Magellan Rx Report - Summer 2021 by Prime/Magellan Rx

Magellan Rx Report Summer 2021

Gene Therapies for Rare Diseases: Changing Landscape and Pipeline

HER2+ Metastatic Breast Cancer: CNS Metastases and Proper Management

HIV Update: Treatment n E ec e Management

CAR-T Update: Expanding Landscape and Payer Implications

Magellan Rx Report MEDICAL AND PHARMACY BENEFIT MANAGEMENT Summer 2021

ALS:

Robust Pipeline and Payer Impact magellanrx.com

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IN THIS ISSUE | Summer 2021

Managed Care Newsstand

HIV Update:

Amyotrophic Lateral Sclerosis:

CAR-T Update:

Gene Therapies for Rare Diseases:

COVID-19 and Oncology Care:

HER2+ Metastatic Breast Cancer:

Pipeline

Robust Pipeline and Payer Impact

Changing Landscape and Pipeline

CNS Metastases and Proper Management

Published By Magellan Rx Management 15950 N. 76th St. Scottsdale, AZ 85260

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

Tel: 401-344-1000 Fax: 401-619-5215

SVP, Market General Manager, MRx Specialty

CMO, Magellan Health, Magellan Rx Management

Steve Cutts, Pharm.D.

Haita Makanji, Pharm.D.

VP, Clinical Strategy and Innovation, Specialty

magellanrx.com Editor Lindsay Speicher, J.D.

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

Advertising, Sales and Distribution Carole Kallas ckallas@magellanhealth.com 401-344-1132

The content of Magellan Rx 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.

Expanding Landscape and Payer Implications

Long-Term Implications

Editorial Advisory Board Mona M. Chitre, Pharm.D., CGP

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

Dennis Bourdette M.D., FAAN, FANA

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

Yousaf Ali M.D., FACR

Misty Greficz

Director, Marketing

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

Joe Tavares

Steven L. D’Amato, B.S.Pharm.

Corrado Panno

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

Stacy Inman, Pharm.D.

Natalie Tate, Pharm.D., MBA, BCPS

SVP, Sales and Business Development, Specialty VP, Business Development, Magellan Method Senior Clinical Project Manager, Magellan Method

Carole Kallas Project Manager

Brian Kinsella, Esq. TM

Treatment and Effective Management

Senior Legal Counsel

Alina Young

Associate Legal Counsel

Executive Director, New England Cancer Specialists

Chief Medical Officer, International Myeloma Foundation Vice President, Pharmacy Management, BlueCross BlueShield of Tennessee

Steve Marciniak, R.Ph.

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

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

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

Lilly Ackley

VP, Corporate Communications

Maria James

Director, External Communications

ISSN: 2159-5372

10444M

A NOTE FROM OUR CMO

Dear Managed Care Colleagues, Welcome to our summer 2021 issue of the Magellan R Report n the first hal o 2021, widespread vaccine administration and reopening as COVID-19 infections slowed have been front of mind. Despite COVID-related health concerns, there have been many exciting advancements — including 30 new drug approvals. In this issue, Magellan Rx Management continues to provide our readers with the most up-to-date information across health trends, changing treatment landscapes, and clinical advances. Our cover story (page 6) focuses on amyotrophic lateral sclerosis (ALS), the current treatment landscape, and a robust pipeline. As treatment options have been limited for this condition, which has 5,000 new cases diagnosed annually, new therapies will increase payer awareness in this area. In another article, we highlight the area of gene therapies, specifically in the treatment o rare diseases (pa e ) he growing availability of these innovative, potentially curative treatments will change many aspects of healthcare and managed care moving forward, including disease management opportunities and economic impact.

Other timely topics in this issue include developments in human immunodeficiency irus (H ) treatment (pa e ) and C R(page 35) and the impact of COVID-19 on oncology care (page 40). As always, the issue is rounded out with our pipeline update (page 45) and managed care newsstand (page 4). o learn more about a ellan R ana ement 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 ie edica cer Magellan Health & Magellan Rx Management

We also discuss the complexities of HER2+ metastatic breast cancer, specifically ocusin on central ner ous system metastases (pa e ) he story addresses the challen es and outcomes o treatment, as well as the resulting impact on payers.

SUBSCRIBE TODAY! 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.

