2022 Summer Prime Therapeutics Report

Biomarker Testing: Metastatic Colorectal Cancer Management Gene Therapy: Focus on Blood Disorders

Heart Failure: Treatment and Management Update

Update: Multiple Myeloma Advances and Payer Impact

Prime Therapeutics

IN THIS ISSUE | Summer 2022

Published By

Magellan Rx Management

4801 E. Washington St., Ste. 100 Phoenix, AZ 85034

Tel: 401-344-1000

Fax: 401-619-5215

magellanrx.com

Editor

Lindsay Speicher, J.D.

Project Manager, Specialty lspeicher@magellanhealth.com 401-344-1105

Advertising, Sales and Distribution

Carole Kallas

ckallas@magellanhealth.com 401-344-1132

The content of Magellan RxTM Report — including text, graphics, images, and information obtained from third parties, licensors, and other material (“content”) — is for informational purposes only. The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Magellan RxTM Report does not verify any claims or other information appearing in any of the advertisements contained in the publication and cannot take responsibility for any losses or other damages incurred by readers in reliance on such content. Developed by D Custom.

Contributors

Caroline Carney, M.D., 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

Brooke Kachura Senior Director, 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 Ofcer & 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 Ofcer, International Myeloma Foundation

Natalie Tate, Pharm.D., MBA, BCPS VP, Pharmacy Management, BlueCross BlueShield of Tennessee

Steve Marciniak, R.Ph.

Director II, Medical Beneft 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

A NOTE FROM OUR CMO

Dear Managed Care Colleagues,

Welcome to our summer 2022 issue of the Magellan Rx Report! So many exciting advances have occurred so far this year. According to the FDA, there have been 15 novel drug approvals, with several more in the pipeline for the remainder of 2022. These approvals present considerable opportunities for improved treatment outcomes and disease management across disease states. As challenges associated with the COVID-19 pandemic remain, innovation and advances in preventing and treating other chronic and terminal conditions continue. Magellan Rx Management is committed to keeping our readers informed and updated across the spectrum of diseases.

In our cover story (page 12), we update readers on psoriasis, including the categoryʼs treatment landscape and pipeline. We also discuss strategies payers may use to manage this population.

In another article, we highlight the importance of biomarker testing in metastatic colorectal cancer (page 6) and explore the associated cost management opportunities.

We know gene therapy is a category of interest for our readers. We focus on the ever-evolving gene therapy space on page 17, specifcally exploring the treatment of blood disorders, including management opportunities and challenges for payers.

Other timely topics in this issue include an update on CAR-T therapy in multiple myeloma treatment (page 28), a discussion of chronic heart failure treatment and management (page 22), and a biosimilar update (page 32). As always, the issue is rounded out with our pipeline update (page 42) and managed care newsstand (page 4).

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 Ofcer Magellan Health & Magellan Rx Management

Stay on top of managed care trends and become a Magellan Rx Report subscriber. Email us at MagellanRxReport@magellanhealth.com to subscribe today. Magellan Rx Report provides pharmacy and medical management solutions for managed care executives and clinicians. We hope you enjoy the issue; thank you for reading. SUBSCRIBE TODAY!

MANAGED CARE NEWSSTAND

CMS Issues Final Rule for Medicare Advantage/Part D

In April, the Centers for Medicare & Medicaid Services (CMS) released the pre-publication of a fnal regulation containing revisions to the Medicare Advantage and Part D Prescription Drug Beneft programs for CY 2023. CMS also issued a related press release and fact sheet. Highlights from the fnal rule include the following:

1. CMS fnalized the proposal to require Part D plans to apply all price concessions they receive from network pharmacies at the point of sale by revising the current defnition of “negotiated drug price” to eliminate the current exception for contingent pharmacy price concessions from inclusion in the total pharmacy network price concessions that can reasonably be determined at the point of sale. Instead, the new defnition would include the lowest net price a pharmacy could receive for a covered drug net of the maximum possible negative adjustment or incentive fees receivable under any contingency payment arrangements between the sponsor and pharmacy. However, CMS has delayed this requirement to go into efect Jan. 1, 2024.

2. The fnal rule requires, for 2025 and subsequent years, that all FIDE SNPs have exclusively aligned enrollment (i.e., limit enrollment to individuals in the afliated Medicaid MCO) and cover Medicaid home health, durable medical equipment, and behavioral health services through a capitated contract with the state Medicaid agency.

3. CMS fnalized that the Medicare Advantage plan maximum out-of-pocket limit is calculated based on the accrual of

all Medicare cost-sharing in the plan beneft, including amounts paid by the benefciary, Medicaid, or other secondary insurance — and amounts remaining unpaid because of state limits.

4. CMS fnalized a technical change to the COVID-19 disaster relief policy for 2023 Star Ratings that applies to three Health Outcomes Survey measures: monitoring physical activity, reducing the risk of falling, and improving bladder control.

Congress Takes Steps to Advance Healthcare Bills

In May, the House Energy and Commerce Committee marked up and advanced six bipartisan healthcare bills. According to Chairman Frank Pallone, “[W]e will take a critical step in reauthorizing the user fee programs at the Food and Drug Administration (FDA) that help ensure our nation’s drugs and medical devices are safe and efective. We will also bolster our nation’s response to the mental health and substance use disorder crises by reauthorizing programs that help those in greatest need. Additionally, the Committee will authorize President Biden’s groundbreaking ARPA-H initiative to accelerate biomedical research to revolutionize how we treat the deadliest disease afecting Americans.” Some highlights of the initiative include:

SAMHSA and HRSA Funding: H.R. 7666, Restoring Hope for Mental Health and WellBeing Act, would reauthorize Substance Abuse and Mental Health Services Administration (SAMHSA) and Health Resources and Services Administration (HRSA) programs to address the mental health and substance use disorder (SUD) crisis and support comprehensive behavioral health services by integrating behavioral health into more care settings.

X-Waiver: At the markup, committee members adopted several amendments to the legislation, including an amendment Magellan Rx has long supported that removes

In April, the Centers for Medicare & Medicaid Services released the prepublication of a fnal regulation containing revisions to the Medicare Advantage and Part D Prescription Drug Beneft programs for CY 2023.

the x-waiver. The Mainstreaming Addiction Treatment (MAT) Act would remove the requirement that healthcare providers apply for and receive an x-waiver from the Drug Enforcement Administration to prescribe buprenorphine for the treatment of a SUD.

OUD and SUD Training: Committee members also adopted an amendment that included MAT Act provisions requiring that providers licensed under state law to prescribe controlled substances (including buprenorphine) complete at least 8 hours of training on how to efectively manage opioid and other SUDs. The bill will not go to the full House for a vote and is likely to advance.

FDA User Fee Authorization: The Food and Drug Amendments of 2022 (H.R. 7667) was amended and forwarded to the full House foor by a vote of 55-0. The PreApproval Information Exchange (PIE) Act that Magellan supports, which would allow

health plans and PBMs to access clinical and economic information about new drugs prior to FDA approval, was one of the approved amendments. This language will enable plans and PBMs to assess a drug’s efcacy and value compared to competing products. That information will help our member companies make more informed coverage decisions, more efectively estimate a new drug’s impact on healthcare costs, and help patients get timely access.

This is the frst legislative step toward the President’s desk. The FDA bill needs to be signed by the end of September to ensure that the FDA can continue to operate at full capacity. It is expected that these bills will come to the House foor in the near future for a vote.

Public Health Emergency Likely Extended Until October

The federal public health emergency (PHE) established shortly after COVID-19 hit in 2020 will likely be extended through October after federal health ofcials failed to announce an expiration date on its selfimposed deadline. U.S. Department of Health and Human Services (HHS) Secretary Xavier

Becerra promised to give 60 days’ notice to states before the emergency expires, a deadline that came and went without an announcement, signaling a likely extension.

Over the course of the COVID-19 pandemic, HHS and Congress took steps to provide relief to providers, states, and other parts of the healthcare industry. These policies include enforcement discretion, fexibility for rules and regulations (e.g., telehealth fexibilities), and funding increases. Many of these policies are tied to the PHE that HHS initially declared in January 2020. Each PHE declaration lasts for 90 days; to date, both the Trump administration and the Biden administration have renewed the PHE at each opportunity, most recently on April 12.

CMS Releases Overview of Federal Rules and Regulations Applicable to Unwinding of PHE

In spring 2020, Congress established a “continuous enrollment” policy for Medicaid for the duration of the PHE. Under the policy, states who accepted a higher federal matching rate ofered by Congress were prohibited from dropping anyone from Medicaid coverage through the duration of the COVID-19 PHE. When the PHE ends, states will be expected to initiate eligibility reviews of all enrolled benefciaries.

Trump administration. The regulation, which goes into efect next year, said that any copay assistance, such as coupons or other cost-sharing help, must be included in the calculation of the best price of the drug.

Drug Importation Back on the Menu

The White House budget ofce is reviewing an FDA question-and-answer document on drug importation. The Trump administration fnalized a rule to let states import drugs from Canada, but the Canadian government blocked the rule from taking efect by halting bulk exports of prescription drugs. Around the same time, PhRMA sued over the rule. President Biden signed an executive order aimed at letting states import Canadian drugs, but the status of Biden’s efort is unclear. Regardless, states continue to seek clarifcation from the FDA as they look to import drugs from Canada.

NCQA Releases White Paper on Impact Telehealth has on Health Equity

In spring 2020, Congress established a “continuous enrollment” policy for Medicaid for the duration of the PHE.

Court Strikes Down HHS Rule Impacting Medicaid Drug Rebate Program

In May, the U.S. District Court for the District of Columbia found in favor of the Pharmaceutical Research and Manufacturers of America’s (PhRMA) arguments against the Medicaid best price rule that would require coupons that are “accumulated” to count against average manufacturer price (AMP) and best price. The ruling focuses on a CMS rule fnalized in December 2020 under the

To address the impact telehealth has on health equity, the National Committee for Quality Assurance (NCQA) released a new white paper, “The Future of Telehealth Roundtable: The Potential Impact of Emerging Technologies on Health Equity.” The report outlines a combination of patient-centric, policy-focused, technologybased solutions, including:

• Tailoring telehealth use and access to individual preferences and needs.

• Addressing regulatory, policy, and infrastructure barriers to fair telehealth access.

• Leveraging telehealth and digital technologies to promote equitable care delivery.

Biomarker Testing: Metastatic Colorectal Cancer

Management

Performing biomarker testing at diagnosis can lead to earlier introduction of targeted treatment and reduce the risk of toxic efects from other treatments.

Mona Chitre, Pharm.D.

Chief Pharmacy Ofcer & VP

Integrated Clinical Strategy

Excellus Health Plan

Colorectal cancer (CRC) is the fourth-most diagnosed cancer and second-leading cause of cancerrelated deaths in the U.S. Around 8% of new cancer cases in the United States in 2021 were CRC.1 Twenty-two percent of CRC patients are metastatic at diagnosis, and an estimated 50% to 60% of all CRC patients will go on to develop metastases (or metastatic CRC [mCRC]).1, 2 Of patients diagnosed with mCRC, 14.7% will survive past fve years.1, 2

Biomarkers are present in an estimated 73% to 87% of mCRC cases.3 More than half (55%) of these cases are positive for rat sarcoma virus (RAS), specifcally Kirsten RAS (KRAS) and neuroblastoma RAS (NRAS). The prevalence of other biomarker targets in mCRC cases are: human epidermal growth factor 2 (HER2) (2% to 6%), tyrosine receptor kinase (TRK) fusions (0.5% to 2%), defcient MisMatch Repair (dMMR) or high levels of microsatellite instability (MSI-H) (4%), high tumor mutational burden (TMB-H) (5%), BRAF V600E (5% to 10%), and BRAF non-V600E (2% to 5%).3 The presence of biomarkers can be important in indicating the treatment course.

Current Standard of Care in mCRC

The current standard of care in mCRC typically includes chemotherapy as first- and second-line treatment and chemotherapy in combination with anti-epidermal growth factor receptor (EGFR) therapies (such as cetuximab or panitumumab) for some types of mCRC. The National Comprehensive Cancer Network (NCCN) outlines recommended treatment regimens for lines of treatment for mCRC, outlining recommendations for biomarkerspecific diagnoses (Table 1). 3 Treatment recommendations are outlined for RAS/BRAF WT left-sided tumors, dMMR/ MSI-H tumors, BRAF V600E mutation positive tumors, and HER2+ tumors. However, notably, none of the recommended treatments for HER2+ mCRC is approved by the U.S. Food and Drug Administration (FDA) for the treatment of mCRC.

Table 1. NCCN Recommended Treatment Regimens for mCRC3

Standard Chemotherapy Combinations

CAPEOX (capecitabine, oxaliplatin)

FOLFOX (leucovorin, fuorouracil, oxaliplatin)

FOLFIRI (leucovorin, fuorouacil, irinotecan)

FOLFIRINOX (leucovorin, fuorouracil, irinotecan, oxaliplatin)

First-Line Treatment for mCRC With Unresectable Metastases

Indication

mCRC with no actionable biomarker

RAS/BRAF WT left-sided tumors only

The use of chemotherapy for mCRC has limited efcacy, especially when used as second-line therapy following frst-line chemotherapy.4-7 Data shows the overall response rate (ORR) for FOLFOX and FOLFIRI frst-line therapies as 38.0% and 56.0%, respectively.4, 5 However, this is reduced drastically when looking at the overall response rate in second-line therapies, with an ORR of 15% and 4% for FOLFOX and FOLFIRI, respectively.5 Outcomes worsen as patients progress through lines of therapy.4-7 Refractory therapies show ORRs of 1.6% and 1.0% for trifuridine/tipiracil and regorafenib, respectively.6, 7

CAPEOX/FOLFOX/FOLFIRI/FOLFIRINOX + bevacizumab

FOLFOX/FOLFIRI + cetuximab or panitumumab

dMMR/MSI-H tumors pembrolizumab or nivolumab + ipilimumab

HER2+ (RAS and BRAF wild-type) (when intensive therapy is not appropriate)* trastuzumab + pertuzumab/lapatinib

Subsequent-Line Treatments

Indication

mCRC

RAS left-sided only tumors

BRAF V600E mutation positive tumors

dMMR/MSI-H tumors

HER2+ (RAS and BRAF wild-type) (when intensive therapy is not appropriate)*

NTRK gene fusion

FOLFIRI/FOLFOX + bevacizumab

FOLFIRI/FOLFOX + (cetuximab or panitumumab)

encorafenib + (cetuximab or panitumumab)

nivolumab + ipilimumab, pembrolizumab, or dostarlimab

trastuzumab + pertuzumab/lapatinib or fam-trastuzumab deruxtecan

Larotrectinib or entrectinib

Treatment for mCRC That Has Progressed Through All Other Available Regimens

Indication Regimen

mCRC

regorafenib or trifuridine + tipiracil + bevacizumab

*The recommended treatments for HER2+ mCRC are not approved by the FDA for the indication of mCRC.

