoa2035807.

12. Yu, Evan Y., et al. “Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): a multicentre, single-arm, phase 2 trial.” Lancet Oncology, June 2021, https://pubmed.ncbi.nlm.nih.gov/33991512/.

13. Mamtani, Ronac, et al. “Quality of Life, Functioning, and Symptoms in Patients with Previously Treated Locally Advanced or Metastatic Urothelial Carcinoma From EV-301: A Randomized Phase 3 Trial of Enfortumab Vedotin versus Chemotherapy.”Journal of Clinical Oncology, 2021 ASCO Annual Meeting I, https://ascopubs.org/ doi/10.1200/JCO.2021.39.15_suppl.4539.

14. Mar, Nataliya, et al. “Study EV-103: New Randomized Cohort Testing Enfortumab Vedotin as Monotherapy or in Combination with Pembrolizumab in Locally Advanced or Metastatic Urothelial Cancer.” Journal of Clinical Oncology, 2020 ASCO Annual Meeting I, https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl. TPS5092.

15. “Astellas and Seattle Genetics Receive FDA Breakthrough Therapy Designation for PADCEV™ (enfortumab vedotin-ejfv) in Combination with Pembrolizumab in First-Line Advanced Bladder Cancer.” Astellas and SeattleGenetics, 19 Feb. 2020, https://www. astellas.com/en/system/files/news/2020-02/20200220_en_1.pdf.

16. Holmes, Christopher J., et al. “Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer.” Journal of Clinical Oncology, 30 Aug. 2022, https:// ascopubs.org/action/showCitFormats?doi=10.1200/JCO.22.01643.

17. “Bladder Cancer.” IPD Analytics, https://ipdanalytics.com.

18. Aly, A., et al. “The Real-World Lifetime Economic Burden of Urothelial Carcinoma by Stage at Diagnosis.” Journal of Clinical Pathways, May 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC7433100/pdf/nihms-1607319.pdf.

19. Walia, AS., et al. “Cost-Effectiveness of Immune Checkpoint Inhibitors in Urothelial Carcinoma-A Review.” Cancers (Basel), 24 Dec. 2021, https://pubmed.ncbi.nlm.nih.gov/35008237/.

Gene Therapy: Rare Disease Management

As the number of gene therapies in the market increases, payers and manufacturers will continue to collaborate to transform reimbursement and payment models.

While there are around 7,000 identified rare diseases, only about 5% have FDA-approved treatment.1 As more than 80% of rare diseases have a known monogenic cause, gene therapies present particularly promising treatment potential. Traditional small molecule drugs have worked to minimize symptoms, but most have not worked to cure the underlying disease, which can lead to frequent administration of the drug or multiple drugs required for proper disease management.1 Successful gene therapies may present a single-dose, curative treatment option for those living with otherwise difficult-to-treat rare diseases.1

Carly Rodriguez, Pharm.D., FAMCP Vice President & Chief Pharmacy Officer Moda Health

Potentially 90 new gene and cellular therapies could receive approval by 2031.2 According to an MIT Report, this wave of new approvals would result in $30 billion in healthcare spending.2 A recent survey of researchers knowledgeable about genetic therapies for rare diseases found that respondents believed gene therapy would be the standard of care for rare genetic diseases before 20363—a major shift in the treatment landscape. Though there was a small delay in the development and approvals of some gene therapy products, a wave of products is nearing approval and will be coming to market.4

GENE THERAPY | Continued

Currently Available Gene Therapies

Since the approval of voretigene neparvovec-rzyl (LUXTURNA®, Spark Therapeutics) for the treatment of confirmed biallelic RPE65 mutation-associated retinal dystrophy in 2017, other advances in gene therapy have created opportunity and promise for many rare diseases. The FDA approved onasemnogene abeparvovec-xioi (ZOLGENSMA®, Novartis) for spinal muscular atrophy (SMA) in 2019. Most recently, betibeglogene autotemcel (Zynteglo®, bluebird bio) was approved for beta thalassemia. The current pipeline of gene therapies being reviewed and investigated is expansive (Table 1) and include Duchenne muscular dystrophy (DMD), sickle cell disease, hemophilia, epidermolysis bullosa, Huntington’s disease, choroideremia, cerebral adrenoleukodystrophy, and several more.

Recent Approvals

Betibeglogene Autotemcel (Zynteglo®)

In August 2022, the U.S. Food and Drug Administration approved betibeglogene autotemcel (beti-cel) (Zynteglo®, bluebird bio) for adult and pediatric patients with beta thalassemia who require regular blood cell transfusions.5 Beti-cel is a one-time gene therapy administered as a single dose, customized using the patient’s own bone marrow stem cells that are genetically modified to produce functional beta globin.5 This gene therapy was granted a rare pediatric disease voucher, in addition to receiving Priority Review, Fast Track, Breakthrough Therapy, and Orphan designations. FDA approval was based on safety and effectiveness results from two multicenter clinical studies of adult and pediatric patients with beta thalassemia requiring regular blood transfusions. Effectiveness was established based on the achievement of transfusion independence: when a patient maintains a predetermined level of hemoglobin without needing any red blood cell transfusions for at least 12 months. Of the 41 patients receiving beti-cel in the studies, 89% achieved transfusion independence.5 Common adverse reactions associated with beti-cel treatment included reduced platelet and other blood cell levels, as well as mucositis, febrile neutropenia, vomiting, pyrexia, alopecia, epistaxis, abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus. Treatment with beti-cel presents a potential risk of blood cancer, however, no cases were seen in studies with beticel. Hypersensitivity reactions during beti-cel administration as well as thrombocytopenia and bleeding should be monitored.5 Patients treated with beti-cel should undergo regular blood monitoring for at least 15 years for any evidence of cancer.

A report in June 2022, by the Institute for Clinical and Economic Review, determined that beti-cel provides net health benefits to patients with

beta thalassemia.6 Cost-effectiveness modeling found that treatment with beti-cel met commonly accepted value thresholds at a price of up to $2.77 million with an 80% payback option for patients who do not achieve and maintain transfusion independence over a five-year period.6 The initial price of beti-cel is $2.8 million.

Elivaldogene Autotemcel (SKYSONA®)7

In September 2022, elivaldogene autotemcel (eli-cel) (SKYSONA®, bluebird bio) received FDA accelerated approval to slow the progression of neurologic dysfunction in boys aged 4 to 17 years with early, active cerebral adrenoleukodystrophy (CALD). The FDA also lifted the clinical hold that was put in place in August 2021.

Approval was based on data from the phase 2/3 ALD-102 and phase 3 ALD-104 studies. In the studies, patients treated with eli-cel were assessed using neurologic function score (NFS) associated with CALD progerssion. Patients treated with eli-cel estimated 72% likelihood of Major Functional Disabilities (MFD)-free survival at 24 months from the time of first NFS>1 versus 43% in untreated patients. Adverse reactions associated with eli-cel included mucositis, nausea, vomiting, febrile neutropenia, alopecia, decreased appetite, abdominal pain, constipation, pyrexia, diarrhea, headache, and rash. The most common Grade 3 or 4 abnormalities associated with eli-cel include leukopenia, lymphopenia, thrombocytopenia, neutropeia, anemia, and hypokalemia.

Payer Management

Gene therapies carry particularly high price tags; for example, onasemnogene abeparvovec for SMA has a list price of $2.125 million per dose and beti-cel has a price of $2.8 million for a single dose.4 As more gene therapies are approved and become available for rare or orphan diseases, high prices may be expected beyond that of conventional medical interventions.4 Actively monitoring the gene therapy pipeline and tracking data on newly approved products and products under review will be key to determining appropriate access and management strategies as gene therapy products launch.4 Managing cost and ensuring access to these potentially curative therapies requires collaboration between payers and pharmaceutical manufacturers; the need for consensus for coverage of these gene therapies is clear.2

In 2020, healthcare leaders from government, industry, and academia formed a work group to establish a guideline for payment models for advanced therapies.2 The work group highlighted key challenges in managing coverage and payment for these therapies, including the difficulty in assessing accurate prices for short-term drugs that

could have long-term, potentially curative impact. In some cases, the long-term impact of the newer gene therapies is still unproven, which must be accounted for in drug pricing and management. Future unknowns must also be considered; while the gene therapies currently approved largely focus on rare diseases, there may be potential uses not yet explored for the therapies, which could lead to increased utilization across multiple disease states.2

Still, payers, providers, and manufacturers have sought solutions. Alternative payment models may help finance gene therapies. Some of these include outcomes- or milestone-based agreements, subscription payment models, and risk pools. A milestone-based arrangement requires a payer to pay a certain amount up front with partial reimbursement guaranteed if the therapy fails to provide the intended outcome within a certain timeframe.8 Subscriptionbased models include a fixed fee for unlimited access to certain therapies; the payer takes on the risk as it guarantees to provide as much therapy as required.8 The subscription-based model potentially allows payers to manage the actuarial fluctuations that occur with the funding of gene therapies.8 One manufactureradvanced model prices therapies solely on the intrinsic value of the product and returns all cost offsets to the payers. Vastly different from a typical reimbursement model, this arrangement could ease

Table 1. Gene Therapy Pipeline: Rare Diseases12

some payer concerns regarding cost management associated with gene therapies.8

In 2021, about 12% of payers implemented more than 10 valuebased contracts with manufacturers involving outcomes-based measures.9 A 2020 survey of managed care professionals showed that 62% of U.S. payers currently use traditional strategies, such as formulary or utilization management tools, to manage cell and gene therapies.10 Many payers (66% of respondents) plan to leverage reinsurance in the near future. Respondents also noted they anticipate an increase in the utilization of value- and outcomesbased contracting and installment payments as techniques to manage gene therapies.10

As the number of gene therapies in the market increases, payers and manufacturers will continue to collaborate to transform reimbursement and payment models.11 Cited concerns around the current reimbursement models include limitations around program complexity, burden of information tracking, insurance, regulatory barriers, and government pricing and reporting requirements.11 Collaborative development of creative payment models by all stakeholders will be key to effectively manage these treatments, allow access to the patient population, and ease the financial burden.

Drug Manufacturer Administration Indication Status

etranacogene dezaparvovec (AMT-061)uniQure; CSL Behring IV

hemophilia B pending (November 2022)

beremagene geperpavec (VyjuvekTM)Krystal Biotech topical epidermolysis bullosa pending (02/17/2023)

debcoemagene autoficel (D-Fi) Castle Creek Biosciences; Fibrocell Technologies

EB-101

delandistrogene moxeparvovec (SRP-9001)

fordadistrogene movaparvovec (PF-06939926)

Abeona Therapeutics

Therapeutics

bullosa phase 3

epidermolysis bullosa phase 3

phase 3

phase 3

timrepigene emparvovec (BIIB111/AAV2-REP1)

lenadogene nolparvovec (GS010)GenSight

type IIIA phase 3

phase 3 olenasufligene relduparvovec (LYS-SAF302)

phase 3

simoladagene autotemcel (OTL-101)Orchard

OTL-103

phase 3

phase 3 onasemnogene abeparvovec-xioi (ZOLGENSMA®)

phase 3

GENE THERAPY

Table 1. Gene Therapy Pipeline: Rare Diseases (Cont.)

pariglasgene brecaparvovec (DTX401)Ultragenyx

IV

von Gierke disease (glycogen storage disease type I) phase 3

UX701 Ultragenyx IV Wilson disease phase 3 botaretigene sparoparvovec (AAV-RPGR)MeiraGTx/Janssen other retinitis pigmentosa phase 3 atidarsagene autotemcel (OTL-200)Orchard Therapeutics/GSKIV metachromatic leukodystrophy phase 3 laruparetigene zosaparvovec (AGTC-501)Applied Genetic Technologiesinjectableretinitis pigmentosa phase 3 avalotcagene ontaparvovec (DTX301)Ultragenyx IV urea cycle disorders phase 3 giroctocogene fitelparvovec (SB-525)Sangamo Therapeutics; Pfizer IV hemophilia A phase 3 fidanacogene elaparvovec (PF-0683845)Spark Therapeutics; Pfizer IV hemophilia B phase 3 lovotibeglogene autotemcel (Lovo-cel)bluebird bio IV SCD phase 3 exagamglogene autotemcel (CTX001)CRISPR Therapeutics/VertexIV

beta thalassemia; SCD phase 3 eladocagene exuparvovec (PTC-AADC)PTC Therapeutics injectable AADC deficiency phase 2

SB-FIX Sangamo Therapeutics IV hemophilia B phase 2 verbrinacogene setparvovec (FLT180a)Freeline Therapeutics injectablehemophilia B phase 2

AskBio009

Baxalta/Shire IV hemophilia B phase 2

AMT-060 uniQure IV hemophilia B phase 2

SPK-8011 Spark Therapeutics; RocheIV hemophilia A phase 2

DTX201

Dimension Therapeutics; BayerIV hemophilia A phase 2

SGT-001 Solid Biosciences IV DMD phase 2

scAAV9.U7.ACCA

Astellas IV DMD phase 2

GALGT2 Sarepta Therapeutics injectable DMD phase 2

KB105 Krystal Biotech topical ichthyosis phase 2

LYS-GM101 Lysogene IV GM1 gangliosidosis phase 2

AXO-AAV-GM1

Axovant; Sio Gene TherapiesTBD GM2 gangliosidosis (Tay-Sachs and Sandhoff) phase 2

AAV-CNGA3 MeiraGTx/Janssen other achromatopsia phase 2

AAV-CNGB3 MeiraGTx/Janssen other achromatopsia phase 2

BBP-631

Adrenas Therapeutics; BridgeBioIV congenital adrenal hyperplasia phase 2

AMT-130 uniQure injectableHuntington’s disease phase 2

SAR439483

Atsena Therapeutics other; intravitrealleber congenital amaurosis phase 2

BBP-812 BridgeBio; Aspa TherapeuticsIV canavan disease phase 2

RP-L201 Rocket Pharma IV primary immunodeficiency phase 2

Drug Manufacturer Administration Indication Status

Table 1. Gene Therapy Pipeline: Rare Diseases (Cont.)