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MANAGED CARE NEWSSTAND Comprehensive Addiction and Recovery Act 3.0 Introduced U.S. Sens. Jeanne Shaheen, D-N.H., Rob Portman, R-Ohio, and Sheldon Whitehouse, R-R.I., introduced the bipartisan Comprehensive Addiction and Recovery Act (CARA) 3.0 to help combat the opioid epidemic, which has been exacerbated by the COVID-19 pandemic. The bill increases the funding authorization levels for the CARA programs enacted in 2016. The bipartisan national e ort as desi ned to ensure that federal resources were devoted to evidence-based education, treatment, and recovery programs that work. CARA programs were funded at $782 million in 2021. Several key provisions of CARA 2.0 were enacted as part of the SUPPORT Act on Oct. 24, 2018. CARA 3.0 builds on these e orts by increasin the undin authorization levels and laying out new policy reforms to strengthen the federal government’s response to this crisis (e.g., it permanently allows providers to prescribe medication-assisted treatment via audio-only telehealth).

New X-Waiver Guidelines Issued The Department of Health and Human Services (HHS) issued new practice guidelines as it looks for ways to address the opioid epidemic. The new guidelines are slightly different from those issued under the Trump administration, which were rescinded in January. Physicians, nurse practitioners, physician assistants, clinical nurse

4 | Magellan Rx Report | Summer 2021

specialists, certified nurse anesthetists, and certified nurse midwives may now treat up to 30 patients with buprenorphine under a waiver established under the new guidance. Providers will still need to submit notice of their intention to prescribe buprenorphine to the Substance Abuse and Mental Health Services Administration, but they will now be exempted from training requirements.

GAO Reports on Behavioral Health During the COVID-19 Pandemic The U.S. Government Accountability O ce ( O) recently released a report on issues related to the demand for behavioral health, coverage and payment for these services, and how they have changed during the COVID-19 pandemic. The report, the result of a request made by Sen. Ron Wyden, D-Ore., last year, describes: (1) what is known about the need for and availability of behavioral health services and how these have changed during the COVID-19 pandemic; and (2) what issues selected sta eholders identified re ardin the payment of claims for behavioral health ser ices Key findin s ocus on workforce shortage, denials and delay of payment, and parity issues.

HRSA Implements COVID-19 Coverage Assistance Fund On May 3, the Health Resources and Services Administration (HRSA) announced a new program covering the cost of administering COVID-19 vaccines to patients enrolled in health plans that either do not cover vaccination fees or cover them with patient cost-sharing. This new program is called the HRSA COVID-19 Coverage Assistance Fund (CAF). Providers

must enroll in the CAF program and submit uncovered claims for vaccines administered on or after Dec. 14, 2020. Prior to submitting claims for reimbursement under the program, providers are required to bill the patient’s health plan and recei e confirmation that accine administration is not covered or includes patient cost-sharing.

House Committees Hold Hearings on Drug-Pricing Legislation The House Committee on Energy and Commerce and the House Committee on Education and Labor held hearings on major drug pricing legislation on May 4 and 5 with the hopes of bringing the bill to the oor in the comin ee s House emocratic and Republican leaders filed separate bills that were similar in scope to the bills introduced in the last Congress. The Democratic bill, HR3, passed the House in late 2019 nearly along party lines. The Republican bill, HR19, the counter to the Democratic bill, did not receive a vote in the last Congress. The Senate Committee on Finance passed its own drug-pricing bill in 2019, but that bill ne er made it to the oor he emocratic bill calls for government negotiation of high-cost drugs that have little or no competition. The bill also proposes a edicare in ation rebate amon the many other provisions. Both bills call for capping out-of-pocket costs for Part D beneficiaries and eliminatin the co era e ap in the Part benefit, but they di er on payment responsibilities in the catastrophic phase; the Democratic bill calls for drug manufacturers to bear a greater share of the cost burden in this phase. Witnesses at the hearing said these Part D redesign proposals would do little to control costs but would likely increase premiums and overall program costs he Con ressional ud et O ce (CBO) estimates that HR3 would save

$450 billion over a 10-year period. The Democratic proposal would use most of those savings to provide dental, hearing, and ision benefits under edicare Following the hearing, a number of Democratic House members have expressed concern over the bill. Recent media reports suggest that as many as eight to 10 Democrats may not support the bill. Democrats hold a six-seat majority and can lose few Democratic members if most — if not all — Republicans oppose the bill. Negotiations are likely to continue in the coming weeks to try and shore up Democratic support for the bill. If it passes, it faces an unlikely future in the Senate. The Senate failed to take up HR3 in 2020 when the Republicans controlled the chamber. Democrats now hold the majority, but the Senate is evenly divided at 50-50, so the bill will likely require all Democratic senators to support it. At this point, passage of a major drug-pricing bill appears unlikely, but the recent hearings and legislative action suggest that drug-pricing will remain a si nificant issue ithin Con ress over the coming years.