BIOMARKER TESTING

According to the NCCN guidelines, the use of biomarker testing is recommended in patients with CRC, specifcally noting the following biomarkers: KRAS, NRAS, and BRAF mutations; MMR or MSI; HER2; and NTRK gene fusions.

Biomarkers in mCRC Management

The presence of certain biomarkers can be associated with poor response to standard CRC therapies.8 According to the NCCN guidelines, the use of biomarker testing is recommended in patients with CRC, specifcally noting the following biomarkers: KRAS, NRAS, and BRAF mutations; MMR or MSI; HER2; and NTRK

gene fusions.3 Testing may be performed for individual genes or as part of a Next Generation Sequencing (NGS) panel, although no specifc methodology is recommended by NCCN. NGS panels are able to detect actionable genetic alterations, such as NTRK fusions. The determination of tumor gene status for RAS and BRAF mutations and HER2 amplifcations should be performed at diagnosis or in general if testing has not yet been performed.

While biomarker testing rates vary, testing for emerging biomarkers remains low.9 Due to incorporation into the guidelines and the availability of targeted therapies, testing rates for more established biomarkers, such as KRAS/NRAS, BRAF, and MSI-H/ dMMR have increased over the past decade.10 Most patients (67%) have been tested for at least one biomarker prior to initiating frst-line therapy.9 Still, adherence to the guidelines remains poor overall. A retrospective review showed that between 2013 and 2017, only 40% of patients with mCRC completed guidelinerecommended biomarker testing.9 Emerging biomarkers may be overlooked or forgotten by providers, which contributes to unequal testing across provider centers and difculty budgeting and planning for payers. Testing for emerging biomarkers remains largely unknown.11 HER2 is an emerging biomarker found in 2% to 6% of the mCRC population, and this amplifcation is associated with primary resistance and poor response to anti-EGFR therapies, as well as increased incidence with brain metastases, which confer a poor prognosis and require efective, central nervous system-penetrant systemic therapies.11 Early testing for

biomarkers, including emerging biomarkers such as HER2, may help identify patients who can beneft from targeted therapies.

Management Strategies

The U.S. Centers for Medicare and Medicaid Services (CMS) National Quality Forum (NQF) Quality Measures support testing for established biomarkers, but not yet for newer, emerging biomarkers.12, 13 For example, NQF Quality Measures 1860 and 1859 support testing for RAS (KRAS or NRAS) gene mutations prior to starting anti-EGFR therapy. Evidence suggests that antiEGFR therapies ofer no clinical beneft to patients diagnosed with KRAS- or NRAS-mutated tumors.12, 13 These quality measures aim to discourage and reduce the use of anti-EGFR therapy in patients who likely will not beneft.12, 13 Similar quality measures may be developed for emerging biomarkers in time, such as HER2, as CMS increasingly focuses on value-based care, quality, and precision medicine for benefciaries.12, 13

Faster and more comprehensive sequencing of human genomes is made possible with advances in NGS technology. This testing can lead to precision therapy for patients in a timely manner, improving outcomes for these patients.11 Targeted treatment options are becoming increasingly crucial in informing treatment and management decisions, and ultimately, improving outcomes.14 Biomarker testing, specifcally NGS testing, can efectively and efciently lead to customized and well-informed treatment decision making.11, 14 Proper testing may lead to the selection of appropriate therapies that have the highest probability of clinical beneft and therapeutic impact and may lead to the exclusion of expensive treatments that would have a low probability of therapeutic efect or clinical beneft in some cases.14 Other genomic tests for individual biomarkers rely on the provider to determine which biomarkers to test for and may lead to the exclusion of testing for certain emerging biomarkers. This could cause viable, targeted treatment options to be inadvertently overlooked, which could lead to the utilization of multiple lines of inefective therapies for patients with mCRC with specifc biomarkers; this can also lead to unnecessary costs for care. Ultimately, NGS testing may present an opportunity for patients to access precision therapy in a timely manner that may improve outcomes and avoid unnecessary, inefective treatment lines.15-17

Cost savings may result from an increase in genetic testing. A study used a decision analytic model to determine the savings that could result from NGS tests in comparison to panel tests, exclusionary tests, or sequential tests in patients with small cell lung cancer.18 Results showed that utilization of NGS tests was associated with $1.3 million to $2.1 million in savings, using CMS reimbursement

Proper testing may lead to the selection of appropriate therapies that have the highest probability of clinical beneft and therapeutic impact and may lead to the exclusion of expensive treatments that would have a low probability of therapeutic efect or clinical beneft in some cases.

as the model.18 When looking to commercial payers, NGS testing remained the least expensive biomarker testing modality.18

A cost-efectiveness assessment conducted on data from 2013 to 2017 showed that the one-time cost for a comprehensive NGS panel was around $6,500, compared to the cost of antiEGFR therapy at around $6,000 per week throughout the cost of treatment.9 The review showed that 59.7% of the patients received anti-EGFR therapy; however, upon review, only 23.5% of those patients would have been candidates for that treatment based on biomarker testing.9 An additional study showed that HER2+ patients with mCRC were 50% less likely to achieve a complete or partial response when treated with anti-EGFR therapy than patients with HER2- tumors.19 Biomarker testing can lead to more appropriate and efective treatment choices — leading to better outcomes and reducing unnecessary costs.

Performing biomarker testing at diagnosis can lead to earlier introduction of targeted treatment and reduce the risk of toxic efects from other treatments. An NGS panel can be more costefective than using several individual biomarker tests to identify genomic alternations. Payment for an NGS panel is typically less than the cost of therapy, which can be expensive and potentially inefective if more targeted approaches are possible. Prescribers should be educated on biomarker testing, stressing importance of testing at mCRC diagnosis, in order to ensure that all information is available to make optimal and cost-efective treatment choices.

BIOMARKER TESTING |

References

1. “Cancer Stat Facts: Colorectal Cancer.” National Cancer Institute, https://seer.cancer.gov/statfacts/html/colorect.html.

2. Holch, Julian, et al. “Patterns and Dynamics of Distant Metastases in Metastatic Colorectal Cancer.” Visceral Medicine, Mar. 2017, https:// pubmed.ncbi.nlm.nih.gov/28612020/.

3. “NCCN Clinical Practice Guidelines in Oncology for Colon Cancer V.1.2022.” National Comprehensive Cancer Network.

4. Saltz, Leonard, et al. “Bevacizumab in combination with oxaliplatinbased chemotherapy as frst-line therapy in metastatic colorectal cancer: a randomized phase III study.” Journal of Clinical Oncology, 20 Apr. 2008, https://pubmed.ncbi.nlm.nih.gov/18421054/.

5. Tournigand, Christophe, et al. “FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.” Journal of Clinical Oncology, 15 Jan. 2004, https:// pubmed.ncbi.nlm.nih.gov/14657227/.

6. Mayer, Robert, et al. “Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer.” New England Journal of Medicine, 2015, https://www.nejm.org/doi/full/10.1056/NEJMoa1414325.

7. Grothey, Axel, et al. “Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomized, placebo-controlled, phase 3 trial.” Lancet, 26 Jan. 2013, https://pubmed.ncbi.nlm.nih.gov/23177514/.

8. Lee, M.K.C., et al. “Current and emerging biomarkers in metastatic colorectal cancer.” Current Oncology, Nov. 2019, https://www.ncbi. nlm.nih.gov/pmc/articles/PMC6878935/.

9. Guiterrez, Martin, et al. “Genomic profling for KRAS, NRAS, BRAF, microsatellite instability, and mismatch repair defciency among patients with metastatic colon cancer.” JCO Precision Oncology, 6 Dec. 2019, https://pubmed.ncbi.nlm.nih.gov/32923867/.

10. Carter, Gebra Cuyun, et al. “KRAS testing of patients with metastatic colorectal cancer in a community-based oncology setting: a retrospective database analysis.” Journal of Experimental & Clinical Cancer Research, 27 Mar. 2015, https://jeccr.biomedcentral.com/ articles/10.1186/s13046-015-0146-5.

11. Kim, RY, et al. “Genetic-based biomarkers and next-generation sequencing: the future of personalized care in colorectal cancer.” Personalized Medicine, 1 May 2011, https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC3646399/.

12. “Patients with metastatic colorectal cancer and RAS (KRAS or NRAS) gene mutation spared treatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies.” Centers for Medicare and Medicaid Services, https://cmit.cms.gov/cmit/#/.

13. “RAS (KRAS and NRAS) gene mutation testing performed for patients with metastatic colorectal cancer who receive antiepidermal growth factor receptor (EGFR) monoclonal antibody therapy.” Centers for Medicare and Medicaid Services, https://cmit. cms.gov/cmit/#/.

14. Lieu, Christopher, et al. “Integrating biomarkers and targeted therapy into colorectal cancer management.” American Society of Clinical Oncology Educational Book, Jan. 2019, https://pubmed.ncbi. nlm.nih.gov/31099678/.

15. Tosi, Federica, et al. “Long-term clinical outcome of trastuzumab and lapatinib for HER2-positive metastatic colorectal cancer.” Clinical Colorectal Cancer, 1 Dec. 2020, https://www.clinicalcolorectal-cancer.com/article/S1533-0028(20)30094-3/fulltext.

16. Meric-Bernstam, Funda, et al. “Pertuzumab (P) + trastuzumab (H) treatment of a large, tissue-agnostic cohort of patients with HER2positive advanced solid tumors.” Journal of Clinical Oncology, 2021, https://pubmed.ncbi.nlm.nih.gov/30857956/.

17. Siena, S., et al. “Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial.” The Lancet Oncology, 2021, https://mdanderson.elsevierpure.com/en/publications/ trastuzumab-deruxtecan-ds-8201-in-patients-with-her2expressing-m.

18. Pennell, Nathan, et al. “Economic impact of next-generation sequencing versus single-gene testing to detect genomic alterations in metastatic non-small-cell lung cancer using a decision analytic model.” JCO Precision Oncology, 2019, https://ascopubs. org/doi/full/10.1200/po.18.00356.

19. Sartore-Bianchi, Andrea, et al. “HER2 positivity predicts unresponsiveness to EGFR-targeted treatment in metastatic colorectal cancer.” Oncologist, Oct. 2019, https://www.ncbi.nlm.nih. gov/pmc/articles/PMC6795149/.

BIOLOGIC OPTIONS IN THE MARKETPLACE ARE EVOLVING

Unbranded Biologics Are Another Option for Your Formulary

Brand-Name Biologic1

Approved based on a full complement of safety and effectiveness data

Produced through biotechnology in a living system (ie, a “cell line”)

*“Brand-name biologic” refers to the reference biologic.

Unbranded Biologic 2

The same as the brand-name biologic

Produced using the same cell line as the brand-name biologic

Biosimilar 1,3

Highly similar to brand-name biologic* with no clinically meaningful differences

Produced using a different cell line

• An approved brand-name biologic being marketed under its approved biologics license† without the brand name

• Considered by the FDA to be the same product as the brand-name biologic under the same biologics license‡

• The same in strength, dosage form, route of administration, and presentation as the brand-name biologic

†Biologics are FDA approved through a biologics license application (BLA).

‡No difference in strength, dosage form and route of administration, and presentation vs its approved brand-name biologic.

To learn more about biologic innovations, visit https://www.janssen.com/us/biologic-innovation

FDA = US Food and Drug Administration.

References: 1. US Food and Drug Administration. Biosimilar and Interchangeable Products. Accessed May 25, 2022. https://www.fda.gov/drugs/biosimilars/biosimilar-and-interchangeable-products#biological 2. US Food and Drug Administration. FAQs – Purple Book. Accessed May 25, 2022. https://purplebooksearch.fda.gov/faqs 3. Declerck P et al. Biosimilarity versus manufacturing change: two distinct concepts. Pharm Res. 2016;33(2):261-268.

© Janssen Biotech, Inc. 2022 06/22 cp-321634v1

Psoriasis: Current Treatment Landscape and Management

The introduction of numerous alternatives in the psoriasis treatment landscape may lead to a potential need for more efective cost management for payers.

Ryan Steadman, Pharm.D., MBA SVP, Pharmacy

CareSource

Psoriasis is a chronic infammatory skin disease that afects around 3% of adults in the U.S.; recent data suggests that more than 7.5 million adults over age 20 have psoriasis.1 It is most commonly found in non-Hispanic, white individuals.1

Psoriasis is an autoimmune disorder that occurs when the immune system becomes overactive, causing skin cells to multiply too quickly.2 It causes patches of skin to become scaly and infamed and most often afects skin on the scalp, elbows, or knees. While the cause of the immune response resulting in psoriasis is unknown, family history can be a risk factor, and there are some known genes that may contribute to the development.2 Other external factors that can increase the risk of developing psoriasis include streptococcal, HIV, smoking, obesity, and certain medications such as those treating heart disease, malaria, or mental health problems. Symptomatic psoriasis can be cyclical, faring for periods of time before subsiding or going into remission.2

There are diferent types of psoriasis that vary in severity, presentation, and population. The symptoms of psoriasis depend on the individual and the type of psoriasis.2 The most common type is plaque psoriasis, which appears as raised, red patches of skin covered by silvery-white scales that develop in symmetrical patterns on the body, primarily on the scalp, trunk, and limbs.2 Other less common types of psoriasis include guttate psoriasis, which appears most often in children or young adults and presents as small, red dots on the torso or limbs; pustular psoriasis, which can be triggered by medications, infections, or stress, and appears as pus-flled bumps, or pustules, surrounded by red skin typically on the hands and feet; inverse psoriasis, which appears as smooth, red patches in folds of skin which can be made worse by rubbing and sweating; and erythrodermic psoriasis, which is rare and severe and characterized by red, scaly skin over most of the body.2

Psoriasis is typically diagnosed with a medical exam, where providers will gain insight into an individual’s health and history, such as symptoms of itching or burning skin, recent illness or severe stress, utilization of certain pharmacotherapy, family history of psoriasis, and joint tenderness.3

An estimated 30% of individuals with psoriasis will develop psoriatic arthritis (PsA); however, not all cases of PsA develop from psoriasis.3 PsA often presents with the following symptoms: pain, swelling, or stifness in one or more joints; joints that are red and warm to the touch; frequent joint tenderness or stifness; sausagelike swelling in one or more fngers or toes; pain in and around the feet and ankles; changes to the nails, such as pitting or separation from the nail bed; and pain in the lower back, above the tailbone.3 PsA is easier to diagnosis and confrm when a patient has psoriasis; diagnosis typically includes a health history and physical exam with additional blood tests to check the erythrocyte sedimentation rate and uric acid levels, as well as imaging when appropriate.4 Individuals with PsA are more likely to develop diabetes, high blood pressure, high cholesterol, and obesity.4

Treatment Landscape

Treatment of psoriasis is dependent on the type and severity. In mild to moderate cases, individuals with psoriasis can be treated topically with corticosteroids and other topical therapies such as vitamin-D based products, retinoids, coal tar, and anthralin. Phototherapy may be used in some cases. In more severe cases, systemic treatment may be appropriate. Systemic therapies include methotrexate, biologics (tumor necrosis factor (TNF)-alpha inhibitors, interleukin (IL) antagonists), immunosuppressants, and phosphodiesterase 4 (PDE4) inhibitors. comorbidities such as PsA impacts treatment decisions.