Drug Manufacturer

RP-L102

RGX-111

RGX-121

4D-310

AVR-RD-02

AVR-RD-04

Rocket Pharma IV

Regenxbio injectable

Indication

Fanconi anemia phase 2

Hurler and Hurler-Scheie forms of mucopolysaccharidosis I phase 2

Regenxbio injectablemucopolysaccharidosis II (Hunter syndrome)phase 2

4D Molecular TherapeuticsIV

AvroBio

Fabry disease phase 2

Gaucher disease type I phase 2

AvroBio injectablecystinosis phase 2

BMN 307 BioMarin IV phenylketonuria phase 2

SPK-3006 Spark Therapeutics/RocheIV

PR001

Pompe disease (glycogen storage disease type II) phase 2

REGENXBIO/Prevail Therapeutics injectableParkinson’s disease;

References

1. National Center for Advancing Translational Sciences, “Gene Therapy Platform for Rare Diseases.” National Institutes of Health, 18 March 2022, https://ncats.nih.gov/trnd/projects/gene-therapy.

2. “Top Payer Strategies Around Payment Models for Advanced Therapies.” HealthPayer Intelligence, 27 July 2022, https:// healthpayerintelligence.com/features/top-payer-strategies-aroundpayment-models-for-advanced-therapies.

3. Braga, Luiza Amar Maciel, et al. “Future of genetic therapies for rare genetic diseases: what to expect for the next 15 years?” Therapeutic Advances in Rare Disease, 10 June 2022, https://journals.sagepub. com/doi/full/10.1177/26330040221100840.

4. Minemyer, Paige. “The gene therapy pipeline may be at a ‘tipping point.’ Here’s why Optum says payers need to take notice.” FierceHealthcare, 8 Aug. 2022, https://www.fiercehealthcare.com/ payers/gene-therapy-pipeline-may-be-tipping-point-heres-whyoptum-says-payers-need-take-notice.

5. “FDA Approves First Cell-Based Gene Therapy to Treat Adult and Pediatric Patients with Beta-thalassemia Who Require Regular Blood Transfusions.” U.S. Food & Drug Administration, 17 Aug. 2022, https://www.fda.gov/news-events/press-announcements/ fda-approves-first-cell-based-gene-therapy-treat-adult-andpediatric-patients-beta-thalassemia-who.

6. Beaudoin, Francesca L., et al. “Betibeglogene Autotemcel for Beta Thalassemia: Effectiveness and Value.” Institute for Clinical and Economic Review, 2 June 2022, https://icer.org/wpcontent/uploads/2021/11/ICER_Beta-Thalassemia_EvidenceReport_060222-1.pdf.

7. “bluebird bio Receives FDA Accelerated Approval for SKYSONA® Gene Therapy for Early, Active Cerebral Adrenoleukodystrophy (CALD),” bluebird bio, 16 Sept. 2022, https://investor.bluebirdbio. com/news-releases/news-release-details/bluebird-bio-receivesfda-accelerated-approval-skysonar-gene.

8. Vaidya, Anuja. “Innovative payment models to support cell and gene therapies on the rise (video).” MedCity News, 9 Dec. 2022, https://medcitynews.com/2020/12/innovative-payment-modelsto-support-cell-and-gene-therapies-on-the-rise/?rf=1.

9. Waddill, Kelsey. “12% of Payers Implement 10 or More OutcomesBased Contracts.” HealthPayer Intelligence, 4 Nov. 2021, https:// healthpayerintelligence.com/news/12-of-payers-implement-10-ormore-outcomes-based-contracts.

10. Smith, Diane, et al. “Current and future payment of cell and gene therapies,” AmerisourceBergen, 2021 AMCP Virtual Meeting, April 2021, https://www.xcenda.com/-/media/assets/xcenda/english/ content-assets/conference-and-poster-presentations/2021/currentand-future-payment-of-cell-and-gene-therapies.pdf.

11. Neumann, Ulrich. “Paying for cell and gene therapy — Is the future already here?” Reuters Events, 2 Nov. 2020, https://www. reutersevents.com/pharma/medical/paying-cell-and-gene-therapyfuture-already-here.

12. “Gene Therapies: Rare Diseases.” IPD Analytics, https://ipdanalytics.com.

Age-Related Macular Degeneration and Diabetic Macular Edema:

Treatment Advances and Payer Strategies

Due to the high degree of variability in eye diseases, managing these conditions requires flexibility and strong provider engagement.

Age-Related Macular Degeneration (AMD)

Age-related macular degeneration (AMD) is an eye disease that affects approximately 15 million Americans.1 AMD occurs when aging causes damage to the macula; it is the leading cause of vision loss for older adults. Those at highest risk for AMD are older than 55 years, have a family history of AMD, are white, or smoke. While it does not cause complete vision loss, it does cause loss of central vision, which can make it difficult to see faces, read, drive, or do other daily activities.1

Scott McLelland, Pharm.D.

There are two types of AMD: dry and wet. Dry AMD (dAMD) is also called atrophic AMD and occurs when the macula thins with age. The three stages of dAMD—early, intermediate, and late—typically progress slowly over several years. Wet AMD (wAMD), otherwise known as advanced neovascular AMD, is a less common form of late AMD that causes faster vision loss. wAMD is always late-stage; however, any stage of dAMD can develop into wAMD, which occurs when abnormal blood vessels grow in the back of the eye and damage the macula. While there are no available treatments for late-stage dAMD, there are treatment options for wAMD.1

Symptoms of AMD vary depending on the stage. Early dAMD presents with no symptoms. While some people with intermediate dAMD have no symptoms, others may notice mild blurriness or trouble seeing in low light. Symptoms of late AMD, whether wet or dry, can include straight lines looking wavy or crooked, a blurry area near the center of vision that gets bigger over time, colors that appear less bright, and trouble seeing in low lighting.1

Ophthalmologists check for AMD as part of a comprehensive dilated eye exam. Some may recommend optical coherence tomography.1

Diabetic Macular Edema (DME)

Diabetic macular edema (DME) is the buildup of fluid in the macula caused by diabetic retinopathy, a complication of diabetes.2 Diabetic retinopathy is the most common diabetic eye disease; it is the leading cause of irreversible blindness in adult Americans. Typically, diabetic retinopathy affects both eyes, and most commonly, DME is the cause of vision loss in those with diabetic retinopathy.2 The risk of blindness increases with poor blood sugar control and other associated medical conditions including high blood pressure. DME is most likely to occur as diabetic retinopathy progresses; however, it can occur at any stage of the condition.2 An estimated 7.7 million Americans live with diabetic retinopathy, with about 750,000 of those having DME.2

Treatment Landscape

AMD

Treatment depends on the type and stage of disease.1 While there is no treatment for patients with early or intermediate AMD, ophthalmologists may recommend vitamins or dietary supplements that may help to prevent further progression of AMD. The goal of treatment for wAMD is prevention of further vision loss.1 Anti-VEGF treatments can be injected in the eye to reduce new blood vessel

growth or edema.1 Currently, there are seven anti-VEGF treatments approved by the U.S. Food and Drug Administration (FDA) and available to treat AMD: brolucizumab (BEOVU®), ranibizumab-nuna (BYOOVIZTM), ranibizumab-qgrn (CIMERLITM), aflibercept (EYLEA®), ranibizumab (LUCENTIS®), ranibizumab implant (SusvimoTM), faricimab (Vabysmo®). Off-label bevacizumab (Avastin®) is also successfully used to treat wAMD. The landscape of drugs in this category has become more dynamic with the entrace of biosimilars along with historical use of compounded Avastin® 1

DME

Often, DME is treated by first addressing the underlying cause— such as high blood sugar or high blood pressure—which can help prevent further damage or progression.2 After this is resolved, an ophthalmologist or retina specialist will address the damage to the retina. Anti-VEGF treatments are often used as a first-line treatment in patients with DME. Other treatments, such as focal-grid macular laser surgery, may help to slow leaking and reduce swelling.2

Recent Approvals

Faricimab-svoa (Vabysmo®)

In January 2022, the FDA approved faricimab-svoa (Vabysmo®, Genentech) for the treatment of wAMD and DME. Faricimab-svoa

Diabetic

is the most common diabetic eye

it is the leading cause

in

AMD AND DME

treatments are administered one to four months apart in the first year, following four initial monthly doses, based on evaluation of the patient’s anatomy and outcomes.3 FDA approval was based on results from four phase 3 studies in wAMD and DME.3 Two phase 3 studies evaluated the efficacy, durability, and safety of faricimabsvoa (TENAYA and LUCERNE).4 The primary end point of these

Table 1. Pipeline: AMD and DME5

studies was change in best-corrected visual acuity (BCVA). The two trials included 1,329 patients randomized to receive faricimab or aflibercept.4 In patients receiving faricimab at intervals spanning up to four months, BCVA change from baseline was noninferior to patients treated with aflibercept every two months. Ocular adverse events occurred at a comparable incidence across the groups.4

Drug Manufacturer Route of Administration Mechanism of Action Indication Status

VEGF Inhibitor

aflibercept (Eylea High-Dose (HD)) Regeneron; Bayerintravitreal

bevacizumab-vikg (LYTENAVA™)Outlook Therapeuticsophthalmic

tarcocimab tedromer (KSI-301)Kodiak Sciences intravitreal

conbercept

OPT-302

VEGF biosimilars

Chengdu Kanghong Pharmaceutical intravitreal

Opthea; Vegenicsintravitreal

VEGF inhibitor

VEGF inhibitor

wAMD; DME phase 3

wAMD; DME; macular edema following RVO phase 3

VEGF inhibitor BRVO; CRVO; to be submitted for AMD phase 3

VEGF inhibitor wAMD phase 3

VEGF inhibitor wAMD phase 3 DME phase 2

aflibercept (MYL-1701P)

Momenta; Viatris intravitreal

VEGF inhibitor DME pending ranibizumab (Xlucane™) Xbrane; Bausch + Lombintravitreal

VEGF inhibitor wAMD phase 3 ranibizumab (LUBT010)

Lupin intravitreal

VEGF inhibitor wAMD phase 3 aflibercept (ABP 938) Amgen intravitreal VEGF inhibitor wAMD phase 3 aflibercept (SCD411) Samchundang Pharmintravitreal

VEGF inhibitor wAMD phase 3 aflibercept (SB15) Samsung Bioepis; Biogenintravitreal

VEGF inhibitor wAMD phase 3 aflibercept (CT-P42) Celltrion intravitreal

VEGF inhibitor DME phase 3 aflibercept (SOK583A1) Sandoz; Hexal intravitreal

VEGF inhibitor wAMD phase 3 Non-VEGF

danazol (Optina)

Ampio Pharmaceuticalsoral vascular agents DME phase 3 dexamethasone (OCS-01) Oculis ophthalmic corticosteroid DME phase 3

RGX-314

ADVM-022

Dry AMD

Regenxbio; AbbVieophthalmic gene therapy

wAMD phase 3 diabetic retinopathy phase 2

Adverum Biotechnologies intravitreal gene therapy DME; diabetic retinopathy phase 2

pegcetacoplan (APL-2) Apellis intravitreal complement inhibitors geographic atrophy secondary to dry AMD pending (1H 2023)

avacincaptad

ALK-001

Abbreviations:

(Zimura)Ophthotech; Archemixintravitreal

Alkeus Pharmaceuticalsoral

inhibitors

geographic atrophy secondary to dry AMD phase 3

Stargardt disease phase 2

A analogue dry AMD phase 3

Stargardt disease phase 2

The YOSEMITE and RHINE phase 3 trials evaluated efficacy, durability, and safety of faricimab in patients with DME.5 In these trials, 1,891 patients were randomized to receive faricimab every eight weeks, faricimab over a personalized treatment interval, or aflibercept every eight weeks.6 The primary end point was mean change in BCVA at one year, average over weeks 48, 52, and 56.6

Patients treated with faricimab every eight weeks achieved a BCVA noninferior to patients treated with aflibercept every eight weeks. Incidence in ocular adverse events were similar between faricimab and aflibercept groups.6 The trials have shown that faricimab-svoa is generally well-tolerated, with the most common adverse event being conjunctival hemorrhage.7

Ranibizumab 100 mg/mL Injection (Susvimo®)