House Votes on a Package of Mental Health Bills The U.S. House voted on a package of 14 mental health bills on May 12. The bills included increased authorization of funding for the National Suicide Prevention Lifeline and funding to conduct a suicide prevention media campaign. Other bills included funding directed to improving suicide awareness in emergency medical facilities and funding to support school-based awareness campaigns. The 988 Suicide Prevention Lifeline is expected to be in place by July 2022. Additional bills included block grants to support individual wellness programs for those involved in communitybased or anizations and first responders

who deal with addiction and mental health issues, as well as funding for school-based mental health services. The package of bills has broad support. It is not clear when the Senate may take up the legislation, but it is expected that the package of bills will pass Congress at some point this year.

President Biden Releases FY2022 Budget On May 28, President Joe Biden released a trillion proposed bud et or fiscal year 2022. The proposal, which is expected to undergo many changes before being signed into law, presents a significant increase in federal spending and includes si nificant in estments in President Biden’s top priorities, including infrastructure, education, research, public health, paid family leave, and child care. The budget also calls on Congress to act “to further strengthen healthcare by lowering prescription drug costs and expanding and improving health coverage.” The president’s healthcare agenda includes cutting prescription drug costs by letting Medicare negotiate prices, reducing deductibles or ordable Care ct ( C ) marketplace plans, improving Medicare benefits, creatin a public option and i ing people age 60 and older the option to enroll in Medicare, and closing the Medicaid coverage gap to help millions of uninsured Americans gain health insurance.

FDA Announces New Drug Supply Chain Guidance On June 3, the U.S. Food and Drug Administration (FDA) announced two new finalized and t o dra t uidance documents to further enhance the security of prescription drugs in the U.S. supply chain ia proper identification and trac ing. The guidance documents lay out the

FDA’s recommendations for compliance with applicable Drug Supply Chain Security Act (DSCSA) requirements, including those for enhanced drug distribution security at the package level that go into e ect in o ember On June 8, the Biden-Harris administration announced its ey findin s rom the reviews directed under a February Executive Order on America’s Supply Chains, as well as immediate actions the administration will take to strengthen American supply chains to promote economic security, national security, and good-paying union jobs. The administration has called on HHS and other agencies to: •

•

Establish a public-private consortium — leveraging the Defense Production Act (DPA) and existing partnerships — to bolster the production of critical drugs on U.S. soil. Invest around $60 million from the DPA appropriation in the American Rescue Plan to create “novel platform technologies” for domestic active pharmaceutical ingredient (API) production. Increase funding of advanced manufacturing technologies for drug and API production.

HHS Looks to Rescind Insulin Rule The U.S. Department of Health and Human Services (HHS) is proposing to rescind the Trump administration drug rule that required community health centers to pass on all their insulin and epinephrine discount savings to patients. The proposal to retract the rule is under re ie at the hite House O ce of Management and Budget (OMB). Once it clears OMB, HHS can publish it at any time. The rule was previously delayed until July 20, 2021.

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Amyotrophic Lateral Sclerosis: Robust Pipeline and Payer Impact The strong ALS pipeline promises innovative treatment possibilities for a debilitating disease that, historically, has had limited options. With several phase-three therapies in the pipeline, this category may become a priority for payers. myotrophic lateral sclerosis ( S) is a pro ressi e, disablin , atal neurode enerati e disorder a ectin up to 30,000 adults in the United States, with an estimated 5,000 new cases diagnosed every year.1 The estimated national economic burden of ALS, which includes medical, nonmedical, and indirect costs, ranges from $256 million to $1.023 billion.2 This burden is expected to increase proportionately to the increase in prevalence and may be up 34% by 2040.2 Individually, the total cost of care for an ALS patient can be si nificant around , annually 2 Contributing factors in total cost of care often include hospitalizations, in-home care, nutrition, physical and occupational therapy, and drug therapy.3 he patient burden e tends beyond financial cost patients e perience si nificantly decreased uality o life as the disease progresses, with family and caregivers often impacted as well.2 Christina Barrington, Pharm.D. Vice President, Pharmacy Programs Priority Health

ALS is most common in adults over 60. The cause is unknown, but studies suggest links to both genetics and environmental factors.1, 3 arlier disease is defined by t itchin and crampin o the muscles, loss of muscle control in the hands and arms, impaired use of the arms and legs, weakness and fatigue, trippin and allin , droppin thin s, slurred or thic speech, and di culty projectin oice s the disease pro resses, symptoms become more se ere and include shortness o breath, di culty breathin , di culty s allo in , and paralysis 2 Diagnosis is typically based on a review of symptom history and a physical exam, often accompanied by a series of tests to rule out other diseases that present with similar symptoms.3 The presence of upper and lower motor neuron symptoms strongly suggests ALS. Disease pro ression is typically measured usin the idely accepted S unctional Ratin Scale ( S RS-R) point increases in the S RS-R can re ect a substantial decline in unction 4