The American Academy of Dermatology (AAD) issued guidelines for the treatment of psoriasis in 2020.6 The guidelines included recommendations for the treatment of psoriasis, including topical therapy and alternative modalities.6 The guidelines recommend topical corticosteroids for the treatment of plaque psoriasis not involving intertriginous areas, which can exceed 12 weeks of treatment when supervised by a physician. sparing agents, including vitamin D analogs, tazarotene, and calcineurin inhibitors can be used alone or in combination with steroids to treat psoriasis.6 The AAD recommends that topical treatments be combined with biologics or other systemic agents to increase therapy efcacy.6 The AAD guidelines include a fowchart with guidelines for clinical decision-making to determine whether biologic treatment is appropriate for individual patients, as well as recommendations for ongoing monitoring and screening when biologic treatments are employed.7

The AAD recommends that topical treatments be combined with biologics or other systemic agents to increase therapy efcacy.

Recent Approvals

Apremilast (Otezla®)

In December 2021, the U.S. Food and Drug Administration (FDA) expanded the approval for apremilast (Otezla®, Amgen) for the treatment of adult patients with plaque psoriasis who are candidates for phototherapy or systemic therapy, regardless of disease severity (mild, moderate, or severe). This approval makes apremilast the frst and only oral therapy approved across all plaque psoriasis severities.8 FDA approval was based on the phase three ADVANCE trial of 595 patients with plaque psoriasis randomized to receive either apremilast Results showed that fve times as many individuals with mild-to-moderate plaque psoriasis receiving apremilast achieved the primary endpoint of static Physician Global Assessment (sPGA) response at week 16 compared to placebo (21.6% vs. 4.1%); based

PSORIASIS

on study outcomes, sPGA response is defned as sPGA score of clear (0) or almost clear (1) and with at least a two-point reduction from baseline at week 16.9 The apremilast group had statistically signifcant improvement in the following symptoms compared to the placebo group: Whole Body Itch Numeric Rating Scale (NRS) response (43.2% vs. 18.6%) and Scalp Physician Global Assessment (ScPGA) response (44% vs. 16.6%); for the study, Whole Body Itch NRS response was defned as at least a four-point reduction from baseline, and ScPGA response was defned as clear (0) or almost clear (1) and at least a two-point reduction from baseline at week 16.9 Improvements across these symptom measurements were noted as early as week two and maintained through week 32.9 Adverse reactions associated with treatment with apremilast included diarrhea, headache, nausea, and nasopharyngitis.9

Apremilast is currently being investigated for the treatment of genital psoriasis. The phase three DISCREET study included 289 patients with moderate-to-severe plaque psoriasis with body surface involvement of 1% or greater in the non-genital area who had an inadequate response or intolerance to topical therapy for psoriasis afecting the genital area.10, 11 Participants were randomized to receive either apremilast or placebo. Results showed that patients treated with apremilast achieved clinically meaningful and statistically signifcant improvement in the primary endpoint of modifed static Physician’s Global Assessment of Genitalia (sPGA-G) response compared with placebo.10, 11 In the study, improvement was defned as a score of clear (0) or almost clear (1), with at least a two-point reduction from the baseline at week 16. Secondary endpoints were met with improvements in the Genital Psoriasis Itch Numerical Rating Scale, defned as at least a four-point reduction from baseline score of 4 or greater.10, 11

Payer Impact

In the U.S., psoriasis was associated with an estimated $12.2 billion in medical costs in 2013. Additional cost associated with psoriasis totaled $11.8 billion in reduced health-related quality of life and $11.2 billion in productivity losses.12 Within the specialty category, autoimmune disorders such as psoriasis represent a particularly high-impact therapeutic category.13 Psoriasis is among the top fve conditions that drive drug spend, as annual treatment costs, particularly when biologics are used, can total around $50,000.13 Certain strategies can be used to manage these costs, including utilization management (UM) criteria. UM criteria can be helpful in ensuring that patients are utilizing appropriate and efective dosages of high-cost drugs. Other targeted interventions and digital tools may be valuable in enhancing safety, reducing waste, and improving outcomes. Identifying lower-cost, efective treatment modalities may be efective in managing this category. For example, phototherapy has proven efective for patients with

Psoriasis is among the top fve conditions that drive drug spend, as annual treatment costs, particularly when biologics are used, can total around $50,000.

mild-to-moderate psoriasis and is a lower-cost alternative.

There is a great deal of competition in this category with biologics, non-biologics, and biosimilar agents available as alternatives. There are upcoming biosimilar opportunities in this category, with potential biosimilars for ustekinumab (STELARA®) and certolizumab (CIMZIA®) being investigated. In recent years, the introduction of IL-23 products with less frequent dosing intervals have added additional competition to the space. The introduction of numerous alternatives in the psoriasis treatment landscape may lead to a potential need for more efective cost management for payers. Despite the need for utilization and cost management, a wide variety of treatment options in this category creates the opportunity for efective treatment and improved resolution of psoriasis symptoms.

deucravacitinib (BMS986165) Bristol Myers Squibb oral

rofumilast (ARQ-151) Arcutis Biotherapeutics topical

tapinarof Dermavant Sciences topical

spesolimab (BI 655130) Boehringer Ingelheim IV

bimekizumab (Bimzelx) UCB SC

pending (09/10/2022)

psoriasis pending (07/29/2022)

plaque psoriasis pending (Q2 2022)

antagonist pustular psoriasis pending

antagonist plaque psoriasis pending vunakizumab (SHR-1314) Jiangsu Hengrui Medicine SC

antagonist plaque psoriasis phase three

sonelokimab (M1095) Merck KGaA; Ablynx SC

antagonist plaque psoriasis phase two EDP1815 Evelo Biosciences oral

imsidolimab (ANB019) AnaptysBio SC

Biosimilars

adalimumab biosimilar (AVT02) Alvotech; Teva Pharmaceuticals SC

adalimumab biosimilar (MSB11022) Fresenius SC

agent plaque psoriasis phase two

antagonist pustular psoriasis phase two

inhibitor plaque psoriasis pending (December 2022)

inhibitor plaque psoriasis pending (Q4 2022) adalimumab biosimilar (ABP 501 HC) Amgen SC

inhibitor plaque psoriasis phase three

Abbreviations: IL-17 = interleukin 17; IL-36R = interleukin 36 receptor; IV = intravenous; PDE4 = phosphodiesterase-4; SC = subcutaneous; TNF = tumor necrosis factor; TYK2 = tyrosine kinase 2

References

1. Armstrong, April, et al. “Psoriasis Prevalence in Adults in the United States.” JAMA Dermatology, 30 June 2021, https://jamanetwork. com/journals/jamadermatology/article-abstract/2781378.

2. “Psoriasis.” National Institute of Arthritis and Musculoskeletal and Skin Diseases, 2020, https://www.niams.nih.gov/health-topics/ psoriasis.

3. “Psoriasis: Diagnosis, Treatment, and Steps to Take.” National Institute of Arthritis and Musculoskeletal and Skin Diseases, 2020, https://www.niams.nih.gov/health-topics/psoriasis/diagnosistreatment-and-steps-to-take.

4. “Psoriatic Arthritis.” Johns Hopkins Medicine, https://www. hopkinsmedicine.org/health/conditions-and-diseases/arthritis/ psoriatic-arthritis.

5. Rendon, Adriana, et al. “Psoriasis Pathogenesis and Treatment.” International Journal of Molecular Sciences, March 2019, https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC6471628/#:~:text=Mild%20to%20moderate%20 psoriasis%20can,highly%20relevant%20in%20treatment%20 selection.

6. “Psoriasis Clinical Guideline.” American Academy of Dermatology Association, https://www.aad.org/member/clinical-quality/ guidelines/psoriasis.

7. “Clinical Guideline Flowchart for Treatment Psoriasis Patients Using Biologics.” American Academy of Dermatology Association, https://assets.ctfassets.net/1ny4yoiyrqia/ ijp03p4xuQAsDudu8Es2l/0f337cbec0d0ecec7c3e485bf3a92e19/ AAD-Biologics-pathway.pdf.

8. “FDA approves Otezla® (apremilast) for the treatment of adult patients with plaque psoriasis, regardless of severity level.” Amgen, 20 Dec. 2021, https://www.amgen.com/newsroom/ press-releases/2021/12/fda-approves-otezla-apremilast-for-thetreatment-of-adult-patients-with-plaque-psoriasis-regardless-ofseverity-level.

9. Stein Gold, Linda, et al. “Efcacy and safety of apremilast in patients with mild-to-moderate plaque psoriasis: Results of a phase 3, multicenter, randomized, double-blind, placebo-controlled trial.” Journal of the American Academy of Dermatology, Jan. 2022, https:// pubmed.ncbi.nlm.nih.gov/34343599/.

10. Antrim, Aislinn. “Apremilast Shows Statistically Signifcant Improvements in Genital Psoriasis.” Pharmacy Times, 18 Jan. 2022, https://www.pharmacytimes.com/view/apremilast-showsstatistically-signifcant-improvements-in-genital-psoriasis.

11. “Amgen Announces Positive Top-Line Results from Otezla® (apremilast) Phase 3 DISCREET Study In Moderate to Severe Genital Psoriasis.” Amgen, 1 Dec. 2021, https://www.amgen.com/ newsroom/press-releases/2021/12/amgen-announces-positivetopline-results-from-otezla-apremilast-phase-3-discreet-study-inmoderate-to-severe-genital-psoriasis.

12. Vanderpuye-Orgle, Jacqueline, et al. “Evaluating the economic burden of psoriasis in the United States.” Journal of the American Academy of Dermatology, June 2015, https://pubmed.ncbi.nlm.nih. gov/25882886/#:~:text=The%20total%20burden%20of%20 psoriasis,from%20productivity%20losses%20(32%25).

13. Shah, Prem. “Industry Voices — Reimagining cost management for autoimmune diseases.” Fierce Healthcare, 2 Nov. 2021, https:// www.fercehealthcare.com/payer/industry-voices-reimagining-costmanagement-for-autoimmune-diseases.

Gene Therapy:

Focus on Blood Disorders

Innovative payment models and proper management will be key to managing cost impact and ensuring appropriate patients retain access.

Ben Barner, Pharm.D., MBA Senior Director, Pharmacy

Fallon Health

Gene therapy works via agents that can replace a disease-causing gene with a functioning copy of the gene, deactivate a disease-causing gene that is misfunctioning, or introduce a new or modifed gene to help treat the disease.1 Types of gene therapies include plasmid DNA, viral vectors, bacterial vectors, human gene-editing technology, and patient-derived cellular gene therapy products.1 Presently, gene therapies are available to treat a number of indications, including multiple myeloma, lymphoma, leukemia, prostate cancer, retinal dystrophy, and spinal muscular atrophy.2

The gene therapy landscape continues to expand with a robust pipeline and up to 20 potential approvals over the next few years.3 The investment in research and development for gene therapy is increasing in the biopharmaceutical industry, with advances from gene-insertion methods and innovations allowing therapies to penetrate hard-to-reach tissues.4

Focus on Blood Disorders

Gene therapy may ofer an opportunity for improved outcomes in populations with certain blood disorders. Current research shows promising results associated with gene therapy in patients with beta thalassemia and sickle cell disease, which are the most common severe hereditary blood disorders globally.5 An estimated 1 in 100,000 individuals in the U.S. lives with symptomatic beta thalassemia.6 Sickle cell disease afects 100,000 individuals in the U.S.7 The main treatment for beta thalassemia is recurrent red blood cell transfusions, sometimes occurring as often as every few weeks. While bone marrow or stem cell transplants can ofer a cure for patients with beta thalassemia and sickle cell disease, fnding a donor can be an insurmountable hurdle.5

In treating blood disorders specifcally, the objective is for gene therapies to serve as one-time administrations that target the cause of the disease, ultimately eliminating the need for frequent interventions or a donor.8 Ex vivo gene editing using CRISPR is a recent innovation in the gene therapy feld. This gene editing process uses DNA sequences from bacteria and a CRISPR-associated enzyme to edit the patient’s genome.8 The sequences are then transcribed onto RNA that locates and identifes

GENE THERAPY

Gene therapy may offer an opportunity for improved outcomes in similar patient populations; it is being investigated and researched in the treatment of hemophilia A, hemophilia B, and Fanconi anemia.

DNA sequences that are causing the condition. Packaged together with Cas9, transcribed RNA identifes and locates the targeted sequence and removes it from the DNA, resulting in a repaired or deactivated problematic gene.8

Recent clinical trials have shown some promising outcomes in these populations with gene therapy, and some are currently under FDA review. Gene therapy may ofer an opportunity for improved outcomes in similar patient populations; it is being investigated and researched in the treatment of hemophilia A, hemophilia B, and Fanconi anemia.