The FDA approved 100 mg/mL ranibizumab injection (Susvimo®, Genentech) for the treatment of wAMD in October 2021. The product is approved for intravitreal use via ocular implant for patients who have previously responded to at least two anti-VEGF injections.8 Susvimo® is the first and only FDA-approved treatment for wAMD that offers as few as two treatments per year. Typically, anti-VEGF treatment for wAMD requires injections administered as often as monthly. This ranibizumab injection offers a one-time implant, or Port Delivery System (PDS), that is refilled about every six months.8 The Archway study evaluated the efficacy and safety of the PDS with ranibizumab relative to monthly ranibizumab

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injections, measuring BCVA following 36-40 weeks of treatment.9 The PDS with ranibizumab was found to be non-inferior to monthly injections; patients receiving monthly injections gained 0.5 letters on average compared to 0.2 letters on average for patient in the PDS group.9

Launch of Ranibizumab Biosimilars

In September 2021, the FDA approved ranibizumab-nuna (Byooviz®, Biogen) for wAMD, which was the first biosimilar referencing ranibizumab (Lucentis®, Genentech) and the first ophthalmology biosimilar in the U.S. market. The biosimilar launched in the U.S. markets in June.10 Byooviz is listed for $1,130 per single-use 0.5 mg vial to be administered intravitreally; this list price will be around 15% lower in price than the ASP of the reference drug.10

In August, the FDA approved ranibizumab-eqrn (Cimerli®, Coherus Biosciences) as the first and only biosimilar product interchangeable with the reference drug for all five indications – wAMD, macular edema following retinal vein occlusion, DME, diabetic retinpathy, and myopic choroidal neovascularization.11 In a head-to-head study, the ranibizumab-eqrn met its primary endpoint of change from baseline in BCVA at week 8 compared to the reference product. Overall safety and immunogenicity profile was comparable with the reference product as well. This biosimilar

is expected to become available on the market in early October.11 The interchangeability designation will allow ranibizumab-eqrn to be substituted without the intervention of the provider, subject to state pharmacy laws.11

A June 2022 survey suggested a split amongst ophthalmologists in regard to the decision to utilize Byooviz® with their patients within the first three months of launch.12 Notably, the survey was conducted before the approval of interchangeable biosimilar, Cimerli®. Still, some ophthalmologists may hesitate to switch patients who are doing well on the reference drug regardless of payer preference and savings.12 While pricing is important to set a biosimilar apart, demonstrating value by engaging providers, payers, and patients in an effort to facilitate access and provide education support will be key; interchangeability will also be a factor in distinguishing biosimilar products.13 The launch of this biosimilar presents opportunity for savings and competitive pricing within the ophthalmology space.12

Payer Management of AMD and DME

When it comes to managing patients with eye diseases, flexibility is key. Appropriate treatment can be patient specific; especially in patients with DME and AMD, there is a high degree of variability.14 Treatment decisions and treatment intervals may vary between patients, so proper management will require provider engagement.14 Additionally, managing the underlying cause can be crucial to achieving positive outcomes. Especially in patients with DME, controlling blood sugar

and encouraging healthier diets and exercise can potentially have a positive impact on the treatment of the eye disease.14

Proper and timely diagnosis and treatment is critical to improving long-term outcomes as well as managing costs.15 Both the clinical and economic impacts of delaying treatment in patients with these eye diseases can be significant and often irreversible. Any delay, such as improper dosing or intervals between treatments, can lead to complications that will require additional, more expensive treatments in the long-term, which can tremendously increase costs.15 During the COVID-19 pandemic, many patients were not receiving treatment; as provider offices began to reopen and patients returned to resume treatments, there were many instances of severe complications that resulted in permanent vision loss.15 This instance illustrated the real cost of delays or pauses in treatment for patients with eye disease. Early detection, provider education, and access to appropriate treatments can lead to better outcomes and more effective cost management in these populations.15

While treatment options in this category are growing, bevacizumab (Avastin®) remains a cost-effective therapy for payers to initially consider (Table 2). Notably, the cost for compounded bevacizumab is considerably less than other therapies and many payers do not currently require compounded bevacizumab prior authorization where the drug is clinically appropriate. Biosimilars entering the market can compete in this space as they will be FDA approved, leading to fair reimbursement. This category is seeing new entrants providing potential for better treatment, extended outcomes, and improved cost management.

dbll (Beovu®)

faricimabsvoa (VABYSMO®)

1. “Age-Related Macular Degeneration (AMD).” National Eye Institute, National Institutes of Health, 22 June 2021, https://www.nei.nih. gov/learn-about-eye-health/eye-conditions-and-diseases/agerelated-macular-degeneration.

2. “Macular Edema.” National Eye Institute, National Institutes of Health, 8 July 2019, https://www.nei.nih.gov/learn-about-eyehealth/eye-conditions-and-diseases/macular-edema.

3. “FDA Approves Genentech’s Vabysmo, the First Bispecific Antibody for the Eye, to Treat Two Leading Causes of Vision Loss.” Genentech, 28 Jan. 2022, https://www.gene.com/media/pressreleases/14943/2022-01-28/fda-approves-genentechs-vabysmothe-firs.

4. Heier, Jeffrey S., et al. “Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials.” The Lancet, 24 Jan. 2022, https://www.thelancet.com/journals/lancet/article/PIIS01406736(22)00010-1/fulltext.

5. Wykoff, Charles C., et al. “Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials.” The Lancet, 24 Jan. 2022, https://www.thelancet.com/journals/lancet/article/PIIS01406736(22)00018-6/fulltext.

6. “Eye Diseases.” IPD Analytics, https://ipdanalytics.com.

7. Gallagher, Ashley. “FDA Approves Vabysmo for Treatment of 2 Leading Causes of Vision Loss.” Pharmacy Times, 1 Feb. 2022, https://www.pharmacytimes.com/view/fda-approves-vabysmo-fortreatment-of-2-leading-causes-of-vision-loss.

8. Biopharm International Editors, “FDA Approves Genentech’s Susvimo for Wet AMD,” Biopharm International.com, 29 Oct. 2021, https://www.biopharminternational.com/view/fda-approvesgenentech-s-susvimo-for-wet-amd

9. Holekamp, Nancy M, et al., “Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration”, Ophthalmology, March 2022, https://pubmed.ncbi.nlm.nih.gov/34597713/

10. Jeremias, Skylar. “First Ophthalmology Biosimilar Launches in US.” American Journal of Managed Care, 2 June 2022, https://www. centerforbiosimilars.com/view/first-lucentis-biosimilar-launchesin-us.

11. Arthur, Rachel. “FDA approves Cimerli as the first interchangeable biosimilar to Lucentis for all indications.” BioPharma-Reporter.com, 4 Aug. 2022, https://www.biopharmareporter.com/Article/2022/08/04/FDA-approves-Cimerli-as-thefirst-interchangeable-biosimilar-to-Lucentis#:~:text=FDA%20 approves%20Cimerli%20as%20the%20first%20 interchangeable%20biosimilar%20to%20Lucentis%20for%20 all%20indications&te.

12. Hagen, Tony. “Biogen Launches Educational Program to Overcome Hesitation About Byooviz.” Managed Healthcare Executive, 14 July 2022, https://www.managedhealthcareexecutive.com/view/biogenlaunches-educational-program-to-overcome-hesitation-aboutbyooviz.

13. Cohen, Joshua P. “Biosimilars appear ready for prime time in the U.S. as reimbursement is increasingly value-based.” LyfeGen, https:// lyfegen.com/biosimilars-appear-ready-for-prime-time-in-the-u-sas-reimbursement-is-increasingly-value-based/.

14. Kenney, Jim, et al. “Approaching Treatment of Wet AMD and DME With Anti-VEGF Agents.” American Journal of Managed Care, 23 Feb. 2022, https://www.ajmc.com/view/approaching-treatment-of-wetamd-and-dme-with-anti-vegf-agents.

15. Kenney, Jim, et al. “Impact of Therapy Delays in Wet AMD and DME.” American Journal of Managed Care. 9 March 2022, https://www. ajmc.com/view/impact-of-therapy-delays-in-wet-amd-and-dme.

REDEFINE THEIR STORYLINE

ZUMA-7 is a phase 3, randomized open-label, multicenter study of YESCARTA single-infusion therapy vs salvage chemotherapy +/- HDT+ASCT, a current standard therapy, in 359 adult patients with relapsed or refractory large B-cell lymphoma (R/R LBCL).1,3 Patients were randomized 1:1 to YESCARTA (N=180) and standard therapy (N=179) and stratified by response to 1L therapy and 2L age-adjusted IPI.1 Two recipients of nonconformal product are included in the YESCARTA arm for the efficacy analysis.1 The primary endpoint was event-free survival (EFS).1* The median follow-up time for the primary analysis was 19.2 months.4‡

In the ZUMA-7 trial, safety was evaluated in 168 patients with primary refractory or first relapse of LBCL treated with YESCARTA1

ZUMA-7 safety data were consistent with previous YESCARTA ≥3L LBCL clinical trial data and real-world experience3,5-7

• No new safety signals were identified

• 7% of patients receiving YESCARTA experienced Grade ≥3 CRS, and 25% experienced Grade ≥3 NTs1

RECOMMENDED BY Axicabtagene ciloleucel (YESCARTA) is the FIRST CAR T with a Category 1 recommendation from NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for treatment of 2L DLBCL patients with primary refractory or relapsed disease within 12 months.8

•

The National Comprehensive Cancer Network® (NCCN®) makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

*EFS is defined as the time from randomization to the earliest date of disease progression or relapse, best response of stable disease up to and including the day 150 assessment, commencement of new lymphoma therapy, or death from any cause. Response was assessed by an independent review committee, per the International Working Group Lugano classification (Cheson 2014).1

†Standard-care chemotherapy could include 2 to 3 cycles of R-ICE, R-GDP, R-ESHAP, R-DHAP, or R-DHAX followed by high-dose chemotherapy and autologous stem cell transplant in patients with disease response.3

‡YESCARTA mEFS 8.3 months (95% CI, 4.5-15.8) vs standard therapy mEFS 2.0 months (95% CI, 1.6-2.8) (KM estimate).1

1L=first line; 2L=second line; 3L=third line; ASCT=autologous stem cell transplant; CAR T=chimeric antigen receptor T cell; CI=confidence interval; CRS=cytokine release syndrome; HDT=highdose therapy; HR=hazard ratio; IPI=International Prognostic Index; KM=Kaplan-Meier; mEFS=median event-free survival; NT=neurologic toxicity; R-DHAP=rituximab, dexamethasone, high-dose cytarabine, cisplatin; R-DHAX=rituximab, dexamethasone, high-dose cytarabine, oxaliplatin; R-ESHAP=rituximab, etoposide, methylprednisolone, high-dose cytarabine, cisplatin; R-GDP=rituximab, gemcitabine, dexamethasone, cisplatin; R-ICE=rituximab, ifosfamide, carboplatin, etoposide.

INDICATION

YESCARTA® is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

• Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.

Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

• Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Do not administer YESCARTA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.

• Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment

with YESCARTA. Provide supportive care and/or corticosteroids as needed.

• YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.

CYTOKINE RELEASE SYNDROME (CRS)

CRS, including fatal or life-threatening reactions, occurred. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL), including ≥ Grade 3 in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including ≥ Grade 3 in 9%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. For patients with LBCL in ZUMA-1, the median time to onset of CRS was 2 days following infusion (range: 1-12 days) and the median duration was 7 days (range: 2-58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1-10 days) and the median duration was 7 days (range: 2-43 days). CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including ≥ Grade 3 in 8%. Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and median duration was 6 days (range: 1-27 days) for patients with iNHL.

IN RISK OF EFS* EVENTS WITH YESCARTA® vs STANDARD THERAPY2†

0.398 (95% CI, 0.31-0.51) (P<0.0001)

The tick marks represent censored

of blinded central

who did not meet the event

events and censoring times were determined on the

IMPORTANT SAFETY INFORMATION

CYTOKINE RELEASE SYNDROME (continued)

Key manifestations of CRS (≥ 10%) in all patients combined included fever (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events, CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1-8 days) and the median duration of CRS was 7 days (range: 2-16 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Thirty-one of the 39 patients (79%) developed CRS and were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing ≥ Grade 3 CRS. The median time to onset of CRS was 5 days (range: 1-15 days) and the median duration of CRS was 4 days (range: 1-10 days). Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities.

Please see additional Important Safety Information and Brief Summary of full Prescribing Information on following pages, including BOXED WARNING

Ensure that 2 doses of tocilizumab are available prior to YESCARTA infusion. Monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES

Neurologic toxicities (including immune effector cell-associated neurotoxicity syndrome) that were fatal or life-threatening occurred. Neurologic toxicities occurred in 78% (330/422) of patients with NHL receiving YESCARTA, including ≥ Grade 3 in 25%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including ≥ Grade 3 in 31% and in 74% (124/168) of patients in ZUMA-7 including ≥ Grade 3 in 25%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range: 1-133 days) and median duration was 15 days in patients with LBCL in ZUMA-7. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including ≥ Grade 3 in 21%.

median time to onset was 6 days (range: 1-79 days)

the median duration was 16 days. Ninety-eight percent

all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within

first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of infusion for 87% of affected patients with LBCL and 74% of affected patients with iNHL.

NEUROLOGIC TOXICITIES(continued)

The most common neurologic toxicities (≥ 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of those patients, 85% (33/39) developed neurologic toxicities; 8% (3/39) developed Grade 3, and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurologic toxicities was 6 days (range: 1-274 days) with a median duration of 12 days (range: 1-107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset and decrease the duration of CRS.

Monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS

Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program called the YESCARTA and TECARTUS REMS Program which requires that: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer YESCARTA are trained about the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS

Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.

SERIOUS INFECTIONS

Severe or life-threatening infections occurred. Infections (all grades) occurred in 45% of patients with NHL. ≥ Grade 3 infections occurred in 17% of patients, including ≥ Grade 3 infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, and fungal infections in 1%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 36% of patients with NHL and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broadspectrum antibiotics, fluids, and other supportive care as medically indicated.

In immunosuppressed patients, including those who have received YESCARTA, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive

YESCARTA,

multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with drugs directed against B cells, including YESCARTA. Perform screening for HBV, HCV, and HIV and management in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion.

≥ Grade 3 cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA

B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia was reported as an adverse reaction in 14% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES

Secondary malignancies may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS

The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting.

Please see additional Important Safety Information on previous page and Brief Summary of full Prescribing Information on following pages, including BOXED WARNING.

References: 1. YESCARTA® (axicabtagene ciloleucel). Prescribing information. Kite Pharma, Inc; 2022. 2. Data on file [1]. Kite Pharma, Inc; 2021. 3. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med 2022;386(7):640-654. 4. Data on file [2]. Kite Pharma, Inc; 2021. 5. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol 2019;20(1):31-42. 6. Nastoupil LJ, Jain MD, Feng L, et al. Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2020;38(27):3119-3128. 7. Sanderson R, Benjamin R, Patten P, et al. Axi-cel for large B-cell lymphoma: real-world outcomes from a prospective UK cohort. Poster presented at: European Society for Blood and Marrow Transplantation (EBMT) Virtual Annual Meeting; August 29-September 1, 2020. 8. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.2.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 21, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org.

Pharma, Inc. GILEAD

of Gilead Sciences, Inc.

other trademarks referenced herein are the property of their respective owners.

2022 Kite Pharma, Inc. All rights reserved. | US-YESP-0130 04/2022

YESCARTA® (axicabtagene ciloleucel) suspension for intravenous infusion

Brief Summary of full Prescribing Information. See full Prescribing Information. Rx Only.

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

• Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Do not administer YESCARTA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.

• Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids as needed.

• YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.

INDICATIONS AND USAGE

YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

• Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.

• Adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.

DOSAGE AND ADMINISTRATION

For autologous use only. For intravenous use only.

Dose: Each single infusion bag of YESCARTA contains a suspension of chimeric antigen receptor (CAR)-positive T cells in approximately 68 mL. The target dose is 2 × 106 CAR-positive viable T cells per kg body weight, with a maximum of 2 × 108 CAR-positive viable T cells.

Administration: YESCARTA is for autologous use only. The patient’s identity must match the patient identifiers on the YESCARTA cassette and infusion bag. Do not infuse YESCARTA if the information on the patient-specific label does not match the intended patient.

Preparing Patient for YESCARTA Infusion : Confirm availability of YESCARTA prior to starting the lymphodepleting regimen. Pre-treatment : Administer a lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m2 intravenously and fludarabine 30 mg/m2 intravenously on the fifth, fourth, and third day before infusion of YESCARTA. Premedication : Administer acetaminophen 650 mg PO and diphenhydramine 12.5 mg intravenously or PO approximately 1 hour before YESCARTA infusion. Consider the use of prophylactic corticosteroid in patients after weighing the potential benefits and risks.

Preparation of YESCARTA for Infusion : Coordinate the timing of YESCARTA thaw and infusion. Confirm the infusion time in advance, and adjust the start time of YESCARTA thaw such that it will be available for infusion when the patient is ready. Confirm patient identity: Prior to YESCARTA preparation, match the patient’s identity with the patient identifiers on the YESCARTA cassette. Do not remove the YESCARTA product bag from the cassette if the information on the patient-specific label does not match the intended patient. Once patient identification is confirmed, remove the YESCARTA product bag from the cassette and check that the patient information on the cassette label matches the bag label. Inspect the product bag for any breaches of container integrity such as breaks or cracks before thawing. If the bag is compromised, follow the local guidelines (or call Kite at 1-844-454-KITE). Place the infusion bag inside a second sterile bag per local guidelines. Thaw YESCARTA at approximately 37°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. Gently mix the contents of the bag to disperse clumps of cellular material. If visible cell clumps remain continue to gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not wash, spin down, and/or re-suspend YESCARTA in new medium prior to infusion. Once thawed, YESCARTA may be stored at room temperature (20°C to 25°C) for up to 3 hours.

Administration : For autologous use only. Ensure that tocilizumab and emergency equipment are available prior to infusion and during the recovery period. Do NOT use a leukodepleting filter. Central venous access is recommended for the infusion of YESCARTA. Confirm the patient’s identity matches the patient identifiers on the YESCARTA product bag. Prime the tubing with normal saline prior to infusion. Infuse the entire contents of the YESCARTA bag within 30 minutes by either gravity or a peristaltic pump. YESCARTA is stable at room temperature for up to 3 hours after thaw. Gently agitate the product bag during YESCARTA infusion to prevent cell clumping. After the entire content of the product bag is infused, rinse the tubing with normal saline at the same infusion rate to ensure all product is delivered. YESCARTA contains human blood cells that are genetically modified with replication incompetent retroviral vector. Follow universal precautions and local biosafety guidelines for handling and disposal to avoid potential transmission of infectious diseases.

Monitoring : Administer YESCARTA at a certified healthcare facility. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS and neurologic toxicities. Instruct patients to remain within proximity of the certified healthcare facility for at least 4 weeks following infusion.

Management of Severe Adverse Reactions

Cytokine Release Syndrome : Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in CRS Grading and Management Guidance.

Patients who experience Grade 2 or higher CRS (e.g., hypotension not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous cardiac telemetry and pulse oximetry. For patients experiencing severe CRS, consider performing an echocardiogram to assess cardiac function. For severe or life-threatening CRS, consider intensive-care supportive therapy.

CRS Grading a and Management Guidance

Grade 1: Symptoms require symptomatic treatment only (e.g., fever, nausea, fatigue, headache, myalgia, malaise).

• Tocilizumab: If symptoms (e.g., fever) not improving after 24 hours, consider managing as Grade 2.

• Corticosteroids: If not improving after 3 days, administer one dose of dexamethasone 10 mg intravenously.

Grade 2: Symptoms require and respond to moderate intervention. Oxygen requirement less than 40% FiO2 or hypotension responsive to fluids or low-dose of one vasopressor or Grade 2 organ toxicity.b

• Tocilizumab: Administer tocilizumabc 8 mg/kg intravenously over 1 hour (not to exceed 800 mg). If no clinical improvement in the signs and symptoms of CRS after the first dose, repeat tocilizumab every 8 hours as needed. Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses. If improving, discontinue tocilizumab.

• Corticosteroids: Administer dexamethasone 10 mg intravenously once daily. If improving, manage as Grade 1 above and continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate. If not improving, manage as appropriate grade below.

Grade 3: Symptoms require and respond to aggressive intervention. Oxygen requirement greater than or equal to 40% FiO2 or hypotension requiring high-dose or multiple vasopressors or Grade 3 organ toxicity or Grade 4 transaminitis.

• Tocilizumab: Per Grade 2. If improving, manage as appropriate grade above.

• Corticosteroids: Dexamethasone 10 mg intravenously three times a day. If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate. If not improving, manage as Grade 4.

Grade 4: Life-threatening symptoms. Requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD) or Grade 4 organ toxicity (excluding transaminitis).

• Tocilizumab: Per Grade 2. If improving, manage as appropriate grade above.

• Corticosteroids: Administer methylprednisolone 1000 mg intravenously once per day for 3 days. If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate. If not improving, consider methylprednisolone 1000 mg 2-3 times a day or alternate therapy.d

a. Lee et al. 2014. b. Refer to Neurologic Toxicity/ICANS Grading and Management Guidance. c. Refer to tocilizumab Prescribing Information for details. d. Alternate therapy includes (but is not limited to): anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG and ATG.

Neurologic Toxicity : Monitor patients for signs and symptoms of neurologic toxicity/ immune effector cell-associated neurotoxicity syndrome (ICANS) (see Neurologic Toxicity/ICANS Grading and Management Guidance). Rule out other causes of neurologic symptoms. Patients who experience Grade 2 or higher neurologic toxicities/ ICANS should be monitored with continuous cardiac telemetry and pulse oximetry. Provide intensive-care supportive therapy for severe or life-threatening neurologic toxicities. Consider levetiracetam for seizure prophylaxis for any grade of neurologic toxicities.

Neurologic Toxicity/ICANS Gradinga and Management Guidance

Grade 1

• Concurrent CRS: Administer tocilizumab per CRS Grading and Management Guidance for management of Grade 1 CRS. In addition, administer one dose of dexamethasone 10 mg intravenously. If not improving after 2 days, repeat dexamethasone 10 mg intravenously.

• No Concurrent CRS: Administer one dose of dexamethasone 10 mg intravenously. If not improving after 2 days, repeat dexamethasone 10 mg intravenously.

• Concurrent and No Concurrent CRS: Consider levetiracetam for seizure prophylaxis.

Grade 2

• Concurrent CRS: Administer tocilizumab per CRS Grading and Management Guidance for management of Grade 2 CRS. In addition, administer dexamethasone 10 mg intravenously four times a day. If improving, continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate. If not improving, manage as appropriate grade below.

• No Concurrent CRS: Administer dexamethasone 10 mg intravenously four times a day. If improving, continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate. If not improving, manage as appropriate grade below.

• Concurrent or No Concurrent CRS: Consider levetiracetam for seizure prophylaxis.

Grade 3

• Concurrent CRS: Administer tocilizumab per CRS Grading and Management Guidance for management of Grade 2 CRS. In addition, administer methylprednisolone 1000 mg intravenously once daily. If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate. If not improving, manage as Grade 4.

• No Concurrent CRS: Administer methylprednisolone 1000 mg intravenously once daily. If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate. If not improving, manage as Grade 4.

• Concurrent and No Concurrent CRS: Consider levetiracetam for seizure prophylaxis.

Grade 4

• Concurrent CRS: Administer tocilizumab per CRS Grading and Management Guidance for management of Grade 2 CRS. In addition, administer methylprednisolone 1000 mg intravenously twice per day. If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate. If not improving, consider 1000 mg of methylprednisolone intravenously 3 times a day or alternate therapy.b

• No Concurrent CRS: Administer methylprednisolone 1000 mg intravenously twice per day. If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate. If not improving, consider 1000 mg of methylprednisolone intravenously 3 times a day or alternate therapy.b

• Concurrent and No Concurrent CRS: Consider levetiracetam for seizure prophylaxis.

a. Severity based on Common Terminology Criteria for Adverse Events. b. Alternate therapy includes (but is not limited to): anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG and ATG.

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS

Cytokine Release Syndrome: CRS, including fatal or life-threatening reactions, occurred following treatment with YESCARTA. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL) receiving YESCARTA, including ≥ Grade 3 (Lee grading system1) CRS in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including ≥ Grade 3 CRS in 9%. Among patients with LBCL who died after receiving YESCARTA, four had ongoing CRS events at the time of death. For patients with LBCL in ZUMA-1, the median time to onset of CRS was 2 days following infusion (range: 1 to 12 days) and the median duration of CRS was 7 days (range: 2 to 58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1 to 10 days) and the median duration was 7 days (range: 2 to 43 days).

Key manifestations of CRS (≥ 10%) in all patients combined included fever (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include, cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in two subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events (see CRS Grading and Management Guidance), CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1 to 8 days) and the median duration of CRS was 7 days (range: 2 to 16 days).

Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Thirty-one of the 39 patients (79%) developed CRS at which point the patients were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing Grade 3 or higher CRS. The median time to onset of CRS was 5 days (range: 1 to 15 days) and the median duration of CRS was 4 days (range: 1 to 10 days). Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities. Ensure that 2 doses of tocilizumab are available prior to infusion of YESCARTA. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

Neurologic Toxicities: Neurologic toxicities (including ICANS) that were fatal or life-threatening occurred following treatment with YESCARTA. Neurologic toxicities occurred in 78% (330/422) of patients with NHL receiving YESCARTA, including ≥ Grade 3 cases in 25%.

Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including ≥ Grade 3 cases in 31% and in 74% (124/168) of patients in ZUMA-7 including ≥ Grade 3 cases in 25%. The median time to onset was 4 days (range: 1 to 43 days) and the median duration was 17 days in patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range: 1 to 133 days) and median duration was 15 days in patients with LBCL in ZUMA-7. Ninety-eight percent of all neurologic toxicities in patients with LBCL occurred within the first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of YESCARTA infusion in 87% of affected patients with LBCL.