Gene Therapy Clinical Trials: Blood Disorders

CTX001

In June 2021, results from a trial of beta thalassemia and sickle cell patients treated with a CRISPR-Cas9-based therapy (CTX001) showed that all 15 patients with beta thalassemia treated with the therapy experienced rapidly improved hemoglobin levels and no longer required transfusions.9 All seven patients with sickle cell disease who received therapy had increased hemoglobin levels and were without severe pain for at least three months.9 Improvements persisted in fve beta thalassemia patients and two sickle cell patients more than a year after treatment.9

Betibeglogene Autotemcel (Zynteglo/formerly LentiGlobin)

The FDA is currently reviewing betibeglogene autotemcel (bluebird bio), formerly LentiGlobin, which is a gene therapy for the treatment

of beta thalassemia. In an open-label, phase 3 study, the efcacy and safety of betibeglogene autotemcel, also referred to as beticel, in adult and pediatric patients with transfusion-dependent beta thalassemia (TDT) was assessed with transfusion independence as the primary endpoint.10 The endpoint was reached in 20 of 22 patients (91%), which includes 6 of 7 patients who were 12 years of age or younger (86%).10 Of the patients in the study, four had at least one adverse event determined to be related or possibly related to treatment. All adverse events were nonserious with the exception of thrombocytopenia in one patient.10 The treatment is already approved in the European Union as Zynteglo®

In November 2021, the Institute for Clinical and Economic Review (ICER) assessed the comparative clinical efectiveness and value of betibeglogene autotemcel for the treatment of beta thalassemia.11 In a draft evidence report, ICER concluded that the evidence suggests that betibeglogene autotemcel provides net health benefts to patients with TDT.11 Additionally, when considering the high annual costs of standard care for TDT, traditional costefectiveness modeling fnds betibeglogene autotemcel meets commonly accepted value thresholds at a cumulative price of $2.1 million if paid through an outcomes-based contract for patients with sustained transfusion independence.11

Valoctocogene roxaparvovec (Roctavian)

In August 2020, BioMarin received a Complete Response Letter (CRL) for valococogene roxaparvovec (Roctavian) for severe hemophilia A.12 In the CRL, the FDA requested at least two additional years of data in order to confrm safety and efcacy for substantial evidence of a durable efect using annual bleed rate (ABR) as the primary endpoint.12 BioMarin announced results from an ongoing phase three study, GENEr8-1.13 Results from the study show that ABR was signifcantly reduced by 4.1 treated bleeds per year, or 85% from a baseline mean of 4.8, in the pre-specifed primary analysis in participants from a prior study.13 Through the entire efcacy evaluation period, the mean ABR was 0.8; median ABR was 0.9 during year one and 0.7 during year two.13 Study results also showed valoctocogene roxaparvovec signifcantly reduced mean annualized Factor VIII infusion rate by 133 infusions per year, or 98% from baseline.13 Overall, valoctocogene roxaparvovec was well tolerated. Most common adverse reactions included transient infusion associated reactions and mild to moderate rise in liver enzymes with no longlasting clinical sequelae, as well as headache, nausea, aspartate aminotransferase elevation, and fatigue.13

A Biologics License Application is anticipated to be resubmitted in September 2022.

Drug Manufacturer

betibeglogene autotemcel (Zynteglo/formerly LentiGlobin) bluebird

valoctocogene roxaparvovec (Roctavian)

fdanacogene elaparvovec (PF-06838435) Spark Therapeutics/Pfzer IV

etranacogene dezaparvovec (AMT-061) uniQure/CSL Behring

giroctocogene ftelparvovec (SB-525) Sangamo Therapeutics/Pfzer IV

SB-FIX Sangamo Therapeutics IV

SPK-8011 Roche/Spark Therapeutics IV hemophilia A phase two

SHP654 Shire/Baxalta IV hemophilia A phase two

DTX201 Dimension Therapeutics/Bayer IV hemophilia A phase two

Other

elivaldogene autotemcel (Lenti-D™) bluebird bio IV adrenoleukodystrophy pending (09/16/2022)

olenasufigene relduparvovec (LYS-SAF302) Lysogene other mucopolysaccharidosis type IIIA phase three

timrepigene emparvovec (AAV2-REP1) Biogen/Nightstar Therapeutics intravitreal Choroideremia phase three

lenadogene nolparvovec (GS010) GenSight ophthalmic Leber hereditary optic neuropathy phase three

EB-101 Abeona Therapeutics other epidermolysis bullosa phase three

simoladagene autotemcel (OTL-101) Orchard Therapeutics injectable severe combined immunodefciency phase three

fordadistrogene movaparvovec (PF-06939926) Pfzer IV Duchenne muscular dystrophy phase three

debcoemagene autofcel (D-Fi) Paragon Biosciences/Castle Creek Biosciences injectable Epidermolysis bullosa phase three Gene Therapy Pipeline

Managed Care Impact

While the potential curative outcomes associated with gene therapy are exciting, these treatments are expensive, and the economic burden on payers can be excessive.2 The cost for available gene therapy ranges from around $370,000 to $2.1 million for single-dose treatments.2 Payers have proposed various alternative payment strategies that would spread costs over time; some include supplemental stop-loss strategies, outcomes-

based contracts, installment payments, and performance-based annuities.2 Payers may consider certain steps when managing patient access to this type of advanced therapy, such as:2

• Beneft assessment (medical vs. pharmacy).

• Contract assessment (cost reimbursement and rates).

• Clinical assessment (prior authorization use or ancillary services scope).

This category will continue to be a high priority for payers as the gene therapy landscape continues to expand and ofer exciting potential curative opportunities for patients.

• Utilization notifcation process (gene therapy usage communication).

• Management and monitoring (ongoing treatment and outcomes).

• Afordability and risk assessment (utilization likelihood and fnancial stability).

In 2016, the Massachusetts Institute of Technology’s NEWDIGS initiative launched the Financing and Reimbursement of Cures in the U.S. (FoCUS) project, aiming to outline the challenges and fnancial impact created by gene therapy and provide models to manage the economic burden. 14 Two surveys were conducted to assess payer perspectives on the management of high-cost therapies. In 2017, the frst FoCUS survey illustrated that payers had variable awareness and readiness to manage the new cost of the emerging gene therapies (namely, LUXTURNA ® at the time). 14 Of respondents, a third were newly aware and learning about these therapies, with 40% observing and waiting and 27% engaged in management. 14 Respondents were overall open to fnancing strategies, and nearly half were willing to engage in innovative payment models, performancebased annuities, and risk pooling. 14 The more recent FoCUS survey represented 153 payer segments, including fully insured plans, self-insured employers, Medicare, and Medicaid. 14 Payers reported concerns about fnancial risk and impact of high-cost therapies; however, nearly all responders are covering the available gene therapies. 14 Survey responses show a motivation to manage the fnancial risk associated with gene therapy, giving it a high priority in the near future.14 Finally, payers reported seeing value in alternative fnancing models, including reduction in the upfront budget impact of new therapy, alignment of the timing of therapy costs with benefts, and limitation of payment for therapy that works by including performance-based requirements for initial or continued payment. 14 Other payer surveys showed that payers were generally becoming more aware of and concerned about the management of gene therapies, with 100% of payers

starting to consider coverage or operational issues associated with these treatments. 14

Payers have identifed numerous concerns related to gene therapy’s management and strategy. These concerns include:14

• Operational barriers such as program administration complexity, identifcation of milestone measures, and information burden for tracking patients.

• Strategic barriers such as payers for patients who are no longer insured or who no longer respond to therapy.

• Structural barriers such as uncertainty in cost accounting for multi-year agreements, pricing and reporting regulations, insurance regulatory barriers, and the CMS regulatory burden.

Payers have grown more aware of the need for proper gene therapy management. In turn, some now manage the category using many of the current management strategies employed for other high-cost treatments.14 Others have used diferent methods, with many implementing short-term, milestone-based contracts. In these contracts, gene therapies are paid for upfront with potential for refunds tied to failure to achieve performance or outcome metrics over the two years following treatment.14

This category will continue to be a high priority for payers as the gene therapy landscape continues to expand and ofer exciting potential curative opportunities for patients, specifcally in the ever-growing pipeline for gene therapy for blood disorders. Innovative payment models and proper management will be key to ensuring access to the appropriate patients and managing cost impact.

References

1. “What is Gene Therapy?” U.S. Food & Drug Administration, 25 July 2018, https://www.fda.gov/vaccines-blood-biologics/cellular-genetherapy-products/what-gene-therapy.

2. Thomas, Joe. “Cell and Gene Therapy: Key Payer Considerations.” Truveris, 12 Aug. 2021, https://truveris.com/cell-gene-therapypayer-considerations/.

3. 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.

4. Weintraub, Arlene. “The next generation of gene therapy for rare diseases forges ahead as developers weather hurdles.” Fierce Biotech, 14 Dec. 2020, https://www.fercebiotech.com/biotech/ next-generation-gene-therapy-for-rare-diseases-forges-ahead-asdevelopers-weather-hurdles.

5. “Clinical Trial for Beta-Thalassemia Brings Important Insights for Treating Blood Disorders with Stem Cell Gene Therapy.” Memorial Sloan Kettering Cancer Center, 6 Jan. 2022, https://www.mskcc.org/ news/clinical-trial-beta--thalassemia-brings-important-insightstreating-blood-disorders-stem-cell-gene-therapy.

6. “Beta Thalassemia.” National Organization for Rare Disorders, 2018, https://rarediseases.org/rare-diseases/thalassemiamajor/#afected-populations.

7. “Sickle Cell Disease (SCD).” Centers for Disease Control and Prevention, May 2022, https://www.cdc.gov/ncbddd/sicklecell/data. html.

8. Daley, Jim. “Four Success Stories in Gene Therapy.” Scientifc American, 1. Nov. 2021, https://www.scientifcamerican.com/article/ four-success-stories-in-gene-therapy/.

9. “Vertex and CRISPR Therapeutics Present New Data in 22 Patients with Greater than 3 Months Follow-Up Post-Treatment with Investigational CRISPR/Cas9 Gene-Editing Therapy, CTX001™ at European Hematology Association Annual Meeting.” Vertex, 11 June 2021, https://investors.vrtx.com/news-releases/news-releasedetails/vertex-and-crispr-therapeutics-present-new-data-22patients.

10. Locatelli, Franco, et al. “Betibeglogene Autotemcel Gene Therapy for Non- β0/β0 Genotype β-Thalassemia.” The New England Journal of Medicine, 3 Feb. 2022, https://www.nejm.org/doi/full/10.1056/ NEJMoa2113206.

11. Beaudoin, Francesca L., et al. “Betibeglogene Autotemcel for Beta Thalassemia: Efectiveness and Value.” Institute for Clinical and Economic Review, 13 Apr. 2022, https://icer.org/wp-content/ uploads/2021/11/ICER_Beta-Thalassemia_Draft-Report_041322. pdf.

12. “BioMarin Receives Complete Response Letter (CRL) from FDA for Valoctocogene Roxaparvovec Gene Therapy for Severe Hemophilia A.” BioMarin, Aug. 2020, https://investors.biomarin.com/202008-19-BioMarin-Receives-Complete-Response-Letter-CRL-fromFDA-for-Valoctocogene-Roxaparvovec-Gene-Therapy-for-SevereHemophilia-A.

13. “BioMarin Announces Stable and Durable Annualized Bleed Control in the Largest Phase 3 Gene Therapy Study in Adults with Severe Hemophilia A; 134-Participant Study Met All Primary and Secondary Efcacy Endpoints at Two Year Analysis.” BioMarin, Jan. 2022, https://investors.biomarin.com/2022-01-09-BioMarin-AnnouncesStable-and-Durable-Annualized-Bleed-Control-in-the-LargestPhase-3-Gene-Therapy-Study-in-Adults-with-Severe-HemophiliaA-134-Participant-Study-Met-All-Primary-and-Secondary-EfcacyEndpoints-at-Two-Year-Analysis.

14. Barlow, Jane F., et al. “Payer Perspectives on Gene Therapy Reimbursement.” PharmExec.com, 7 Apr. 2020, https://www. pharmexec.com/view/payer-perspectives-gene-therapyreimbursement

Chronic Heart Failure:

Treatment and Management Update

The payment landscape in heart failure management is evolving, and value-based models are being utilized more frequently.

Lindsay Speicher, JD Project Manager, Specialty Magellan Rx Management

Chronic heart failure is a progressive syndrome occurring when the heart cannot pump enough blood and oxygen to support other organs.1 Currently, an estimated 6.2 million Americans have heart failure, and the condition was noted on 13.4% of death certifcates in 2018.1 The total cost of care for heart failure was estimated at $43.6 billion in the U.S. in 2020, with more than 70% attributed to medical costs. The annual total cost of care for heart failure is projected to increase by more than $25 billion, to $69.7 billion by 2030.2

Common symptoms occurring in individuals with heart failure include shortness of breath during daily activities; having trouble breathing while lying down; weight gain with swelling in the feet, legs, ankles, or stomach; and a general feeling of tiredness or weakness. Heart failure can occur secondary to other medical conditions, including coronary artery disease, heart attacks, diabetes, high blood pressure, obesity, valvular heart disease, and other conditions related to heart disease.1

Heart failure is typically classifed by providers according to the severity of the symptoms. The most commonly used system is the New York Heart Association Functional Classifcation (Table 1), which categorizes patients in one of four classes determined by limitations during physical activities.3

In March 2021, a universal defnition and classifcation of heart failure was proposed from the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society, and Writing Committee of the Universal Defnition of Heart Failure (Table 2).5 The publication also set forth new and revised classifcations of heart failure, according to left ventricular ejection fraction (LVEF).5

Treatment

Heart failure can often be treated with the objective of improving symptoms. Management often includes a comprehensive plan of pharmaceutical therapy, lifestyle changes, and devices or surgical procedures, when needed. Therapies for heart failure often include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor lockers (ARBs or angiotensin-2 receptor antagonists), angiotensin-receptor neprilysin inhibitors (ARNIs), If channel blockers, beta blockers, aldosterone antagonists, hydralazine and isosorbide dinitrate, or diuretics. Less commonly utilized drugs for heart failure include anticoagulants, statins, and digoxin.6 In a 2021 update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment, SGLT2 inhibitors are now included in the guidelines as a frst-line medication for all populations in the treatment of HFrEF.7

For patients with severe heart failure, implantable defbrillators, or ICDs, may be appropriate; these are surgically implanted and deliver electro counter-shocks when abnormal rhythms are detected. Cardiac resynchronization therapy (CRT) is used in patients with heart failure who develop abnormal conduction of the heart’s electrical system impacting the efciency of the heartbeat. While used less frequently to treat heart failure, surgical procedures are recommended when a correctable defect is identifed as causing the heart failure. In these cases, heart transplantation; percutaneous coronary intervention, or angioplasty; coronary artery bypass; or valve replacement may be appropriate.8

Table 1. New York Heart Association (NYHA)

Functional Classifcation4

Class Patient Symptoms

I No physical activity limitation

No undue fatigue, palpitation, or dyspnea with ordinary physical activity

II Slight physical activity limitation

Comfort at rest

Fatigue, palpitation, or dyspnea with ordinary physical activity

III Marked physical activity limitation

Comfort at rest

Fatigue, palpitation, or dyspnea with even less than ordinary activity

IV Cannot do physical activity without discomfort

Symptoms persist at rest

Discomfort increases with any physical activity

Class Objective Assessment

A No evidence of cardiovascular disease

No symptoms or limitations to ordinary physical activity

In a 2021 update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment, SGLT2 inhibitors are now included in the guidelines as a frst-line medication for all populations in the treatment of HFrEF.

Recent Approvals

E ag if zi (JARDIANCE®)

In August 2021, the FDA approved empaglifozin (JARDIANCE® , Lilly) 10 mg indicated to reduce the risk of cardiovascular death plus hospitalization for heart failure in adults with HFrEF. Treatment with empaglifozin can be initiated in adults with HFrEF with an eGFR as low as 20 mL/min/1.73 m2.9 The EMPEROR-Reduced phase three trial investigated the efort of adding empaglifozin 10 mg versus placebo to standard of care in adults with and without type 2 diabetes who had heart failure and LVEF of 40% or less.9 Treatment with empaglifozin signifcantly reduced the risk of primary composite endpoint in time to cardiovascular death or hospitalization for heart failure by 25%, compared to placebo. The study results also showed that treatment with empaglifozin signifcantly reduced the relative risk of frst and recurrent hospitalization for heart failure by 30% (388 events for empaglifozin vs. 553 for placebo).9

B Some objective evidence of minimal cardiovascular disease

Mild symptoms and slight limitation during ordinary activity

Comfort at rest

C Objective evidence of moderate-to-severe cardiovascular disease

Comfort only at rest

Marked limitation in activity, even during less than ordinary activity

D Objective evidence of severe cardiovascular disease

Symptoms persist even at rest

Severe limitations to activity

After that approval, results were presented at a European Society of Cardiology meeting that demonstrated empaglifozin plus standard of care were associated with a 21% reduction for composite primary endpoint of cardiovascular death or hospitalization in adults with HFpEF versus the placebo plus standard of care.10 There was also a signifcant relative risk reduction for hospitalization in those treated with empaglifozin (27%).10

CHRONIC HEART FAILURE

Tables 2a and 2b. Universal Defnition and Classifcation of Heart Failure: Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society, and Writing Committee of the Universal Defnition of Heart Failure Treatment Pipeline5

A At

B

C

D

HFrEF reduced EF; LVEF <40%

HFmrEF mildly reduced EF; LVEF 41% to 49%

HFpEF preserved EF; LVEF >50%

HFimpEF improved EF; baseline LVEF <40%, a >10-point increase from baseline LVEF, second measurement of LVEF >40%

Sacubitri /Va sarta (ENTRESTO®)

The FDA granted sacubitril/valsartan (ENTRESTO ®, Novartis) approval as the frst therapy to treat patients with HFpEF. The expanded indication for this treatment is to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure. While the study fell short of hitting its primary endpoint, the FDA Cardiovascular

and Renal Drugs Advisory Committee found that sacubitril/ valsartan was worth an indication based on results from the PARAGON-HF trial. 11 The trial showed that sacubitril/valsartan reduced the composite primary endpoint of total heart failure hospitalizations and cardiovascular death by 13%; there was a nearly 15% reduction in total heart failure hospitalizations. Results also showed that sacubitril/valsartan patients experienced less worsening in quality of life based on KCCQ Clinical Summary scores as well as more favorable change in the New York Heart Association class and a reduction in the risk of composite renal endpoint. 12

Vericiguat (VERQUVO®)13

Vericiguat (VERQUVO ®, Merck) received FDA approval for the reduction in risk of cardiovascular death and heart failure hospitalization following a hospitalization for heart failure or need for outpatient IV diuretics in adults with symptomatic chronic heart failure and ejection fraction less than 45%.

The VICTORIA trial included 5,050 adult patients with symptomatic heart failure and LVEF less than 45% following a worsening heart failure event. The study sought to determine whether vericiguat is superior to placebo in combination with other heart failure therapies, in reducing the risk of cardiovascular death or heart failure hospitalization in adults with symptomatic chronic heart failure and ejection fraction less than 45% following a worsening heart failure event; this primary objective was met based on a time-to-event analysis. Vericiguat was associated with a 4.2% reduction in annualized absolute risk when compared to placebo. Adverse events included hypotension and anemia.

Classifcation Heart failure with:

Heart Failure

fnerenone (KERENDIA®) Bayer oral mineralocorticoid receptor antagonist phase three RA

tirzepatide (LY3298176) Lilly SC GLP-1 agonist phase three CD; UC AZD4831 AstraZeneca oral MPO inhibitor phase three RA; JIA

mavacamten (MYK-461) MyoKardia; Bristol Myers Squibb oral cardiac muscle myosin inhibitor phase two plaque psoriasis

IONIS-AGT-LRx Ionis Pharmaceuticals SC antisense oligonucleotide phase two plaque psoriasis; RA

Acute Heart Failure

Istaroxime Windtree Therapeutics/ Sigma-Tau Pharmaceuticals IV SERCA2a phase two plaque psoriasis

Chronic Heart Failure

omecamtiv mecarbil (AMG 423) Amgen; Servier Laboratories oral cardiac muscle myosin activator pending (11/30/22)

rexlemestrocel-L (Revascor) Mesoblast other stem cell therapy phase three

Post-Myocardial Infarction Heart Failure or Left-Ventricular Dysfunction

omecamtiv mecarbil (AMG 423) Amgen; Servier Laboratories oral cardiac muscle myosin activator phase two

fribastat (QGC001) Quantum Genomics oral aminopeptidase A inhibitor phase two

Abbreviations: GLP-1 = glucagon-like peptide-1; IV = intravenous; MPO = myeloperoxidase; SC = subcutaneous; SERCA2a = sarcoplasmic reticulum calcium ATPase

Payer Impact

Currently in the U.S., heart failure is a leading cause of hospitalizations and readmissions, particularly among the elderly, with approximately 30% to 40% of heart failure patients having a history of hospitalization for heart failure. 15 A 2020 review of medical costs associated with heart failure showed that hospitalizations are a key driver of costs. 2 The review also noted that costs are typically higher among patients with HFrEF when compared to HFpEF; thus, there may be value in differentiating between the types of heart failure in management. 2

The current payment system for heart failure care is largely feefor-service reimbursement, which has impacted the quality of care, while the prevalence and costs in the category continue

to rise. The payment landscape in heart failure management is evolving, and value-based models are being utilized more frequently. Since the current alternative payment models addressing heart failure typically focus on short-term episodes and acute events or procedures, there is a gap in management for heart failure patients who need long-term care and prevention strategies. The Value-Based Models Learning Collaborative of the Value in Healthcare Initiative, a collaboration between the American Heart Association and the Duke-Margolis Center for Health Policy at Duke University, developed a framework for a heart failure value-based payment model that focuses longitudinally on disease management and prevention for stage C heart failure population. 15 Innovative approaches to managing this population may be key to ensuring proper and cost-efective care. Drug

cancer patients receiving bone marrow or myelosuppression

AML patients receiving induction or consolidation chemotherapy

cancer patients receiving bone marrow or myelosuppression

AML patients receiving induction or consolidation chemotherapy

CHRONIC HEART FAILURE

References

1. “Heart Failure.” Centers for Disease Control and Prevention, 2020, https://www.cdc.gov/heartdisease/heart_failure.htm.

2. Urbich, Michael, et al. “A Systematic Review of Medical Costs Associated with Heart Failure in the USA (2014-2020).” PharmacoEconomics, 19 Aug. 2020, https://link.springer.com/ article/10.1007/s40273-020-00952-0.

3. “Classes of Heart Failure.” American Heart Association, https://www. heart.org/en/health-topics/heart-failure/what-is-heart-failure/ classes-of-heart-failure.

4. Spacie, Robin, et al. “Heart failure.” InnovAiT, 25 Mar. 2019, https:// journals.sagepub.com/doi/10.1177/1755738019829789.

5. Bozkurt, Biykem, et al. “Universal Defnition and Classifcation of Heart Failure: A Report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Defnition of Heart Failure.” Journal of Cardiac Failure, Apr. 2021, https://www.sciencedirect.com/science/article/pii/ S1071916421000506?via%3Dihub.

6. “Medications Used to Treat Heart Failure.” American Heart Association, https://www.heart.org/en/health-topics/heart-failure/ treatment-options-for-heart-failure/medications-used-to-treatheart-failure.

7. Maddox, Thomas, et al. “2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure with Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee.” Journal of the American College of Cardiology, 16 Feb. 2021, https://www. sciencedirect.com/science/article/pii/S0735109720378670.

8. “Devices and Surgical Procedures to Treat Heart Failures.” American Heart Association, https://www.heart.org/en/health-topics/heartfailure/treatment-options-for-heart-failure/devices-and-surgicalprocedures-to-treat-heart-failure.

9. “US FDA approves Jardiance® (empaglifozin) to treat adults living with heart failure with reduced ejection fraction.” Lilly, 18 Aug. 2021, https://investor.lilly.com/news-releases/news-releasedetails/us-fda-approves-jardiancer-empaglifozin-treat-adultsliving.

10. Kansteiner, Fraiser. “ESC 2021: Eli Lilly, Boehringer’s Jardiance racks up data for 2nd nod in crowded heart failure feld.” Fierce Pharma, 27 Aug. 2021, https://www.fercepharma.com/pharma/esc-2021lilly-boehringer-s-jardiance-sets-course-to-second-heart-failurenod.

11. Cafrey, Mary. “Entresto Wins First NDA Nod in Hard-to-Treat Type of Heart Failure.” American Journal of Managed Care, 16 Feb. 2021, https://www.ajmc.com/view/entresto-wins-frst-fda-nod-in-hard-totreat-type-of-heart-failure/.

12. “Novartis PARGON-HF trial suggests Entresto® beneft in HFpEF patients but narrowly misses primary endpoint.” Novartis, 1 Sept. 2019, https://www.novartis.com/news/media-releases/novartisparagon-hf-trial-suggests-entresto-beneft-hfpef-patients-narrowlymisses-primary-endpoint.

13. “Merck Announces U.S. FDA Approval of VERQUVO® (vericiguat).” Merck, 20 Jan. 2021, https://www.merck.com/news/merckannounces-u-s-fda-approval-of-verquvo-vericiguat/.

14. IPD Analytics. “Chronic Heart Failure.” https://ipdanalytics.com.

15. Joynt Maddox, Karen, et al. “Advancing Value-Based Models for Heart Failure.” Circulation: Cardiovascular Quality and Outcomes, 12 May 2020, https://www.ahajournals.org/doi/10.1161/ CIRCOUTCOMES.120.006483.

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CAR-T Update:

Multiple Myeloma Advances and Payer Impact

CAR-T therapies for multiple myeloma, while not curative, could have a major impact on patients who have few or no other treatment options.

Timothy O’Shea, M.S., Pharm.D Manager, Clinical Pharmacy

New Jersey

Multiple myeloma is blood cancer that afects the plasma cells found in bone marrow.1, 2 These cells produce antibodies that play a key role in helping the immune system fght of infection. Multiple myeloma causes these plasma cells to mutate and grow out of control, producing an abnormal antibody called M protein.1, 2 The multiplication of these cancer cells causes a decrease in red blood cells, white blood cells, and platelets, which often leads to anemia, excessive bleeding, and a compromised immune system. Other complications associated with multiple myeloma include bone damage, hypercalcemia, and kidney damage.1, 2

About 1 in 132 individuals in the U.S. will be diagnosed with multiple myeloma every year.3 Estimates for 2022 predict that more than 34,000 new cases will be diagnosed and 12,600 deaths will occur this year.3

Current Treatment Landscape

NCCN guide i es4

For patients with multiple myeloma, primary treatment is determined by whether or a not a patient is eligible for stem cell transplant, as certain drugs can cause severe damage to healthy cells in bone marrow, making it more challenging to harvest stem cells for transplant. According to National Comprehensive Cancer Network (NCCN) Guidelines from 2022, the preferred primary therapy regimen for transplant candidates

Horizon Blue Cross Blue Shield

is bortezomib/lenalidomide/dexamethasone, with lenalidomide as preferred maintenance therapy. Preferred primary therapies for non-transplant candidates include: bortezomib/lenalidomide/dexamethasone or daratumumab/lenalidomide/dexamethasone, with lenalidomide preferred as maintenance therapy. For patients with previously treated multiple myeloma, preferred regimens for early relapses (one to three prior therapies) include: bortezomib/lenalidomide/dexamethasone, carflzomib/lenalidomide/dexamethasone, daratumumab/(bortezomib or carflzomib or lenalidomide)/dexamethasone, ixazomib/lenalidomide/dexamethasone, and isatuximab-irfc/carflzomib/dexamethasone. For patients with late relapses (more than three prior therapies), NCCN guidelines recommend belantamab mafodotin-blmf or idecabtagene vicleucel.

Recent Approvals

Idecabtage e vic euce (ABECMA®)

In March 2021, the FDA approved the frst cell-based gene therapy for the treatment of adult patients with multiple myeloma.5 Approval was granted to idecabtagene vicleucel (ide-cel) (ABECMA®) for adult patients with multiple myeloma who have not responded to, or whose disease has returned after, at least four prior lines of therapy.5 Ide-cel is a B-cell maturation antigen-directed genetically modifed autologous CAR-T therapy.5

A multicenter study of 128 patients with relapsed myeloma and

refractory myeloma who received at least three prior antimyeloma lines of therapy was conducted to assess safety and efcacy of ide-cel.6 Results of the study showed 73% of patients partially or completely responded to treatment, with 33% of patients showing a complete response, or disappearance of all signs of myeloma.6 Confrmed minimal residual disease-negative status (<10-5 nucleated cells) was observed in 28% of treated patients, and 79% of those had a complete response or better.6 Median progression-free survival was 8.8 months.6 Toxic adverse efects observed in participants included neutropenia (91%), anemia (70%), and thrombocytopenia (63%). Cellular kinetic analysis confrmed CAR-T cells in 59% of patients at six months and 36% at 12 months after infusion.6

Severe potential adverse events associated with ide-cel treatment include cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis/macrophage activation syndrome, neurologic toxicity, and prolonged cytopenia, which can all be fatal or lifethreatening.5 The most common adverse reactions to ide-cel include CRS, fatigue, musculoskeletal pain, and a weakened immune system. Due to the risk of serious side efects, ide-cel has been approved with a REMS strategy.5 REMS program requires hospitals and their associated clinics that dispense the treatment to be certifed and staf involved in prescribing, dispensing or administering ide-cel to be trained to recognize and manage CRS, nervous system toxicities and other side efects.5 Patients must be comprehensively informed of the potential side efects and the importance of promptly returning to the treatment site in the event that side efects occur.5

Ci tacabtage e aut euce (CARVYKTI®)

In February, the U.S. Food and Drug Administration (FDA) approved ciltacabtagene autoleucel (cilta-cel) (CARVYKTI®, Janssen Biotech) for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.7 This therapy is a B-cell maturation antigendirected genetically modifed autologous CAR-T therapy; doses are customized using a patient’s own T-cells, which are collected, genetically modifed, and infused back into the patient.7 The CARTITUDE-1, open-label, multicenter clinical trial evaluated safety and efcacy of cilta-cel in 97 patients with relapsed or refractory multiple myeloma who received at least three prior lines of therapy, which included a proteasome inhibitor, immunomodulatory agent, and an anti-CD38 monoclonal antibody.8 Patients also had disease progression on or after the last chemotherapy regimen. In the trial, patients received cilta-cel within the range of 0.5 to 1.0 x 106 CAR-positive viable T cells per kg of body weight.8 The trial, which

CAR-T UPDATE |

Drug

teclistamab (JNJ-7957) Janssen Biotech SC

iberdomide (CC-220) Celgene; Bristol Myers Squibb oral

motixafortide (BL8040)