The most common neurologic toxicities (≥ 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred with YESCARTA. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred in patients treated with YESCARTA.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in two subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities (see Neurologic Toxicity/ICANS Grading and Management Guidance), neurologic toxicities occurred in 78% (32/41) and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1 to 93 days) with a median duration of 8 days (range: 1 to 144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of these 39 patients, 85% (33/39) developed neurologic toxicities; 8% (3/39) developed Grade 3 and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurological toxicities was 6 days (range: 1 to 274 days) with a median duration of 12 days (range: 1 to 107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset and decrease the duration of CRS.

Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.

YESCARTA and TECARTUS REMS Program: Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program. The required components of the YESCARTA and TECARTUS REMS Program are:

• Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS.

• Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer YESCARTA are trained about the management of CRS and neurologic toxicities.

Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

Hypersensitivity Reactions: Allergic reactions may occur with the infusion of YESCARTA. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in YESCARTA.

Serious Infections: Severe or life-threatening infections occurred in patients after YESCARTA infusion. Infections (all grades) occurred in 45% of patients with NHL. Grade 3 or higher infections occurred in 17% of patients, including Grade 3 or higher infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, and fungal infections in 1%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after YESCARTA infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 36% of patients with NHL after YESCARTA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated. In immunosuppressed patients, including those who have received YESCARTA, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B Virus Reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with drugs directed against B cells, including YESCARTA. Perform screening for HBV, HCV, and HIV and management in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. Grade 3 or higher cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after YESCARTA infusion.

Hypogammaglobulinemia: B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with YESCARTA. Hypogammaglobulinemia was reported as an adverse reaction in 14% of all patients with NHL. Monitor immunoglobulin levels after treatment with YESCARTA and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement.

The safety of immunization with live viral vaccines during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA treatment, and until immune recovery following treatment with YESCARTA.

Secondary Malignancies: Patients treated with YESCARTA may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including altered mental status or seizures, patients receiving YESCARTA are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients to refrain from driving and engaging in hazardous

occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS: The following adverse reactions are described elsewhere in the labeling: Cytokine Release Syndrome, Neurologic Toxicities, Hypersensitivity Reactions, Serious Infections, Prolonged Cytopenias, Hypogammaglobulinemia.

Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Relapsed or Refractory Large B-cell Lymphoma

ZUMA-7: The safety of YESCARTA was evaluated in ZUMA-7, a randomized, open-label, multicenter study in which patients with primary refractory LBCL or first relapse of LBCL received YESCARTA (N = 168) or standard therapy (N = 168). Patients had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous HSCT. The trial excluded patients who were not deemed candidates for transplant or who had a history of central nervous system (CNS) disorders (such as seizures or cerebrovascular ischemia), serious or uncontrolled infection, or autoimmune disease requiring systemic immunosuppression. The study required ANC ≥ 1000/mm3, platelet count ≥ 75,000/mm3, creatinine clearance ≥ 60 mL/min, AST/ALT ≤ 2.5 x ULN, and total bilirubin ≤ 1.5 mg/dL.

The median age of the YESCARTA-treated safety population was 59 years (range: 21 to 80 years); 62% were male. The baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 54% of patients and 1 in 46%.

The most common non-laboratory adverse reactions to YESCARTA (incidence ≥ 20%) included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting. Serious adverse reactions occurred in 50% of patients. The most common serious adverse reactions (> 5%) included CRS, fever, encephalopathy, hypotension, infection with unspecified pathogen, and pneumonia. Fatal adverse reactions occurred in 2% of patients.

The most common (≥ 10%) Grade 3 or higher non-laboratory adverse reactions included febrile neutropenia, encephalopathy, and hypotension. Sixty-seven percent (112/168) of patients received tocilizumab after infusion of YESCARTA. Adverse Reactions in ≥ 10% of Patients Treated with YESCARTA in ZUMA-7

Adverse Reaction

YESCARTA N = 168

Any Grade (%) Grade 3 or Higher (%) Febrile neutropenia3131

Adverse Reaction

Renal and Urinary Disorders

Respiratory, Thoracic and Mediastinal Disorders

Skin and Subcutaneous Tissue Disorders

Vascular Disorders

The following events

insufficiency

Hypoxia

Any Grade

CRS: coagulopathy, tachycardia, arrhythmia,

chills, edema, decreased appetite, musculoskeletal

tremor, dizziness, renal insufficiency, cough, hypoxia, dyspnea, pleural effusion, respiratory

hypotension, and hypertension.

Tachycardia includes tachycardia, sinus tachycardia.

Arrhythmia includes arrhythmia, atrial fibrillation, bradycardia, electrocardiogram QT prolonged, extrasystoles, sinus bradycardia, supraventricular extrasystoles, supraventricular tachycardia, ventricular extrasystoles, ventricular tachycardia.

Diarrhea includes diarrhea, colitis.

d. Abdominal pain includes abdominal pain, abdominal discomfort, abdominal pain lower, abdominal pain upper, dyspepsia.

Fever includes pyrexia.

Fatigue includes fatigue, asthenia, malaise.

Edema includes edema, face edema, fluid overload, generalized edema, hypervolemia, localized edema, edema genital, edema peripheral, periorbital edema, peripheral swelling, pulmonary edema.

h. Musculoskeletal pain includes musculoskeletal pain, arthralgia, arthritis, back pain, bone pain, flank pain, groin pain, musculoskeletal chest pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity.

i. Motor dysfunction includes muscle contractions involuntary, muscle spasms, muscle twitching, muscular weakness.

j. Encephalopathy includes encephalopathy, altered state of consciousness, amnesia, apraxia, bradyphrenia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dysarthria, dysgraphia, dyspraxia, lethargy, loss of consciousness, memory impairment, mental impairment, mental status changes, metabolic encephalopathy, slow speech, somnolence, toxic encephalopathy.

k. Headache includes headache and tension headache.

l. Dizziness includes dizziness, dizziness postural, presyncope, syncope, vertigo.

m. Neuropathy peripheral includes hypoesthesia, lumbar radiculopathy, neuropathy peripheral, paresthesia, peroneal nerve palsy, sciatica.

n. Insomnia includes insomnia and sleep deficit.

o. Delirium includes delirium, agitation, delusion, disorientation, hallucination, irritability, restlessness.

p. Renal insufficiency includes acute kidney injury, blood creatinine increased, chronic kidney disease.

q. Cough includes cough, productive cough, upper-airway cough syndrome.

r. Rash includes rash, dermatitis, dermatitis allergic, dermatitis bullous, drug eruption, erythema, pruritus, rash macular, rash maculo-papular, rash pruritic, urticaria.

Hypotension includes hypotension, capillary leak syndrome, orthostatic hypotension.

Cardiac Disorders Tachycardia a Arrhythmia b 43 14 2 3 Gastrointestinal Disorders Diarrhea c Nausea Abdominal pain d Constipation Vomiting Dry mouth

General Disorders and Administration Site Conditions

Fever e Fatigue f Chills Edema g

40 20 20 20 10

93 52 28 23

3 2 4 0 0 0

Other clinically important adverse reactions that occurred in less than 10% of patients treated with YESCARTA include the following: blood and lymphatic system disorders: coagulopathy (9%), cardiac disorders: cardiac failure (1%), eye disorders: visual impairment (7%), infections and infestations: pneumonia (8%), sepsis (4%), nervous system disorders: ataxia (6%), seizure (3%), myoclonus (2%), facial paralysis (2%), paresis (2%), respiratory, thoracic and mediastinal disorders: dyspnea (8%), pleural effusion (6%), respiratory failure (2%), vascular disorders: hypertension (9%), thrombosis (7%).

9 7 1

Immune System Disorders Cytokine release syndrome Hypogammaglobulinemia 92 11 7 0

Infections and Infestations Infections with pathogen unspecified Viral infections Bacterial infections Fungal infections

25 15 10 10

Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients in ZUMA-7 Following Treatment with YESCARTA1 (N = 168): Leukocyte decrease: 95%, Neutrophil decrease: 94%, Lymphocyte decrease: 94%, Hemoglobin decrease: 40%, Platelet decrease: 26%, Sodium decrease: 12%, Glucose increase: 11%.

8 4 5 1

Metabolism and Nutrition Disorders Decreased appetite 24 4

Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain h Motor dysfunction i 40 15 1 4

Nervous System Disorders Encephalopathy

1Baseline lab values were assessed prior to lymphodepleting chemotherapy. ZUMA-1: The safety of YESCARTA was evaluated in ZUMA-1, a study in which 108 patients with relapsed or refractory LBCL received CD19-positive CAR T cells based on a recommended dose which was weight-based. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression were ineligible. The median age of the study population was 58 years (range: 23 to 76 years); 68% were male. The baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 43% of patients and 1 in 57% of patients.

The most common adverse reactions (incidence ≥ 20%) included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias. Serious adverse reactions occurred in 52% of patients. The most common serious adverse reactions (> 2%) included encephalopathy, fever, lung infection, febrile neutropenia, cardiac arrhythmia, cardiac failure, urinary tract infection, renal insufficiency, aphasia, cardiac arrest, Clostridium difficile infection, delirium, hypotension, and hypoxia.

The most common (≥ 10%) Grade 3 or higher reactions included febrile neutropenia, fever, CRS, encephalopathy, infections with pathogen unspecified, hypotension, hypoxia, and lung infections.

Forty-five percent (49/108) of patients received tocilizumab after infusion of YESCARTA.

Adverse Reactions Observed in ≥ 10% of Patients Treated with YESCARTA in ZUMA-1 (N = 108)

Adverse Reaction

Any Grade (%) Grade 3 or Higher (%)

Blood and Lymphatic System Disorders Febrile neutropenia 3431

Cardiac Disorders Tachycardia a Arrhythmia b 57 23 2 7

Gastrointestinal Disorders Diarrhea Nausea Vomiting Constipation Abdominal pain c Dry mouth

General Disorders and Administration Site Conditions

Fever d Fatigue e Chills Edema f

38 34 26 23 14 11

86 46 40 19

Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients in ZUMA-1

Following Treatment with YESCARTA1 (N = 108): Lymphocyte decrease: 96%, Leukocyte decrease: 96%, Neutrophil decrease: 92%, Hemoglobin decrease: 60%, Platelet decrease: 56%, Phosphate decrease: 52%, Sodium decrease: 19%, Albumin decrease: 19%, Direct bilirubin increased: 14%, Uric acid increased: 13%, Potassium decrease: 11%.

1Baseline lab values were assessed prior to lymphodepleting chemotherapy.

4 0 1 0 1 0

16 3 0 1

Immune System Disorders Cytokine release syndrome Hypogammaglobulinemia g 94 15 13 0

Infections and Infestations

Infections with pathogen unspecified Viral infections Bacterial infections

Investigations Decreased appetite Weight decreased Dehydration

Musculoskeletal and Connective Tissue Disorders Motor dysfunction h Pain in extremity i Back pain Muscle pain Arthralgia

Nervous System Disorders Encephalopathy Headache k Tremor Dizziness l Aphasia m

26 16 13

44 16 11

19 17 15 14 10

57 45 31 21 18

16 4 9

The safety and efficacy of YESCARTA was evaluated in two subsequent cohorts of LBCL patients. The first subsequent, open label, safety management cohort in ZUMA-1 evaluated the safety and efficacy of YESCARTA with the use of tocilizumab and/or corticosteroid and prophylactic levetiracetam (750 mg PO or IV twice daily) for Grade 1 CRS or neurologic events. A total of 46 patients with relapsed or refractory LBCL were enrolled and 41 patients were treated with YESCARTA. Of the remaining 5 patients who were not treated, 2 patients died prior to receiving YESCARTA and 3 patients were ineligible due to disease progression. Twenty-eight patients (68%) treated with YESCARTA received bridging therapy between leukapheresis and lymphodepleting chemotherapy. Thirty-two patients (78%) treated with YESCARTA received tocilizumab and/or corticosteroid for CRS and/or neurologic events. Fifteen of 36 with Grade 1 CRS and 21 of 24 patients with Grade 2 CRS received tocilizumab and/or corticosteroids. Among patients who received treatment for Grade 1 or Grade 2 CRS, most patients (13 of 15 and 19 of 21 patients, respectively) received both tocilizumab and corticosteroids. Most patients received 1 or 2 doses of each drug. Ten of 27 patients with Grade 1 and 7 of 15 patients with Grade 2 neurologic events received corticosteroids alone or in combination with tocilizumab.

2 0 3

The second subsequent, open label, safety management cohort in ZUMA-1 evaluated the safety and efficacy of YESCARTA with the use of prophylactic corticosteroids (oral dexamethasone 10 mg once daily for 3 days, starting prior to YESCARTA infusion on Day 0) and prophylactic levetiracetam (750 mg PO or IV).