BioLineRx; Biokine Therapeutics SC

established efcacy based on overall response rate and duration of response, was evaluated by an independent review committee using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.8 Results showed the overall response rate was 97.9%. The overall survival rate was 89%, and the 12-month progression-free rate was 77%.8 Among participants, hematological adverse events were common, including neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%).8 The cilta-cel label includes warning for cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis/ macrophage activation syndrome, Immune Efector Cell-Associated Neurotoxicity Syndrome, Parkinsonism and Guillain-Barre syndrome and their associated complications, and prolonged and/or recurrent cytopenia.8 This product is approved with a REMS with the requirement that hospitals and their associated clinics dispensing the therapy are specially certifed to recognize and manage CRS and nervous system toxicities.8 The FDA is requiring that Janssen Biotech conduct a postmarketing observational study involving patients treated with cilta-cel with the objective of evaluating long-term safety.7

ICER Review: CAR-T Therapies

In an April 2021 review, the Institute for Clinical and Economic Review (ICER) evaluated the clinical and cost-efectiveness of both cilta-cel and ide-cel.9 For both, a majority of the panel voted that the CAR-T therapies demonstrated a net health beneft superior to usual care, but that there was insufcient evidence to determine whether one of the therapies was superior to the other as there are no headto-head studies.9 ICER also determined that ide-cel and cilta-cel had positive efects on the patient’s and caregiver’s quality of life and the patient’s ability to manage and sustain treatment.9 A majority of the panel found ide-cel had low long-term value for the current cost; pricing was not available for cilta-cel at the time of the review.9

anti-CD3 antibody; Anti-B-cell maturation antigen pending (2H 2022)

cereblon E3 ligase modulator phase three

CXCR4 antagonist phase three

CAR-T Impact on Payers and Management Strategies

In recent years, the uptake of CAR-T therapy has been expanding; CAR-T therapy claims are doubling every six months, according to an analysis of the Medicare fee-for-service population.10 The introduction of CAR-T as a treatment option for those with multiple myeloma will likely contribute to a continuing trend of increased uptake of CAR-T. Historically, the fve-year survival rate for multiple myeloma is 54%, and many patients do not respond efectively to standard multiple myeloma therapies, or relapse after treatment.11 With more CAR-T therapies available for this population, patients with relapsed or refractory multiple myeloma may have a promising opportunity for improved outcomes. In the coming years, these products could also see use in earlier line settings in multiple myeloma, pending results from ongoing studies and FDA approval.12 However, with multiple treatment options for multiple myeloma, including CAR-T, providers will need to determine the most appropriate treatment for patients, and payers will have to actively manage the category to ensure patients have access to treatment. CAR-T therapies for multiple myeloma, while not curative, could have a major impact on patients who have few or no other treatment options.

As many drug therapies that treat multiple myeloma are utilized in combination, costs are driven up with a range of $220,000 to $300,000 per treatment.13 Considering these high costs of the standard of care for multiple myeloma, while the price of CAR-T therapies may present a fnancial burden for both patients and payers, cost-efectiveness analyses, including ICER review, suggest CAR-T therapies for multiple myeloma could have signifcant value at their current price as well as small to substantial net health benefts over standard of care.9 Still, payers should consider certain criteria for eligibility in order to provide access to these medications to appropriate patients while managing costs. Payers should also be cognizant of the budget impact of these products expanding to earlier line settings and explore opportunities for innovative contracting models (e.g., global case rates) to manage the cost of CAR-T.

Multiple Myeloma Pipeline

References

1. “What is Multiple Myeloma?” American Cancer Society, 2018, https://www.cancer.org/cancer/multiple-myeloma/about/what-ismultiple-myeloma.html.

2. “Understanding Multiple Myeloma.” Multiple Myeloma Research Foundation, https://themmrf.org/multiple-myeloma/.

3. “Key Statistics About Multiple Myeloma.” American Cancer Society, 2022, https://www.cancer.org/cancer/multiple-myeloma/about/ key-statistics.html#:~:text=Multiple%20myeloma%20is%20a%20 relatively,men%20and%2015%2C370%20in%20women).

4. Callander, Natalie, et al. “NCCN Guidelines® Insights: Multiple Myeloma, Version 3.2022.” Journal of the National Comprehensive Cancer Network, Jan. 2022, https://jnccn.org/view/journals/ jnccn/20/1/article-p8.xml.

5. “FDA D.I.S.C.O. Burst Edition: FDA approval of ABECMA (idecabtagene vicleucel) the frst FDA approved cell-based gene therapy for the treatment of adult patients with relapsed or refractory multiple myeloma.” U.S. Food & Drug Administration, Apr. 2021, https://www.fda.gov/drugs/resources-information-approveddrugs/fda-disco-burst-edition-fda-approval-abecma-idecabtagenevicleucel-frst-fda-approved-cell-based#:~:text=On%20March%20 26%2C%202021%2C%20the,an%20anti%2DCD38%20 monoclonal%20antibody.

6. Munshi, Nikhil, et al. “Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma.” The New England Journal of Medicine, 25 Feb. 2021, https://www.nejm.org/doi/full/10.1056/ nejmoa2024850.

7. “FDA D.I.S.C.O. Burst Edition: FDA approval of CARVYKTI (ciltacabtagene autoleucel) for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.” U.S. Food & Drug Administration, Mar. 2022, https://www.fda.gov/ drugs/resources-information-approved-drugs/fda-disco-burstedition-fda-approval-carvykti-ciltacabtagene-autoleucel-treatmentadult-patients.

8. Berdeja, Jesus, et al. “Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study.” The Lancet, 24 July 2021, https://www.thelancet.com/journals/lancet/article/PIIS01406736(21)00933-8/fulltext.

9. “Anti B-Cell Maturation Antigen CAR T-cell and Antibody Drug Conjugate Therapy for Heavily Pre-Treated Relapsed and Refractory Multiple Myeloma.” Institute for Clinical and Economic Review, 11 May 2021, https://icer.org/wp-content/uploads/2020/10/ICER_ Multiple-Myeloma_Final-Report_Update_09102021.pdf.

10. Cafrey, Mary. “Real-world data ofer good news for CAR T-cell therapy.” American Journal of Managed Care, 15 Dec. 2020, www. ajmc.com/view/real-world-data-ofers-good-news-for-car-t-celltherapy.

11. “Multiple Myeloma: Statistics.” Cancer.Net, Feb. 2020, https://www.cancer.net/cancer-types/multiple-myeloma/ statistics#:~:text=Multiple%20myeloma%20is%20not%20 a,be%20diagnosed%20with%20multiple%20myeloma.

12. Liu, Angus. “ASCO: J&J, Legend reveal more CAR-T data and a look at Carvykti for earlier myeloma in a diferent population.” Fierce Pharma, 26 May 2022, https://www.fercepharma.com/pharma/ asco-jj-legend-unfold-more-car-t-data-and-look-carvykti-earliermyeloma-difcult-population.

13. “Can We Aford the Cost of Myeloma Therapy?” Medscape, 25 June 2018, http://www.medscape.com/viewarticle/898450.

Biosimilars Update:

Recent Approvals and Pipeline

The biosimilar landscape has steadily expanded since the approval of the frst biosimilar in the U.S. in 2013. These products continue to hold interest for healthcare stakeholder, as they often present an opportunity for competition and improved cost management. There is continued activity and advancement in the space, keeping biosimilars top of mind.

The biosimilar pipeline includes products in development across the following classes: targeted immunomodulators, insulins, supportive care, oncology, ophthalmology, immunosuppressants, bone health, growth hormones, and infertility. This market space is continually expanding, creating opportunities and challenges.

As federal legislators push for lower-cost drugs, biosimilars remain a crucial part of the overall strategy. Additionally, statelevel regulations also have the potential to impact biosimilar launches, with factors at play such as interchangeability and notifcation requirements.

Overall, biosimilars remain an exciting part of the healthcare industry. Here, we outline recent approvals in tihs space, as well as biosimilars currently under FDA review and those in phase three development.

Table 1. Recently Approved

Biosimilars

Drug Manufacturer

pegflgrastim-pbbk (FYLNETRA®) biosimilar to Amgen’s Neulasta)

bevacizumab-maly (Alymsys®) (biosimilar to Genentech’s Avastin)

flgrastim-ayow (RELEUKO®) (biosimilar to Amgen’s Neupogen)

Amneal Pharmaceuticals neutropenia/ leukopenia SC approved 05/26/2022

Amneal Pharmaceuticals CRC IV approved 04/13/2022

Amneal Pharmaceuticals neutropenia/ leukopenia IV; SC approved 02/25/2022

adalimumab-aqvh (YUSIMRY™) (biosimilar to AbbVie’s HUMIRA) Coherus RA; JIA; PSO; PsA; AS; CD SC approved 12/17/2021

insulin glargine-aglr (REZVOGLAR™) (biosimilar to Sanof’s Lantus)

Eli Lilly and Company T1DM; T2DM SC approved 12/17/2021

ranibizumab-nuna (BYOOVIZ™) (biosimilar to Genentech’s Lucentis) Biogen wet AMD; macular edema following RVO; myopic choroidal neovascularization intravitreal approved 09/17/2021

Abbreviations: AMD = age-related macular degeneration; AS = ankylosing spondylitis; CD = Crohn’s disease; CRC = colorectal cancer; IV = intravenous; JIA = juvenile idiopathic arthritis; PsA = psoriatic arthritis; PSO = plaque psoriasis; RA = rheumatoid arthritis; RVO = retinal vein occlusion; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus

Table 2. Biosimilars Submitted for FDA Approval

adalimumab (biosimilar to AbbVie’s HUMIRA®)

Alvotech

trastuzumab (biosimilar to Genentech’s Herceptin®) Novartis

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

adalimumab (biosimilar to AbbVie’s HUMIRA®) Fresenius

adalimumab-afzb (ABRILADA) (biosimilar to AbbVie’s HUMIRA®) Pfzer

bevacizumab (biosimilar to Genentech’s Avastin®) Celltrion

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

submitted BLA; seeking biosimilar interchangeability December 2022

breast cancer; gastric/ gastroesophageal cancer IV submitted BLA 12/20/2022

DME; diabetic retinopathy; macular edema following RVO; wet AMD intravtireal

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

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

brain cancer; cervical cancer; CRC; NSCLC; ovarian cancer; RCC IV

ranibizumab (biosimilar to Genentech’s LUCENTIS®) Coherus BioSciences wet AMD intravitreal

submitted BLA 10/31/2022

submitted — BLA October-December 2022

submitted PAS BLA; seeking biosimilar interchangeability October-December 2022

submitted — BLA 09/30/2022

submitted — BLA 08/02/2022

BIOSIMILARS UPDATE |

Table 2. Biosimilars Submitted for FDA Approval

adalimumab (biosimilar to AbbVie’s HUMIRA) Celltrion

adalimumab-bwwd (HADLIMA™) 100 mg/mL (biosimilar to AbbVie’s HUMIRA)

Organon/Samsung Bioepis

trastuzumab (biosimilar to Genentech’s Herceptin®) Tanvex BioPharma

bevacizumab (biosimilar to Genentech's Avastin®) Bio-Thera Solutions

bevacizumab (biosimilar to Genentech’s Avastin®)

bevacizumab (biosimilar to Genentech’s Avastin®)

bevacizumab (biosimilar to Genentech’s Avastin®)

bevacizumab (biosimilar to Genentech’s Avastin®)

bevacizumab (biosimilar to Genentech’s Avastin®)

Centus Biotherapeutics/ AstraZeneca

Samsung Bioepis/ Merck

Viatris/Biocon

Centus Biotherapeutics/ AstraZeneca

Samsung Bioepis/ Merck

bevacizumab (biosimilar to Genentech’s Avastin®) Viatris/Biocon

flgrastim (biosimilar to Amgen’s NEUPOGEN®) Apotex

pegflgrastim (biosimilar to Amgen’s Neulasta®) Apotex

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

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

breast cancer; gastric/ gastroesophageal cancer IV

brain cancer; cervical cancer; CRC; NSCL; ovarian cancer; RCC IV

brain cancer; cervical cancer; CRC; NSCLC; ovarian cancer; RCC IV

brain cancer; cervical cancer; CRC; NSCLC; ovarian cancer; RCC IV

brain cancer; cervical cancer; CRC; NSCLC; ovarian cancer; RCC IV

brain cancer; cervical cancer; CRC; NSCLC; ovarian cancer; RCC IV

brain cancer; cervical cancer; CRC; NSCLC; ovarian cancer; RCC IV

brain cancer; cervical cancer; CRC; NSCLC; ovarian cancer; RCC IV

neutropenia/leukopenia SC

neutropenia/leukopenia SC

submitted — BLA August 2022

Submitted — BLA August 2022

submitted — BLA August 2022

submitted BLA pending

submitted — BLA pending

submitted BLA pending

submitted BLA pending

submitted BLA pending

submitted BLA pending

submitted BLA pending

submitted BLA pending

submitted BLA pending

pegflgrastim (biosimilar to Amgen's Neulasta®) Fresenius/Merck neutropenia/leukopenia SC submitted BLA pending

pegflgrastim (biosimilar to Amgen’s Neulasta®) Lupin

neutropenia/leukopenia SC submitted BLA pending

Abbreviations: AMD = age-related macular degeneration; AS = ankylosing spondylitis; BLA = Biologics License Application; CD = Crohn’s disease; CRC = colorectal cancer; DME = diabetic macular edema; IV = intravenous; JIA = juvenile idiopathic arthritis; NSCLC = non-small cell lung cancer; PsA = psoriatic arthritis; PSO = plaque psoriasis; RA = rheumatoid arthritis; RCC = renal cell carcinoma; RVO = renal vascular occlusion SC = subcutaneous; UC = ulcerative colitis

Table 3. Biosimilars in Development – Phase Three

eculizumab (biosimilar to Alexion’s SOLIRIS®) Amgen paroxysmal nocturnal hemoglobinuria

flgrastim (biosimilar to Amgen’s NEUPOGEN®) Tanvex BioPharma neutropenia/leukopenia

follitropin alfa (biosimilar to EMD Serono’s Gonal-F®) Allergan female reproductive disorder

phase three

phase three

phase three

infiximab (biosimilar to Janssen’s REMICADE®) Nichi-Iko Pharmaceutical RA; AS; PSO; PsA; CD; UC IV phase three

insulin glargine (biosimilar to Sanof’s Lantus®) Gan & Lee Pharmaceuticals/Sandoz T1DM; T2DM

natalizumab (biosimilar to Biogen’s TYSABRI®) Novartis multiple sclerosis

phase three

phase three

omalizumab (biosimilar to Genentech’s XOLAIR®) Teva Pharmaceuticals asthma (severe); nasal polyps; urticaria (chronic, spontaneous) SC phase three

Biosimilars to Regeneron’s EYLEA

afibercept Amgen

afibercept Celltrion

afibercept Novartis

afibercept SamChunDang

afibercept Santo/Formycon

Biosimilar to Amgen’s Prolia®

DME; diabetic retinopathy; macular edema following RVO; wet AMD intravitreal phase three

DME; diabetic retinopathy; macular edema following RVO; wet AMD intravitreal phase three

DME; diabetic retinopathy; macular edema following RVO; wet AMD intravitreal phase three

DME; diabetic retinopathy; macular edema following RVO; wet AMD intravitreal phase three

DME; diabetic retinopathy; macular edema following RVO; wet AMD intravitreal phase three

denosumab Biocon osteoporosis/osteopenia SC phase three

denosumab Celltrion osteoporosis/osteopenia SC phase three

denosumab Fresenius osteoporosis/osteopenia SC phase three

denosumab Gedeon Richter osteoporosis/osteopenia SC phase three

denosumab Novartis osteoporosis/osteopenia SC phase three

denosumab Teva Pharmaceuticals osteoporosis/osteopenia SC phase three

Biosimilar to Novo Nordisk’s NovoLog®

insulin aspart Sanof T1DM; T2DM SC phase three

insulin aspart Viatris/Biocon T1DM; T2DM SC phase three

Biosimilar to Genentech’s LUCENTIS®

ranibizumab Lupin wet AMD intravitreal phase three

ranibizumab STADA Arzneimittel AG/ Bausch Health wet AMD intravitreal phase three

Table 3. Biosimilars in Development – Phase Three

Biosimilar to Genentech’s RITUXAN®

rituximab Archigen RA; CLL/SLL; NHL (indolent); ANCA-associated vasculitis

rituximab

Biosimilar to Genentech’s ACTEMRA®

tocilizumab

Biosimilars to Janssen’s STELARA®

ustekinumab

ustekinumab

ustekinumab

ustekinumab

Dr. Reddy’s Laboratories/ Fresenius

three

ustekinumab Intas Pharmaceuticals PSO; CD

rituximab

Dr. Reddy’s Laboratories/ Fresenius RA; CLL/SLL; NHL (indolent); ANCA-associated vasculitis

phase three

Abbreviations: AMD = age-related macular degeneration; ANCA = antineutrophil cytoplasmic antibodies; AS = ankylosing spondylitis; BLA = Biologics License Application; CD = Crohn’s disease; CLL = chronic lymphocytic leukemia; CRC = colorectal cancer; DME = diabetic macular edema; IV = intravenous; JIA = juvenile idiopathic arthritis; NHL = non-Hodgkin lymphoma; NSCLC = non-small cell lung cancer; PsA = psoriatic arthritis; PSO = plaque psoriasis; RA = rheumatoid arthritis; RCC = renal cell carcinoma; RVO = renal vascular occlusion; SC = subcutaneous; SLL = small lymphocytic leukemia; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus; UC = ulcerative colitis

1# PRESCRIBED

Indication

In HER2+ MBC following 1L progression and beyond* EMBRACE

TUKYSA + trastuzumab + capecitabine vs placebo + trastuzumab + capecitabine

• Median PFS: 7.8 months (95% CI: 7.5-9.6) vs 5.6 months (95% CI: 4.2-7.1); HR = 0.54 (95% CI: 0.42-0.71); P <0.00001 (primary endpoint) 1†

More than 2 years median overall survival at follow-up analysis2

• Primary analysis‡: 21.9 months (95% CI: 18.3-31.0) vs 17.4 months (95% CI: 13.6-19.9); HR = 0.66 (95% CI: 0.50-0.87); P = 0.0048 (secondary endpoint) 1

• Follow-up analysis§: 24.7 months (95% CI: 21.6-28.9) vs 19.2 months (95% CI: 16.4-21.4); HR = 0.73 (95% CI: 0.59-0.90); median follow-up: 29.6 months2

Safe and well tolerated1,3

Follow-up OS analysis: Results of this prespecifed exploratory analysis are descriptive but not conclusive, are not controlled for type 1 error, and should be interpreted with caution.

• The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, PPE, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash1

• 6% of patients discontinued TUKYSA due to adverse reactions vs 3% with placebo3

See additional follow-up data inside

The TUKYSA regimen is the #1 prescribed treatment for patients with brain metastases in 2L+ HER2+ MBC4II

TUKYSA is indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

Select Important Safety Information

• The Prescribing Information for TUKYSA contains warnings and precautions for diarrhea, hepatotoxicity, and embryo-fetal toxicity, some of which may be severe

• The most common serious adverse reactions in ≥2% of patients who received TUKYSA were diarrhea, vomiting, nausea, abdominal pain, and seizure

Study design: HER2CLIMB was a randomized (2:1) trial of TUKYSA or placebo each in combination with trastuzumab and capecitabine in 612 patients with HER2+ MBC, previously treated with trastuzumab, pertuzumab, and T-DM1. Primary endpoint was PFS per BICR in the frst 480 patients enrolled. Secondary endpoints included OS. A prespecifed exploratory analysis was included to evaluate OS at ~2 years. Please see additional study design on the following page.

*≥1 anti-HER2-based regimen in the metastatic setting.1

†Data from the frst 480 patients.1

‡ Primary analysis (data cutoff: September 4, 2019).3

§Prespecifed exploratory analysis (data cutoff: February 8, 2021).2

IIBased on brand prescriptions from 10/20 to 05/21.4

1L = frst-line; 2L = second-line; BICR = blinded independent central review; CI = confdence interval; HER = human epidermal growth factor receptor; HR = hazard ratio; MBC = metastatic breast cancer; OS = overall survival; PFS = progression-free survival; PPE = palmar-plantar erythrodysesthesia; T-DM1 = ado-trastuzumab emtansine.

Please see full Important Safety Information on the following pages.

In combination with trastuzumab + capecitabine

TUKYSA ACHIEVED A MEDIAN OVERALL SURVIVAL OF MORE THAN 2 YEARS AT FOLLOW-UP ANALYSIS2 *

OS in the total population (N = 612)1,2

PRIMARY ANALYSIS

TUKYSA arm Control arm

FOLLOW-UP ANALYSIS

TUKYSA arm Control arm

Results of this prespecifed exploratory analysis are descriptive but not conclusive, are not controlled for type 1

analysis was February 8, 2021.2

Important Safety Information

Warnings and Precautions

• Diarrhea: TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 12% with Grade 3 and 0.5% with Grade 4. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. Median time to onset of the frst episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to TUKYSA dose reductions in 6% of patients and TUKYSA discontinuation in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB. If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.

• Hepatotoxicity: TUKYSA can cause severe hepatotoxicity. In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase >5 × ULN, 6% had an AST increase >5 × ULN, and 1.5% had a bilirubin increase >3 × ULN (Grade ≥3). Hepatotoxicity led to TUKYSA dose reductions in 8% of patients and TUKYSA discontinuation in 1.5% of patients.

Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.

• Embryo-Fetal Toxicity: TUKYSA can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential, and male patients with female partners of reproductive potential, to use effective contraception during TUKYSA treatment and for at least 1 week after the last dose.

Adverse Reactions

Serious adverse reactions occurred in 26% of patients who received TUKYSA; those occurring in ≥2% of patients were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.

Adverse reactions led to treatment discontinuation in 6% of patients who received TUKYSA; those occurring in ≥1% of patients were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led to dose reduction in 21% of patients who received TUKYSA; those occurring in ≥2% of patients were hepatotoxicity (8%) and diarrhea (6%).

The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

Lab Abnormalities

In HER2CLIMB, Grade ≥3 laboratory abnormalities reported in ≥5% of patients who received TUKYSA were decreased phosphate, increased ALT, decreased potassium, and increased AST.

At the 2-year follow-up analysis2

TEAEs Grade ≥3

61% (245/404) in the TUKYSA arm vs 51% (101/197) in the control arm

CONSISTENT SAFETY PROFILE AT FOLLOW-UP ANALYSIS2†

The most common adverse reactions (≥20%) were diarrhea, PPE, nausea, fatigue, vomiting, decreased appetite, stomatitis, headache, AST increased, anemia, ALT increased, and blood bilirubin increased

TEAEs leading to death

2% (8/404) in the TUKYSA arm vs 3% (6/197) in the control arm

6% TUKYSA vs

3% PLACEBO

The rate of discontinuation due to adverse reactions for the TUKYSA arm remained consistent with the primary analysis2,3†

6% TUKYSA vs

4% PLACEBO

*Study design: HER2CLIMB was a randomized (2:1), double-blind trial of TUKYSA or placebo each in combination with trastuzumab and capecitabine in 612 patients with HER2+ MBC, previously treated with trastuzumab, pertuzumab, and T-DM1. Primary endpoint was PFS per BICR in the frst 480 patients enrolled. Secondary endpoints assessed in the full study population included OS, PFS in patients with brain metastases, confrmed ORR, and safety.

The protocol included a prespecifed exploratory analysis to evaluate OS, PFS (by investigator assessment), and safety in the total study population (N = 612) at ~2 years from the last patient randomized. After the primary analysis, 12.9% of patients in the placebo arm (26/202) crossed over to receive TUKYSA in combination with trastuzumab and capecitabine, with the frst patient crossover in February 2020. Median overall study follow-up: 29.6 months (data cutoff: February 8, 2021). Because formal testing of all alpha-controlled endpoints was considered fnal at the primary analysis, data from this prespecifed updated analysis are for descriptive purposes only.1-3

†Follow-up safety analysis was done as part of a prespecifed exploratory analysis. Results are presented as descriptive data that are not intended to provide conclusions about safety and should be interpreted with caution.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; ORR = objective response rate; TEAE = treatment-emergent adverse event.

The mean increase in serum creatinine was 32% within the frst 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

Drug Interactions

• Strong CYP3A/Moderate CYP2C8 Inducers: Concomitant use may decrease TUKYSA activity. Avoid concomitant use of TUKYSA.

• Strong or Moderate CYP2C8 Inhibitors: Concomitant use of TUKYSA with a strong CYP2C8 inhibitor may increase the risk of TUKYSA toxicity; avoid concomitant use. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors.

• CYP3A Substrates: Concomitant use may increase the toxicity associated with a CYP3A substrate. Avoid concomitant use of TUKYSA where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP3A substrate dosage.

• P-gp Substrates: Concomitant use may increase the toxicity associated with a P-gp substrate. Consider reducing the dosage of P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicity.

Use in Specifc Populations

• Lactation: Advise women not to breastfeed while taking TUKYSA and for at least 1 week after the last dose.

• Renal Impairment: Use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (CLcr < 30 mL/min), because capecitabine is contraindicated in patients with severe renal impairment.

• Hepatic Impairment: Reduce the dose of TUKYSA for patients with severe (Child-Pugh C) hepatic impairment.

Please see Brief Summary of Prescribing Information on adjacent pages.

References: 1. TUKYSA [Prescribing Information]. Bothell, WA: Seagen Inc. April 2020. 2. Curigliano G, Mueller V, Borges V, et al. Updated results of tucatinib vs placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB). Poster presented at: American Society of Clinical Oncology Annual Meeting; June 4-8, 2021. 3. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. 4. Data on fle. Seagen Inc.

TUKYSA® (tucatinib) tablets, for oral use

Brief summary of Prescribing Information (PI). See full PI. Rx Only

INDICATIONS AND USAGE

TUKYSA is indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

DOSAGE AND ADMINISTRATION

Recommended Dosage

The recommended dosage of TUKYSA is 300 mg taken orally twice daily in combination with trastuzumab and capecitabine until disease progression or unacceptable toxicity. Advise patients to swallow TUKYSA tablets whole and not to chew, crush, or split prior to swallowing. Advise patients not to ingest tablet if it is broken, cracked, or not otherwise intact. Advise patients to take TUKYSA approximately 12 hours apart and at the same time each day with or without a meal. If the patient vomits or misses a dose of TUKYSA, instruct the patient to take the next dose at its usual scheduled time.

When given in combination with TUKYSA, the recommended dosage of capecitabine is 1000 mg/m2 orally twice daily taken within 30 minutes after a meal. TUKYSA and capecitabine can be taken at the same time. Refer to the Full Prescribing Information for trastuzumab and capecitabine for additional information.

Dosage Modi cations for Adverse Reactions

The recommended TUKYSA dose reductions and dosage modi cations for adverse reactions are provided in Tables 1 and 2. Refer to the Full Prescribing Information for trastuzumab and capecitabine for information about dosage modi cations for these drugs.

Table 1: Recommended TUKYSA Dose Reductions for Adverse Reactions

Dose Reduction Recommended TUKYSA Dosage

First 250 mg orally twice daily

Second 200 mg orally twice daily

Third 150 mg orally twice daily

Permanently discontinue TUKYSA in patients unable to tolerate 150 mg orally twice daily.

Table 2: Recommended TUKYSA Dosage Modi cations for Adverse Reactions

Severity TUKYSA Dosage Modi cation

Diarrhea1

Grade 3 without anti-diarrheal treatment Initiate or intensify appropriate medical therapy. Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the same dose level.

Grade 3 with anti-diarrheal treatment Initiate or intensify appropriate medical therapy. Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the next lower dose level.

Grade 4 Permanently discontinue TUKYSA.

Hepatotoxicity1,2

Grade 2 bilirubin (>1.5 to 3 × ULN) Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the same dose level.

Grade 3 ALT or AST (> 5 to 20 × ULN) OR Grade 3 bilirubin (> 3 to 10 × ULN) Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the next lower dose level.

Grade 4 ALT or AST (> 20 × ULN) OR Grade 4 bilirubin (> 10 × ULN) Permanently discontinue TUKYSA.

ALT or AST > 3 × ULN AND Bilirubin > 2 × ULN Permanently discontinue TUKYSA.

Other adverse reactions1

Grade 3 Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the next lower dose level.

Grade 4 Permanently discontinue TUKYSA.

1. Grades based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03

2. Abbreviations: ULN = upper limit of normal; ALT = alanine aminotransferase; AST = aspartate aminotransferase

Dosage Modi cations for Severe Hepatic Impairment: For patients with severe hepatic impairment (Child-Pugh C), reduce the recommended dosage to 200 mg orally twice daily.

Dosage Modi cations for Concomitant Use with Strong CYP2C8 Inhibitors: Avoid concomitant use of strong CYP2C8 inhibitors with TUKYSA. If concomitant use with a strong CYP2C8 inhibitor cannot be avoided, reduce the recommended dosage to 100 mg orally twice daily. After discontinuation of the strong CYP2C8 inhibitor for 3 elimination half-lives, resume the TUKYSA dose that was taken prior to initiating the inhibitor.

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

Diarrhea: TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 12% with Grade 3 diarrhea and 0.5% with Grade 4 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. The median time to onset of the rst episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB. If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.