1 2 1 1 0

29 1 2 1 6

Psychiatric Disorders Delirium n 17 6

Respiratory, Thoracic and Mediastinal Disorders Hypoxia o Cough p Dyspnea q Pleural effusion

Renal and Urinary Disorders Renal insufficiency

Vascular Disorders Hypotension

Hypertension Thrombosis

32 30 19 13

Immunogenicity: YESCARTA has the potential to induce anti-product antibodies. The immunogenicity of YESCARTA has been evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of binding antibodies against FMC63, the originating antibody of the anti-CD19 CAR. Eleven patients (4%) tested positive for pre-dose anti-FMC63 antibodies at baseline in ZUMA-7 and ZUMA-1, and one patient (1%) who had a negative test result at baseline had a positive test result post administration of YESCARTA in the screening ELISA in ZUMA-7. Results of a confirmatory cell-based assay, leveraging a properly folded and expressed extracellular portion of the CAR (ScFv, hinge and linker) demonstrated that all patients treated with YESCARTA that had a positive result in the screening ELISA were antibody negative at all time points tested. There is no evidence that the kinetics of initial expansion and persistence of YESCARTA, or the safety or effectiveness of YESCARTA, was altered in these patients.

11 0 3 2

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of YESCARTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous System Disorders : Spinal cord edema, myelitis, quadriplegia, and dysphagia.

5

15 10

following events

renal insufficiency, and hypotension.

Tachycardia includes tachycardia, sinus tachycardia.

15

tachycardia, arrhythmia, fever, chills,

Arrhythmia includes arrhythmia, atrial fibrillation, atrial flutter, atrioventricular block, bundle branch block

electrocardiogram

prolonged,

edema.

USE IN SPECIFIC POPULATIONS

Pregnancy: Risk Summary: There are no available data with YESCARTA use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with YESCARTA to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known if YESCARTA has the potential to be transferred to the fetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia. Therefore, YESCARTA is not recommended for women who are pregnant, and pregnancy after YESCARTA infusion should be discussed with the treating physician. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively.

Lactation: Risk Summary: There is no information regarding the presence of YESCARTA in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for YESCARTA and any potential adverse effects on the breastfed infant from YESCARTA or from the underlying maternal condition.

Females and Males of Reproductive Potential: Pregnancy Testing: Pregnancy status of females with reproductive potential should be verified. Sexually active females of reproductive potential should have a pregnancy test prior to starting treatment with YESCARTA. Contraception: See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy. There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with YESCARTA. Infertility: There are no data on the effect of YESCARTA on fertility.

Pediatric Use: The safety and efficacy of YESCARTA have not been established in pediatric patients.

clinically important adverse reactions

occurred

less than

of patients treated with YESCARTA include the following: blood and lymphatic system disorders: coagulopathy (2%), cardiac disorders: cardiac failure (6%), cardiac arrest (4%), immune system disorders : hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) (1%), hypersensitivity (1%), infections and infestations disorders: fungal infections (5%), nervous system disorders: ataxia (6%), seizure (4%), dyscalculia (2%), myoclonus (2%), respiratory, thoracic and mediastinal disorders: pulmonary edema (9%), skin and subcutaneous tissue disorders: rash (9%), vascular disorders: capillary leak syndrome (3%).

Geriatric Use: Of the 422 patients with NHL who received YESCARTA in clinical trials, 127 patients (30%) were 65 years of age and older. No clinically important differences in safety or effectiveness were observed between patients aged 65 years and older and younger patients.

Manufactured by, Packed by, Distributed by: Kite Pharma, Inc., Santa Monica, CA 90404

US License No 2064

YESCARTA and TECARTUS are trademarks of Kite Pharma, Inc.

Hereditary Transthyretin Amyloidosis (hATTR):

Management Update

Data integration of pharmacy and medical benefit claims will allow payers to determine the total cost of care and promote steps that will facilitate treatment decisions.

The nomenclature has changed with familial forms of transthyretin amyloidosis (ATTR). Previously known as familial amyloid polyneuropathy (FAP) or familial amyloid cardiomyopathy (FAC), it is now called hereditary ATTR (hATTR).1 hATTR is a rare, heterogenous disease resulting from a deposition of soluble and insoluble amyloid fibrils or aggregates in the beta sheets of various organs, including peripheral nerves, heart, kidney, and ocular vitreous.2, 3 Amyloid deposits result when autosomal-dominant mutation in the transthyretin (TTR) gene leads to TTR protein misfolds. The wild-type transthyretin-mediated amyloidosis (ATTRwt), previously known as senile cardiac amyloidosis, is caused by an instability of the natural TTR protein, which is predominantly made in the liver and transports thyroxine and retinol (vitamin A) throughout the body.2

Simone Ndujiuba, Pharm.D., BCOP Director,

Due to signs and symptoms that overlap with a variety of other conditions, hATTR is not readily diagnosed, which makes it difficult to quantify the number of patients currently living with hATTR. Based on current data, it is estimated that 10,000 to 15,000 people live with hATTR in the U.S., with approximately 50,000 individuals with varying phenotypic presentation of the disease worldwide.4. 5 Over the years, advancements in imaging and increased genetic testing have enhanced timely diagnosis. As a result, the number of patients diagnosed with hATTR is projected to increase.6

More than 130 TTR variants have been identified, many with regional clusters around the world. The V30M mutation accounts for an estimated 50% of the world’s variants and is the predominant form in endemic regions. The ATTR V30M is found in parts of Europe and Japan; ATTR V122I is identified in 3-4% of African Americans; and ATTR T60A, the most identified variant in the United Kingdom, has higher rates in people of Irish descent.6

hATTR primarily presents as a somatic and autonomic nervous system impairment, polyneuropathy (hATTR-PN) seen in early adulthood, and cardiomyopathy (hATTR-CM) seen later in life. If the TTR gene sequence does not have a mutation, it is designated as a wild-type (ATTRwt) and leads to cardiomyopathy. Most patients show signs of a combination of peripheral nervous system and cardiac impairment. By their second decade of life, most patients present with initial neurologic symptoms. As patients near their third and fifth decades, hATTR-PN progresses with signs and symptoms that include sensorymotor polyneuropathy with autonomic involvement, postural hypotension, and bladder and erectile dysfunction, to name a few. hATTR-CM commonly occurs by age 60 or older, with a greater incidence in men than women.4 Hypertrophic cardiomyopathy, even if usually latent, is identifiable in at least 50% of the patients.2 Patients with variants such as Val122Ile, Leu111Met, Ile68Leu, and ATTRwt develop cardiac impairment with preserved ejection

fraction. Clinical presentation includes unexplained left ventricular hypertrophy, which results in restrictive cardiomyopathy, heart failure, atrial fibrillation, and conduction abnormalities. Predominant cardiomyopathy with heart failure routinely shows preserved ejection in men older than 60.6 The estimated survival for patients with neurologic dominant hATTR is 5 to 15 years; this estimate is reduced 2.5 to 4 years for patients with cardiac-dominant disease. Overall, if hATTR is left untreated, death may occur within 10 years.7

Treatment

The therapeutic goal for hATTR is reduction in symptom severity and establishment of a long-term treatment plan. In the 1990s, liver transplant to eliminate amyloid protein production was the preferred treatment of choice. However, transplant led to cardiovascular complications, which led to death in 22% of patients and a 20-year survival rate of 55.3%. With increased diagnosis and treatment advancements, therapeutic options have expanded.2 Currently, medication is indicated for treatment of polyneuropathy or cardiomyopathy but not for all types of hATTR. Reduction in cardiovascular mortality and cardiovascularrelated hospitalization is a key goal, so the FDA approval of two oral selective stabilizers of the TTR tetramer, Vyndaqel® (tafamidis meglumine) and Vyndamax™ (tafamidis), with indications for the treatment of the cardiomyopathy of wild-type or hATTR amyloidosis, will help to accomplish this goal.8-9 hATTR-PN parenteral therapy

The therapeutic goal for hATTR is reduction in symptom severity and establishment of a long-term treatment plan.

options that inhibit TTR hepatic production, such as Onpattro® (patisiran), Tegsedi® (inotersen), and Amvuttra™ (vutrisiran), have also been FDA-approved. Multiple agents are in development to target various stages of ATTR pathogenesis.2, 10-12

AMVUTTRA™ (vutrisiran)

In June 2022, the Food and Drug Administration (FDA) approved Amvuttra (vutrisiran) for polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Vutrisiran is supplied as a single-dose prefilled syringe administered by a healthcare professional once every three months (for four doses per year). In the HELIOS-A phase 3 study, vutrisiran (n=122) was compared to active therapy infusion (external placebo) patisiran (N=42).15 The primary end point was change from baseline in neuropathy impairment using the modified Neuropathy Impairment Score +7 (mNIS+7) versus external placebo at month 9. The study was an intention-to-treat, with patients receiving one or more doses of vutrisiran or placebo. At nine months, vutrisiran quickly attained a decrease in serum TTR level, demonstrating a significant improvement in multiple end points when evaluated against the external placebo. The primary end point was achieved: Vutrisiran significantly improved mNIS+7 versus external placebo (LS mean [±SE] change from baseline: −2.2±1.4 [vutrisiran]; +14.8±2.0 [placebo]; difference −17.0; p=3.5×10−12). Vutrisiran also significantly improved quality of life, gait speed, nutritional status, and disability compared to the external placebo. Vutrisiran was well tolerated with mild to moderate adverse effects and no drug discontinuation or death.13

Payment Management Strategies

In 2020, a retrospective trial analyzed claims data for newly diagnosed hATTR. The study determined that the annual mean total cost to treat each patient was $64,066.14 Inpatient care was the greatest expense ($34,461), with outpatient ($23,853) and pharmacy ($5,752) adding to overall expenditure. The highest utilization occurred during the first quarter post-diagnosis, then decreased in following quarters. Insurance type varied; preferred provider organization/point of service plans (65.9%) were most

utilized, followed by comprehensive (12.4%) and consumerdirected health plan/high-deductible health plans (11.4%).14

In a recent meeting of healthcare decision-makers, a group of payers discussed their role in supporting the identification, management, and consideration of medical and pharmacy benefits for patients with rare disease, particularly hATTR.15 The complexity of this disease and its intersection with other conditions creates gaps in payers’ ability to identify affected patients. With the breadth of complications associated with this rare disease, payers recognized the need for collaboration with case management, health plans, and health systems to create a patient-centered program.15 When medication coverage was addressed, payers agreed that identification of actionable mutations makes it easier to justify high-cost medications.15 In addition, test results help to determine if family members also require screening and early intervention. Ultimately, the payers preferred medications processed through the pharmacy benefit. Traditionally, pharmacy claims decrease drug cost variability. With medical claims, the risk for variable cost increases, especially as costs associated with specialists and centers of excellence come into play. Data integration of pharmacy and medical benefit claims will allow payers to determine the total cost of care and promote steps that will facilitate treatment decisions.15

Three phase 3 trials, one for vutrisiran in hATTR-CM and two for eplontersen on cardiomyopathy and polyneuropathy in hATTR, demonstrate continued treatment advancements for this rare disease.16

The complexity of this disease and its intersection with other conditions creates gaps in payers’ ability to identify affected patients.

1. Benson, M. D., et al. “Diagnosis and Screening of Patients with Hereditary Transthyretin Amyloidosis (hATTR): Current Strategies and Guidelines.” Therapeutics and Clinical Risk Management, 14 Aug. 2020, https://doi.org/10.2147/tcrm.s185677.

2. Luigetti, Marco, et al. “Diagnosis and Treatment of Hereditary Transthyretin Amyloidosis (hATTR) Polyneuropathy: Current Perspectives on Improving Patient Care.” Therapeutics and Clinical Risk Management, 21 Feb. 2020, https://doi.org/10.2147/tcrm. s219979.

3. Ruberg, Frederick L., and Matthew S. Maurer. “Expert Analysis and Opinion—Understanding Cardiac Amyloidosis.” American College of Cardiology, 14 Apr. 2021, https://www.acc.org/latest-in-cardiology/ articles/2021/04/14/17/11/understanding-cardiac-amyloidosis.

4. Gertz, Morie A. “Hereditary ATTR Amyloidosis: Burden of Illness and Diagnostic Challenges.” American Journal of Managed Care, Supplements and Featured Publications, 13 June 2017, https:// www.ajmc.com/view/hereditary-attr-amyloidosis-burden-of-illnessand-diagnostic-challenges-article.

5. Lovley, Andrew, et al. “Patient-reported burden of hereditary transthyretin amyloidosis on functioning and well-being.” Journal of Patient-Reported Outcomes, 7 Jan. 2021, https://doi.org/10.1186/ s41687-020-00273-y.

6. Obi, Chukwuemeka A., et al. “ATTR Epidemiology, Genetics, and Prognostic Factors.” Methodist DeBakey Cardiovascular Journal, 14 March 2022, https://doi.org/10.14797/mdcvj.1066.

7. Walker, Scot. “New Medications in the Treatment of Hereditary Transthyretin Amyloidosis,” Hospital Pharmacy, 4 June 2018, https://doi.org/10.1177/0018578718779757.