Hepatotoxicity: TUKYSA can cause severe hepatotoxicity. In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase > 5 × ULN, 6% had an AST increase > 5 × ULN, and 1.5% had a bilirubin increase > 3 × ULN (Grade ≥3). Hepatotoxicity led to dose reduction of TUKYSA in 8% of patients and discontinuation of TUKYSA in 1.5% of patients. Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.

Embryo-Fetal Toxicity: Based on ndings from animal studies and its mechanism of action, TUKYSA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of tucatinib to pregnant rats and rabbits during organogenesis caused embryo-fetal mortality, reduced fetal weight and fetal abnormalities at maternal exposures ≥ 1.3 times the human exposure (AUC) at the recommended dose. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for at least 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TUKYSA and for at least 1 week after the last dose. TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy and contraception information.

ADVERSE REACTIONS

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 re%ect the rates observed in practice.

HER2-Positive Metastatic Breast Cancer (HER2CLIMB)

The safety of TUKYSA in combination with trastuzumab and capecitabine was evaluated in HER2CLIMB. Patients received either TUKYSA 300 mg twice daily plus trastuzumab and capecitabine (n=404) or placebo plus trastuzumab and capecitabine (n=197). The median duration of treatment was 5.8 months (range: 3 days, 2.9 years) for the TUKYSA arm. Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in ≥ 2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.

Adverse reactions leading to treatment discontinuation occurred in 6% of patients who received TUKYSA. Adverse reactions leading to treatment discontinuation of TUKYSA in ≥1% of patients were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions leading to dose reduction occurred in 21% of patients who received TUKYSA. Adverse reactions leading to dose reduction of TUKYSA in ≥2% of patients were hepatotoxicity (8%) and diarrhea (6%).

The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

Table 3: Adverse Reactions (≥10%) in Patients Who Received TUKYSA and with a Difference Between Arms of ≥5% Compared to Placebo in HER2CLIMB (All Grades)

Adverse Reaction TUKYSA + Trastuzumab + Capecitabine (N = 404)

Gastrointestinal disorders

Skin and subcutaneous tissue disorders

Placebo + Trastuzumab + Capecitabine (N = 197)

Adverse Reaction TUKYSA + Trastuzumab + Capecitabine (N = 404) Placebo + Trastuzumab + Capecitabine (N = 197)

Blood and lymphatic system disorders

Musculoskeletal and connective tissue disorders

thoracic and mediastinal disorders

1. Stomatitis includes stomatitis, oropharyngeal pain, oropharyngeal discomfort, mouth ulceration, oral pain, lip ulceration, glossodynia, tongue blistering, lip blister, oral dysesthesia, tongue ulceration, and aphthous ulcer

2. Rash includes rash maculo-papular, rash, dermatitis acneiform, erythema, rash macular, rash papular, rash pustular, rash pruritic, rash erythematous, skin exfoliation, urticaria, dermatitis allergic, palmar erythema, plantar erythema, skin toxicity, and dermatitis

3. Hepatotoxicity includes hyperbilirubinemia, blood bilirubin increased, bilirubin conjugated increased, alanine aminotransferase increased, transaminases increased, hepatotoxicity, aspartate aminotransferase increased, liver function test increased, liver injury, and hepatocellular injury

4. Anemia includes anemia, hemoglobin decreased, and normocytic anemia

5. Due to inhibition of renal tubular transport of creatinine without affecting glomerular function

6. Peripheral neuropathy includes peripheral sensory neuropathy, neuropathy peripheral, peripheral motor neuropathy, and peripheral sensorimotor neuropathy

Table 4: Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who Received TUKYSA and with a Difference of ≥5% Compared to Placebo in HER2CLIMB

TUKYSA + Trastuzumab + Capecitabine1 Placebo + Trastuzumab + Capecitabine1 All Grades % Grades ≥3 % All Grades

Hematology

1. The denominator used to calculate the rate varied from 351 to 400 in the TUKYSA arm and 173 to 197 in the control arm based on the number of patients with a baseline value and at least one post-treatment value. Grading was based on NCI-CTCAE v.4.03 for laboratory abnormalities, except for increased creatinine which only includes patients with a creatinine increase based on the upper limit of normal de nition for grade 1 events (NCI CTCAE v5.0).

2. Laboratory criteria for Grade 1 is identical to laboratory criteria for Grade 2.

3. Due to inhibition of renal tubular transport of creatinine without affecting glomerular function.

4. There is no de nition for Grade 2 in CTCAE v.4.03.

Increased Creatinine: The mean increase in serum creatinine was 32% within the rst 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

DRUG INTERACTIONS

Effects of Other Drugs on TUKYSA

Strong CYP3A Inducers or Moderate CYP2C8 Inducers: Concomitant use of TUKYSA with a strong CYP3A or moderate CYP2C8 inducer decreased tucatinib plasma concentrations, which may reduce TUKYSA activity. Avoid concomitant use of TUKYSA with a strong CYP3A inducer or a moderate CYP2C8 inducer.

Strong or Moderate CYP2C8 Inhibitors: Concomitant use of TUKYSA with a strong CYP2C8 inhibitor increased tucatinib plasma concentrations, which may increase the risk of TUKYSA toxicity. Avoid concomitant use of TUKYSA with a strong CYP2C8 inhibitor. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors.

Effects of TUKYSA on Other Drugs

CYP3A Substrates: Concomitant use of TUKYSA with a CYP3A substrate increased the plasma concentrations of CYP3A substrate, which may increase the toxicity associated with a CYP3A substrate. Avoid concomitant use of TUKYSA with CYP3A substrates,

where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP3A substrate dosage in accordance with approved product labeling.

P-glycoprotein (P-gp) Substrates: Concomitant use of TUKYSA with a P-gp substrate increased the plasma concentrations of P-gp substrate, which may increase the toxicity associated with a P-gp substrate. Consider reducing the dosage of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities.

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary: TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy information. Based on ndings in animals and its mechanism of action, TUKYSA can cause fetal harm when administered to a pregnant woman. There are no available human data on TUKYSA use in pregnant women to inform a drug-associated risk. In animal reproduction studies, administration of tucatinib to pregnant rats and rabbits during organogenesis resulted in embryo-fetal mortality, reduced fetal weight and fetal abnormalities at maternal exposures ≥ 1.3 times the human exposure (AUC) at the recommended dose. Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

Lactation

Risk Summary: TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for lactation information. There are no data on the presence of tucatinib or its metabolites in human or animal milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with TUKYSA and for at least 1 week after the last dose.

Females

and Males of Reproductive Potential

TUKYSA can cause fetal harm when administered to a pregnant woman. TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for contraception and infertility information.

Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating treatment with TUKYSA.

Contraception:

Females: Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for at least 1 week after the last dose.

Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TUKYSA and for at least 1 week after the last dose.

Infertility: Based on ndings from animal studies, TUKYSA may impair male and female fertility.

Pediatric Use: The safety and effectiveness of TUKYSA in pediatric patients have not been established.

Geriatric Use: In HER2CLIMB, 82 patients who received TUKYSA were ≥ 65 years, of whom 8 patients were ≥ 75 years. The incidence of serious adverse reactions in those receiving TUKYSA was 34% in patients ≥ 65 years compared to 24% in patients < 65 years. The most frequent serious adverse reactions in patients who received TUKYSA and ≥ 65 years were diarrhea (9%), vomiting (6%), and nausea (5%). There were no observed overall differences in the effectiveness of TUKYSA in patients ≥ 65 years compared to younger patients. There were too few patients ≥ 75 years to assess differences in effectiveness or safety.

Renal Impairment: The use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (CLcr < 30 mL/min estimated by Cockcroft-Gault Equation), because capecitabine is contraindicated in patients with severe renal impairment. Refer to the Full Prescribing Information of capecitabine for additional information in severe renal impairment. No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min).

Hepatic Impairment: Tucatinib exposure is increased in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of TUKYSA for patients with severe (ChildPugh C) hepatic impairment. No dose adjustment for TUKYSA is required for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

TUKYSA and its logo, and Seagen and are US registered trademarks of Seagen Inc. © 2021 Seagen Inc., Bothell, WA 98021 All rights reserved Printed in USA REF-5155(1) 4/20

afibercept (biosimilar to Regeneron’s EYLEA®)

Viatris/Janssen

treosulfan Medexus Pharmaceuticals/ medac

risankizumab-rzaa (SKYRIZI®) AbbVie

diabetic macular edema; diabetic retinopathy; macular edema following RVO; wet AMD

Pfzer-BioNTech COVID-19 vaccine (Comirnaty®) Pfzer/BioNTech COVID-19 immunization (ages 1215 years)

lumasiran (OXLUMO®) Alnylam Pharmaceuticals primary hyperoxaluria type 1 (advanced)

Ibalizumab-uiyk (TROGARZO®) Theratechnologies HIV-1 infection treatment IV sBLA; breakthrough therapy; fast track; orphan drug 10/03/22

microbiota suspension Ferring

clostridioides difcile infection (recurrent) rectal

durvalumab (IMFINZA®) AstraZeneca biliary tract cancer (locally advanced or metastatic)

fam-trastuzumab deruxtecan-nxki (ENHERTU®) Daiichi Sankyo/ AstraZeneca NSCLC (unresectable or metastatic, HER2-mutant, prior systemic therapy)

ivosidenib (TIBSOVO®) Les Pharmaceuticals AML (previously untreated IDH1mutated)

futibatinib Otsuka cholangiocarcinoma (advanced or metastatic, FGFR2 gene rearrangements)

bevacizumab (biosimilar to Genentech’s Avastin®) Celltrion brain cancer; cervical cancer; colorectal cancer; NSCLC; ovarian cancer; renal cell carcinoma

ublituximab (TG-1101) TG Therapeutics relapsing MS

taurolidine/citrate/heparin Cormedix reduction of catheter-related bloodstream infections related to chronic hemodialysis

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

breakthrough therapy; priority review July-September 2022

sNDA; breakthrough therapy; fast track; orphan drug; priority review September 2022

breakthrough therapy; orphan drug; priority review 09/30/22

PIPELINE

cemiplimab-rwlc (LIBTAYO®) Regeneron Pharmaceuticals

Aprepitant (CINVANTI®) Heron Therapeutics

elivaldogene autotemcel (Lenti-D) bluebird bio

Dasatinib (Dasynoc™) Xspray Pharma

linzagolix

deucravacitinib

adalimumab (biosimilar to AbbVie’s HUMIRA®)

adalimumab-bwwd (Hadlima) 100 mg/mL (biosimilar to AbbVie’s HUMIRA®) Organon/Samsung Bioepis

AS; PSO; PsA; JIA; CD; UC

trastuzumab (biosimilar to Genentech’s Herceptin®) Tanvex BioPharma breast cancer; gastric/ gastroesophageal cancer IV BLA August 2022

cipaglucosidase alfa Amicus Therapeutics

miglustat

Therapeutics

disease (in combination with oral miglustat)

disease (in combination with cipaglucosidase alfa)

baricitinib (Olumiant®) Eli Lilly and Company alopecia areata

betibeglogene autotemcel (Zynteglo) bluebird bio beta thalassemia (transfusiondependent)

teplizumab Provention Bio

1 diabetes mellitus (delay/ prevention)

ustekinumab (STELARA®) Janssen PsA (ages > 5 years) SC sBLA 08/08/22

relugolix/estradiol/ norethindrone (Myfembree®) Myovant Sciences

pimavanserin (NUPLAZID®) Acadia Pharmaceuticals Alzheimer’s disease-related hallucinations and delusions

trivalent measles-mumpsrubella (MMR) vaccine GlaxoSmithKline measles, mumps, and rubella immunization

ranibizumab (biosmilar to Genentech Lucentis®) Coherus

ravulizumab-cwvz (ULTOMIRIS®) AstraZeneca

sNDA; breakthrough therapy 08/04/22

wet AMD; macular edema following RVO; myopic choroidal neovascularization intravitreal BLA 08/02/22

paroxysmal nocturnal hemoglobinuria; hemolytic uremic syndrome (atypical) SC sBLA; orphan drug July 2022

narsoplimab Omeros HSCT-associated thrombotic microangiopathy IV; SC BLA; breakthrough therapy; orphan drug; priority review July 2022

spesolimab Boehringer Ingelheim generalized pustular PSO fares IV; SC BLA; breakthrough therapy; orphan drug; priority review June-July 2022

rofumilast cream Arcutis/ AstraZeneca PSO (mild-severe)

risdiplam (Evrysdi®) Genentech spinal muscular atrophy (presynaptic, ages < 2 months) oral sNDA; breakthrough therapy; fast track 07/25/22

Bulevirtide (Hepcludex®) Gilead Sciences hepatitis D infection treatment (with compensated liver disease)

ruxolitinib (Opzelura™) Incyte vitiligo

vutrisiran Alnylam Pharmaceuticals transthyretin amyloid polyneuropathy

casirivimab/imdevimab (REGEN-COV®) Regeneron Pharmaceuticals

Tislelizumab (BGB-A317) BeiGene

COVID-19 treatment (nonhospitalized patients); COVID-19 postexposure prophylaxis

esophageal squamous cell carcinoma (unresectable, recurrent, locally advanced/metastatic, after prior systemic therapy) IV

BLA; breakthrough therapy; orphan drug 07/19/22

orphan drug 07/12/22

pegloticase (KRYSTEXXA®) Horizon Therapeutics plc gout (in combination with methotrexate) IV sBLA; orphan drug; priority review 07/07/22

olipudase alfa (Xenpozyme®) Sanof Niemann-Pick disease (types A, B, and A/B) IV BLA; breakthrough therapy; orphan drug; priority review 07/03/22

pneumococcal 15-valent conjugate vaccine (VAXNEUVANCE™) Merck invasive pneumococcal disease immunization (ages 6 weeks to 17 years)

PIPELINE

pegloticase (KRYSTEXXA®) Horizon Therapeutics plc gout (in combination with methotrexate)

olipudase alfa (Xenpozyme®) Sanof Niemann-Pick disease (types A, B, and A/B)

orphan drug; priority review 07/07/22

breakthrough therapy; orphan drug; priority review 07/03/22

pneumococcal 15-valent conjugate vaccine (VAXNEUVANCE™) Merck invasive pneumococcal disease immunization (ages 6 weeks to 17 years) IM; IV; SC sBLA; breakthrough therapy; priority review 7/01/22

Abbreviations: AMD = age-related macular degeneration; AS = ankylosing spondylitis; BLA = Biologics License Application; CD = Crohn’s disease; HSCT = hematopoietic stem cell transplantation; 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; RA = rheumatoid arthritis; RVO = retinal vein occlusion; sBLA = supplemental Biologics License Application; SC = subcutaneous; sNDA = supplemental New Drug Application; UC = ulcerative colitis