8. Vyndamax [package insert]. NY, NY; Pfizer; April 2020.

9. Vyndaqel [package insert]. NY, NY; Pfizer; April 2020.

10. Opattro [package insert]. Cambridge, MA; Alnylam; July 2022.

11. Tegsedi [package insert]. Waltham, MA; Akcea; May 2021.

12. Amvuttra [package insert]. Cambridge, MA; June 2022.

13. Gonzalez-Duarte, Alejandra, et al. “HELIOS-A: Results from the phase 3 study of vutrisiran in patients with hereditary transthyretinmediated amyloidosis with polyneuropathy.” Journal of the American College of Cardiology, March 2022, https://www.jacc.org/ doi/10.1016/S0735-1097%2822%2901293-1.

14. Reddy, Sheila R., et al. “The Clinical and Economic Burden of Newly Diagnosed Hereditary Transthyretin (ATTRv) Amyloidosis: A Retrospective Analysis of Claims Data.” Neurology and Therapy, U.S. National Library of Medicine, 25 May 2020, https://pubmed.ncbi. nlm.nih.gov/32451849/

15. “Rare Disease: Access, Reimbursement, and Disease Management A Stakeholder Interchange Report.” American Journal of Managed Care Supplements and Featured Publications, MJH Life Sciences, 3 Feb. 2022, https://www.ajmc.com/view/rare-disease-accessreimbursement-and-disease-management-a-stakeholderinterchange-report.

16. U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/ home.

17. “Hereditary Transthyretin Amyloidosis.” IPD Analytics, https:// ipdanalytics.com.

Product Spotlight: Ivosidenib (Tibsovo®)

A new option for treatment of acute myeloid leukemia.

In May 2022, the U.S. Food and Drug Administration (FDA) approved ivosidenib (Tibsovo®, Servier Pharmaceuticals) in combination with azacitidine for newly diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation, as detected by an FDA-approved test in adults 75 years and older or who have comorbidities that preclude the use of intensive induction chemotherapy.1 Previously, in 2021, the FDA approved ivosidenib for adult patients with previously treated, locally advanced, or metastatic cholangiocarcinoma with an IDH1 mutation as detected by an FDA-approved test.2

Acute Myeloid Leukemia

AML is a rare cancer of the blood and bone marrow that accounts for only 1% of new cancer cases.3 The median age of diagnosis is 68 years, and about 70% of patients do not survive past five years of diagnosis.3, 4

The most common treatment for AML is chemotherapy for induction (cytarabine, daunorubicin) and consolidation (high-dose cytarabine).5 For patients with newly diagnosed AML, the National Comprehensive Cancer Network (NCCN) recommends clinical trials, targeted treatments, chemotherapy, hypomethylating agents, and supportive care as treatment options.6 Notably, elderly patients may not be appropriate candidates for intensive chemotherapy, considering associated toxicities such as myelosuppression, neutropenia, and higher risk of infection.7 Relapsed/refractory (R/R) AML is particularly challenging to manage with relatively few options; NCCN recommends aggressive chemotherapy for suitable patients, but these regimens are associated with substantial toxicities.6, 8, 9 In patients with R/R AML, NCCN also recommends less aggressive therapies or targeted therapies, which can be associated with toxicities such as gastrointestinal toxicity, rash, and myelosuppression.6, 8, 9

The IDH1 mutation is a driver mutation found in 6-10% of both newly diagnosed and R/R AML populations that leads to lack of cellular differentiation in AML and is associated with negative prognosis.10-13 Both the NCCN and the American Society of Hematology/College of American Pathologists recommend testing for mutations, including IDH1, in patients with AML.6, 14

Ivosidenib in Newly Diagnosed AML

FDA approval of ivosidenib for AML was based on a randomized, multicenter, double-blind, placebo-controlled study of 146 patients with newly diagnosed AML with an IDH1 mutation meeting one of the following criteria: 75 years of age or older, baseline Eastern Cooperative Oncology Group performance status of 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin greater than 1.5 times the upper limit of normal, creatinine clearance less than 45 mL/min, or other comorbidity.15 Patients were randomized to receive ivosidenib 500 mg or placebo daily by oral administration on days 1 through 28 in combination with intravenous or subcutaneous azacitidine 75mg/m2/day on days 1 through 8 or days 1 through 5 and 8 through 9 of each 28-day cycle until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation.15 The primary end point was event-free survival (time from randomization until treatment failure, relapse from remission, or death from any cause).15 Eventfree survival at 12 months had an estimated probability of 37% in

the ivosidenib and azacitidine group and 12% in the placebo and azacitidine group.15 Patients treated with ivosidenib and azacitidine had a median overall survival of 24 months compared to 7.9 months for patients treated with placebo and azacitidine.15 Febrile neutropenia occurred at a higher incidence in the placebo group than in the ivosidenib group (34% versus 28%, respectively). The incidence of infection of any grade was 28% with ivosidenib and azacitidine and 49% with placebo and azacitidine.15

NCCN Guidelines recommend ivosidenib as a targeted therapy for select patients with newly diagnosed R/R AML with an IDH1 mutation, specifically adult patients with newly diagnosed AML who are 60 years of age or older or who have comorbidities that preclude use of intensive induction chemotherapy or adult patients with R/R AML.6

Cholangiocarcinoma

Cholangiocarcinomas are a heterogenous group of biliary tract cancers, classified as intrahepatic or extrahepatic, in which tumors develop from the epithelial lining of the biliary tree. Around 8,000 adults in the U.S. are diagnosed with cholangiocarcinoma each year, with extrahepatic cases accounting for 80% of all diagnosed and intrahepatic cases accounting for the remaining 20%.16, 19 Average age at diagnosis is 70 and 72 years old for intrahepatic and extrahepatic cholangiocarcinoma, respectively.19

Typically, individuals have advanced-stage disease at presentation and diagnosis; thus, the five-year survival rate for these patients is low, about 10%.16-18, 20 For patients with unresectable or metastatic cholangiocarcinoma, first-line treatment includes gemcitabine and cisplatin with or without durvalumab.21 There is no clear standard of care for subsequent lines.22-25 The median survival time for patients with advanced-stage cholangiocarcinoma on chemotherapy is less than one year.21, 25 The NCCN recommends molecular testing of unresectable and metastatic tumors, given emerging evidence regarding actionable targets for treatment of cholangiocarcinoma.26

IDH1 mutations are an emerging molecular target for treatment and can be identified using molecular testing.18, 21, 27

Ivosidenib in Cholangiocarcinoma

A randomized 2:1, multicenter, double-blind, placebo-controlled clinical trial evaluated efficacy of ivosidenib in treating cholangiocarcinoma.28

The trial consisted of 185 adults with locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation; participants must have had disease progression following at least one but no more than two prior regimens, including at least one gemcitabine- or 5-flurouracil-containing regimen.28 Patients were randomized, receiving either ivosidenib 500 mg orally once daily or matched placebo until disease progression or unacceptable toxicity, with those in the placebo arm allowed to cross over to ivosidenib after documentation of radiographic disease progression.28 The primary end point of the trial was progression-free survival.28 Patients receiving ivosidenib showed a statistically significant improvement in progression-free survival compared to patients receiving placebo (2.7 months versus 1.4 months, respectively).28 Median overall survival was 10.3 months with ivosidenib versus 7.5 months with placebo.29 When adjusted for the crossover, median overall survival with placebo was 5.1 months. The EORTC Core Quality of Life questionnaire C30 and BIL21 assessed quality of life changes from baseline as well as the PGI-C anchor questions for physical functioning, pain, and appetite loss.29 Patients in the ivosidenib group had preserved physical function, while those in the placebo group experienced a decline from baseline.29 Adverse reactions reported in more than 15% of patients included fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash.28

The NCCN Guidelines recommend ivosidenib as a subsequent-line treatment option for unresectable or metastatic cholangiocarcinoma in patients with an IDH1 mutation following disease progression.26

References

1. “FDA D.I.S.C.O. Burst Edition: FDA approval of Tibsovo (ivosidenib) in combination with azacitidine for newly diagnosed acute myeloid leukemia with a susceptible IDH1 mutation, as detected by an FDA-approved test in adults 75 years or older, or who have comorbidities that preclude use of intensive induction therapy.” U.S. Food & Drug Administration, 17 June 2022, https://www. fda.gov/drugs/resources-information-approved-drugs/fda-discoburst-edition-fda-approval-tibsovo-ivosidenib-combinationazacitidine-newly-diagnosed#:~:text=On%20May%2025%2C%20 2022%2C%20the,use%20of%20intensive%20induction%20 chemotherapy.

2. “FDA D.I.S.C.O. Burst Edition: FDA approval of Tibsovo (ivosidenib) for adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 mutation as detected by an FDA-approved test.” U.S. Food & Drug Administration, 7 Sept. 2021, https://www.fda.gov/drugs/ resources-information-approved-drugs/fda-disco-burst-editionfda-approval-tibsovo-ivosidenib-adult-patients-previously-treatedlocally#:~:text=On%20August%2025%2C%202021%2C%20 FDA,by%20an%20FDA%2Dapproved%20test.

NCCN Guidelines recommend ivosidenib as a targeted therapy for select patients with newly diagnosed R/R AML with an IDH1 mutation, specifically adult patients with newly diagnosed AML who are 60 years of age or older or who have comorbidities that preclude use of intensive induction chemotherapy or adult patients with R/R AML.

3. “Cancer Stat Facts: Leukemia – Acute Myeloid Leukemia (AML).” National Cancer Institute, National Institutes of Health, https://seer. cancer.gov/statfacts/html/amyl.html.

4. Breems, Dimitri A., et al. “Prognostic index for adult patients with acute myeloid leukemia in first relapse,” Journal of Clinical Oncology, 20 March 2005, https://pubmed.ncbi.nlm.nih. gov/15632409/.

5. “Typical Treatment of Acute Myeloid Leukemia (Except APL).” American Cancer Society, 25 May 2022, https://www.cancer.org/ cancer/acute-myeloid-leukemia/treating/typical-treatment-of-aml. html.

6. “NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.3.2021.” National Comprehensive Cancer Network, 2021, NCCN.org.

7. Dombret, Hervé, et al. “How and when to decide between epigenetic therapy and chemotherapy in patients with AML,” Hematology American Society of Hematology Education Program, 8 Dec. 2017, https://pubmed.ncbi.nlm.nih.gov/29222236/.

8. De Kouchkovsky, I., et al. “Acute myeloid leukemia: a comprehensive review and 2016 update,” Blood Cancer Journal, 1 July 2016, https://pubmed.ncbi.nlm.nih.gov/27367478/.

9. Lech-Maranda, Ewa, et al. “Infectious complications in patients with acute myeloid leukemia treated according to the protocol with daunorubicin and cytarabine with or without addition of cladribine. A multicenter study by the Polish Adult Leukemia Group (PALG).” International Journal of Infectious Diseases, 1 Feb. 2010, https:// www.ijidonline.com/article/S1201-9712(09)00193-3/fulltext.

10. Dang, L., et al. “IDH mutations in cancer and progress toward development of targeted therapeutics.” Annals of Oncology, April 2016, https://pubmed.ncbi.nlm.nih.gov/27005468/.

11. Molenaar, Remco J., et al. “Wild-type and mutated IDH1/2 enzymes and therapy responses,” Oncogene, April 2018, https://pubmed. ncbi.nlm.nih.gov/29367755/.

12. Chou, W-C, et al. “Persistence of mutant isocitrate dehydrogenase in patients with acute myeloid leukemia in remission.” Leukemia, March 2012, https://pubmed.ncbi.nlm.nih.gov/21844873/.

13. “Ivosidenib with Chemotherapy New Option for Some People with AML.” National Cancer Institute, https://www.cancer.gov/newsevents/cancer-currents-blog/2022/ivosidenib-chemotherapy-amlidh1.

14. Arber, Daniel A., et al. “Initial Diagnostic Workup of Acute Leukemia: Guideline from the College of American Pathologists and the American Society of Hematology.” Archives of Pathology & Laboratory Medicine, Oct. 2017, https://pubmed.ncbi.nlm.nih. gov/28225303/.

15. Montesinos, Pau, et al. “Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia.” New England Journal of Medicine, 21 April 2022, https://www.nejm.org/doi/10.1056/NEJMoa2117344.

16. Rizvi, Sumera, et al. “Cholangiocarcinoma – evolving concepts and therapeutic strategies.” Nature Reviews Clinical Oncology, Feb. 2018, https://pubmed.ncbi.nlm.nih.gov/28994423/.

17. “What is Bile Duct Cancer?” American Cancer Society, 2 March 2021, https://www.cancer.org/cancer/bile-duct-cancer/about/what-isbile-duct-cancer.html.

18. Javle, Milind, et al. “Biliary cancer: Utility of next-generation sequencing for clinical management.” Cancer, 15 Dec. 2016, https:// pubmed.ncbi.nlm.nih.gov/27622582/.

19. “Key Statistics for Bile Duct Cancer.” American Cancer Society, 12 Jan. 2022, https://www.cancer.org/cancer/bile-duct-cancer/about/ key-statistics.html.

20. “Survival Rates for Bile Duct Cancer.” American Cancer Society, 28 Feb. 2022, https://www.cancer.org/cancer/bile-duct-cancer/ detection-diagnosis-staging/survival-by-stage.html.

21. Boscoe, Audra N., et al. “Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review.” Journal of Gastrointestinal Oncology, Aug. 2019, https://pubmed.ncbi.nlm.nih.gov/31392056/.

22. Brieau, Bertrand, et al. “Second-line chemotherapy for advanced biliary tract cancer after failure of the gemcitabine-platinum combination: A large multicenter study by the Association des Gastro-Entérologues Oncologues.” Cancer, 5 June 2015, https:// acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.29471.

23. Lamarca, A., et al. “Second-line chemotherapy in advanced biliary cancer: a systematic review.” Annals of Oncology, Dec. 2014, https:// pubmed.ncbi.nlm.nih.gov/24769639/.

24. Sebbagh, Sihem, et al. “Efficacy of a sequential treatment strategy with GEMOX-based followed by FOLFIRI-based chemotherapy in advanced biliary tract cancers.” Acta Oncologica, Sept.-Oct. 2016, https://pubmed.ncbi.nlm.nih.gov/27333436/.

25. Chamberlain, Christina X., et al. “Burden of illness for patients with cholangiocarcinoma in the United States: a retrospective claims analysis.” Journal of Gastrointestinal Oncology, April 2021, https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC8107622/.

26. “NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Hepatobiliary Cancers V.3.2021.” National Comprehensive Cancer Network Inc., 2021, NCCN.org.

27. Jusakul, Apinya, et al. “Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma.” Cancer Discovery, Oct. 2017, https://pubmed.ncbi.nlm.nih.gov/28667006/.

28. Abou-Alfa, Ghassan K., et al. “Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study.” Lancet Oncology, 29 Sept. 2020, https://www.ncbi.nlm.nih. gov/pmc/articles/PMC7523268/.

29. Zhu, Andrew X., et al. “Final Overall Survival Efficacy Results of Ivosidenib for Patients with Advanced Cholangiocarcinoma with IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial.” JAMA Oncology, 23 Sept. 2021, https://jamanetwork.com/journals/ jamaoncology/fullarticle/2784216.

Patients are our priority.

Our deep commitment to our patients is fundamental to our unique culture — it is a priority in everything we do. We’re continually expanding our innovative oncology portfolio to bring the promise of tomorrow to the patients we serve.

We consistently engage with patients, their families and advocacy groups to ensure their voices are heard in every initiative we undertake.

Drug ManufacturerClinical Use

ibalizumab-uiyk (TROGARZO®)

TheratechnologiesHIV-1 infection

olipudase alfa (Xenpozyme®) Sanofi Niemann-Pick disease

lumasiran (OXLUMO®) Alnylam Pharmaceuticals

apomorphine infusion pump Supernus Pharmaceuticals

primary hyperoxaluria type 1 (advanced)

Parkinson’s disease

Dosage Form Approval Status

IV

IV

SC

Expected FDA Approval

sBLA; breakthrough therapy; orphan drug; priority review 10/3/22

BLA; breakthrough therapy; orphan drug; priority review 10/3/22

sNDA; breakthrough therapy; orphan drug 10/6/22

SC NDA 10/7/22

Furosemide (FUROSCIX®)scPharmaceuticalsdecompensated heart failureSC

cipaglucosidase alfa Amicus Therapeutics

aflibercept (biosimilar to Regeneron’s EYLEA®) Viatris/Janssen

omidenepag isopropyl Santen Pharmaceutical

upadacitinib (RINVOQ®)AbbVie

sparsentan

teplizumab

Pompe disease (in combination with oral miglustat)

diabetic macular edema; diabetic retinopathy; macular edema following RVO; wet age-related macular degeneration

505(b)(2) NDA 10/8/22

IV BLA; breakthrough therapy; orphan drug 10/29/22

intravitrealBLA October 2022

glaucoma/ocular hypertensionophthalmic NDA 11/4/22

axial spondyloarthritis (nonradiographic) oral sNDA 11/7/22

Travere/Bristol Myers Squibb immunoglobulin A nephropathy (Berger’s disease)

oral

Provention Bio type 1 diabetes mellitus (delay/ prevention) IV

poziotinib Spectrum Pharmaceuticals

pegcetacoplan (EMPAVELI®)Apellis

mirvetuximab soravtansineImmunoGen

ibrexafungerp (BREXAFEMME®)

omburtamab

NDA; seeking accelerated approval; orphan drug; priority review 11/17/22

BLA; breakthrough therapy; orphan drug 11/17/22

NSCLC (locally advanced/metastatic; HER2 exon 20 insertion mutation) oral NDA; fast track 11/24/22

geographic atrophy (secondary to age-related macular degeneration) intravitreal

ovarian cancer (folate receptor alpha-high platinum-resistant) (1-3 prior systemic treatments) IV

Scynexis recurrent vulvovaginal candidiasis prevention oral

Y-mAbs Therapeutics

microbiota suspension Ferring Pharmaceuticals

brain cancer (CNS/leptomeningeal metastasis from neuroblastoma) intracerebroventricular

clostridioides difficile infection (recurrent) rectal

sNDA; fast track; priority review 11/26/22

BLA; seeking accelerated approval; fast track; orphan drug; priority review 11/28/22

sNDA; fast track; orphan drug; priority review; QIDP 11/30/22

BLA; breakthrough therapy; orphan drug; priority review 11/30/22

BLA; breakthrough therapy; fast track; orphan drug September-November 2022

PIPELINE

Drug

etranacogene dezaparvovec (EtranaDez)

asparaginase erwinia chrysanthemi (recombinant)rywn (Rylaze® IM)

CSL Behringhemophilia B IV

Jazz Pharmaceuticals

acute lymphoblastic leukemia/ lymphoblastic lymphoma (3/week dosing, E. coli-derived asparaginase hypersensitivity)

IM

BLA; breakthrough therapy; orphan drug; priority review November 2022

sBLA; fast track; orphan drug; RTOR 12/2/22

adagrasib

Mirati Therapeutics

trastuzumab (biosimilar to Genentech’s Herceptin®) Novartis

cariprazine (VRAYLAR®)AbbVie

abaloparatide (TYMLOS®)Radius Health

toripalimab Coherus BioSciences

lenacapavir Gilead Sciences

NSCLC (KRASG12C mutation, >second-line)

Breast cancer; gastic/ gastroesophageal cancer

oral NDA; seeking accelerated approval; breakthrough therapy; RTOR 12/14/22

IV BLA 12/20/22

major depressive disorder (adjunct)oral sNDA 12/22/22

osteoporosis (men, high-risk for fracture) SC sNDA 12/23/22

nasopharyngeal cancer (advanced recurrent/metastatic, first-line with chemotherapy, monotherapy for >second-line)

IV

BLA; breakthrough therapy; orphan drug 12/23/22

HIV-1 infection (heavily treatmentexperienced) oral; SCNDA; breakthrough therapy12/27/22

ublituximab

oral sNDA; breakthrough therapy; orphan drug 12/28/22

TG Therapeuticsmultiple sclerosis (relapsing)IV BLA 12/28/22 ibrutinib (IMBRUVICA®)AbbVie/Janssen graft versus host disease treatment (ages >1 years, >second-line)

mosunetuzumab Genentech follicular lymphoma (third-line)IV; SC BLA; breakthrough therapy; orphan drug; priority review 12/29/22

Palovarotene (Sohonos™)Ipsen fibrodysplasia ossificans progressive oral

NDA; breakthrough therapy; fast track; orphan drug; priority review 12/29/22

infliximab SC (Remsima®)Celltrion IBS SC BLA September-December 2022

Teclistamab (Tecvayli®) Janssen Pharmaceuticals multiple myeloma (relapsingremitting) SC

tocilizumab (ACTEMRA®)Genentech

adalimumab 50 mg/mL (biosimilar to AbbVie’s Humira®)

COVID-19 treatment (hospitalized adults on systemic corticosteroids and require assisted ventilation)

BLA; breakthrough therapy; orphan drug September-December 2022

IV sBLA; priority review September-December 2022

Fresenius Medical Care RA; AS; PSO; PsA; JIA; CD; UC SC BLA October-December 2022

tremelimumab AstraZeneca

epatocellular carcinoma (as single priming dose for durvalumab)

IV

BLA; orphan drug; priority review October-December 2022

Drug ManufacturerClinical Use

adalimumab-afzb 50 mg/mL (Abrilada™) (biosimilar to AbbVie’s Humira®)

pineapple proteolytic enzymes extract

lecanemab

vonoprazan fumarate (TAKECAB®)

Dosage Form Approval Status

Pfizer RA; AS; PSO; PsA; JIA; CD; UC SC

Vericel burn injury

Expected FDA Approval

PAS BLA for biosimilar interchangeability October-December 2022

topicalBLA; orphan drug 1/1/23

Eisai; BiogenAlzheimer’s disease (early) IV

Phathom Pharmaceuticals

BLA; seeking accelerated approval; breakthrough therapy; fast track; priority review 1/6/23

erosive esophagitis; heartburn relieforal sNDA 1/11/23

sodium phenylbutyrateAcer Therapeuticsurea cycle disorders oral 505(b)(2) NDA 1/15/23 zanubrutinib (BRUKINSA®)BeiGene chronic lymphocytic leukemia; small lymphocytic lymphoma oral sNDA; orphan drug 1/20/23

tofersen Biogen amyotrophic lateral sclerosisintrathecal

pembrolizumab (KEYTRUDA®)

omidubicel

Merck

NDA; orphan drug; priority review 1/25/23

NSCLC (post-surgical resection; stage IB, II, or IIIA) IV sBLA 1/29/23

Gamida Cellhematologic and solid cancersIV

Treosulfan (Trecondi®)Medac

daprodustat

olutasidenib

elacestrant

GSK

BLA; breakthrough therapy; orphan drug; priority review 1/30/23

allogeneic-hematopoietic stem cell transplant conditioning IV NDA; orphan drug January 2023

anemia of chronic kidney disease (dialysis-dependent and -independent) oral NDA 2/1/23

Rigel Pharmaceuticals acute myeloid leukemia (R/R)oral NDA; orphan drug 2/15/23

Menarini

breast cancer (HER+/HER2-, advanced or metastatic) oral

NDA; fast track; priority review 2/17/23

aflibercept (EYLEA®) Regeneron Pharmaceuticals diabetic retinopathy (16-week maintenance regimen) intravitrealsBLA 2/28/23

omaveloxolone

Reata/AbbVieFriedreich’s ataxia oral

omecamtiv mecarbil CytokineticsHFrEF

asparaginase erwinia chrysanthemi (recombinant)rywn (RYLAZE® IV) Jazz Pharmaceuticals

acute lymphoblastic leukemia/ lymphoblastic lymphoma (E. coli-derived asparaginase hypersensitivity)

NDA; fast track; orphan drug; priority review; rare pediatric disease 2/28/23

oral NDA; fast track 2/28/23

IV

sBLA; fast track; orphan drug; RTOR February 2023

PIPELINE

Drug

budesonide-albuterolAstraZenecaasthma

rezafungin

Cidara/Melinta

candidemia/invasive candidiasis; prophylaxis of invasive fungal infections in patients undergoing allogeneic blood and marrow transplantation

zavegepant

trofinetide

amifampridine phosphate (FIRDAPSE®)

tixagevimab/cilgavimab (Evusheld™)

Biohaven/Bristol Myers Squibb migraine (acute treatment)

Acadia Pharmaceuticals

Rett syndrome (ages >2 years)

Catalyst Pharmaceuticals Lambert-Eaton myasthenic syndrome (pediatric)

AstraZenecaCOVID-19 treatment

Expected FDA Approval

inhaled NDA January-February 2023

TBD NDA; fast track; orphan drug; QIDP January-March 2023

intranasal NDA January-March 2023

oral NDA; fast track; orphan drug3/17/23

oral sNDA; breakthrough therapy; orphan drug March 2023

IM; IV BLA March 2023

mirikizumab Eli Lilly UC IV; SC BLA 4/28/23

durvalumab (IMFINZI®)AstraZeneca

adalimumab-adaz 100 mg/mL (Hyrimoz™) (biosimilar to AbbVie’s Humira®)

hepatocellular carcinoma (unresectable)

IV sBLA; orphan drug 4/30/23

Sandoz RA; AS; PSO; PsA; JIA; CD; UC SC sBLA March-April 2023

anthrax vaccine, absorbed Emergent BioSolutions

anthrax infection (post-exposure prophylaxis)

IM BLA; fast track April 2023

Abbreviations: AS = ankylosing spondylitis; BLA = biologics license application; CD = Crohn’s disease; HFrEF = heart failure with reduced ejection fraction; HIV-1 = human immunodeficiency virus-1; IBS = irritable bowel syndrome; IM = intramuscular; IV = intravenous; JIA = juvenile idiopathic arthritis; NDA = new drug application; NSCLC = non-small cell lung cancer; PAS = prior approval supplement; PsA = psoriatic arthritis; PSO = psoriasis; QIDP = qualified infectious disease product; RA = rheumatoid arthritis; R/R = relapsed or refractory; RTOR = Real-Time Oncology Review; RVO = retinal vein occlusion; sBLA = supplemental biologics license application; SC = subcutaneous; sNDA = supplemental new drug application; UC = ulcerative colitis

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