6 | Magellan Rx Report | Summer 2021

Current Treatment Landscape Riluzole (Rilutek®) In 1995, the U.S. Food and Drug Administration (FDA) approved riluzole (Rilutek®) for the treatment of ALS. At the time, it was the only ALS treatment available.5 he first trial or riluzole sho ed that time to tracheostomy or death was about 90 days longer for patients treated with riluzole versus placebo. A second trial showed an early increase in survival rates (about 60 days longer) for patients treated with either 100 mg or 200 mg of riluzole per day, compared with placebo.5 ecause no di erence in sur i al rates as obser ed bet een those treated ith m or m o riluzole per day and there was an increase in adverse events, such as nausea and asthenia, ith the hi her dose the recommended dosin o riluzole is 100 mg per day. Adverse events associated with riluzole include asthenia, spasticity, and mild elevations in aminotransferase levels.5

As more treatment options for ALS become available, updated guidelines will be key to provide clear guidance around the appropriate management and place in therapy for these treatments.

Edaravone (RADICAVA®) The FDA approved edaravone (RADICAVA®) for the treatment of ALS 6 in Edaravone is an IV infusion treatment administered by a healthcare practitioner with an initial treatment cycle of 14 days of dosin ollo ed by dru - ree days Subse uent treatment cycles are dosed on 10 of 14 days followed by 14 drug-free days.6 Edaravone is associated with adverse reactions such as bruising and gait disturbance, as well as more serious risks such as hives, swellin , shortness o breath, and aller ic reactions to sodium bisulfite 6

The MCI186-19 phase three, double-blind, placebo-controlled clinical trial included patients a es to ho met specific inclusion criteria, includin definite or probable S, apan classification grade 1 or 2, a disease duration of less than two years since symptom onset, normal respiratory unction (defined as orced ital capacity (FVC) >80%), a score of >2 on all items on the ALSFRS-R score, and a deterioration of ALSFRS-R score during the 12-week pre-study observation period of 1 to 4 points. , Those treated with edaravone experienced 33% less functional loss during the 24week trial period compared to the placebo group. , Challenges around the use of edaravone include strict coverage criteria and the administration burden of infusion treatment for patients. An oral formulation of edaravone is currently undergoing phase three trials, which presents an opportunity for ease of administration and, potentially, access to treatment.

Treatment Guidelines The American Academy of Neurology (AAN) guidelines currently recommend riluzole for the treatment of ALS.9 The AAN guidelines do not mention edaravone in the treatment of ALS, althou h the uidelines ha e been rea rmed since the appro al of edaravone.9 As more treatment options for ALS become available, updated guidelines will be key to provide clear guidance around the appropriate management and place in therapy for these treatments.

Visit us online at magellanrx.com/mrxreport | 7

AMYOTROPHIC LATERAL SCLEROSIS | Continued

Table 1. ALS Pipeline10 Drug

Manufacturer

Route of Administration

Mechanism of Action

Status

arimoclomol

Orphazyme

oral

molecular chaperone modulator

phase three

BHV-3241 (verdiperstat)

Biohaven Pharmaceuticals

oral

MPO inhibitor

phase three

io en onis Pharmaceuticals

intrathecal

antisense oligonucleotide

phase three

CNM-Au8 (gold nanocrystal)

Clene Nanomedicine

oral

immunomodulator

phase three

masitinib

AB Science

oral

receptor tyrosine kinase inhibitor

phase three

MN-166

KYORIN Pharmaceutical Co edici o a

oral

PDE4 inhibitor

phase three

MT-1186 (edaravone)

Mitsubishi Tanabe Pharma

oral

neuroprotective agent

phase three

NurOwn®

BrainStorm Cell Therapeutics

intrathecal

cellular immunotherapy

phase three

pridopidine

Prilenia Therapeutics

oral

sigma-1 receptor agonist

phase three

RA101495 (zilucoplan)

UCB

complement inhibitor

phase three

ULTOMIRIS® (ravulizumab-cwvz)

Alexion Pharmaceuticals

complement inhibitor

phase three

(to ersen)

Emerging Therapies

Management Implications

nutritionists social or ers respiratory therapists clinical psycholo ists and home care and hospice nurses 3 A patient’s treatment team can e ecti ely de elop and pro ide an indi idualized treatment plan, pro ide special e uipment, and impro e uality o li e 3 Appropriate management by managed care organizations and the care team can optimize outcomes and potentially delay disease progression.3

ALS management should be multidisciplinary, including a comprehensive team comprised of a combination of the following: physicians pharmacists physical, occupational, and speech therapists

Because treatment options for ALS have historically been limited and the patient population is so small, the category has not been a priority for payers. However, with several pipeline therapies in

The ALS pipeline is robust, promising innovative treatment possibilities for this debilitating disease. This is an exciting advancement in a space where options have been limited for patients and providers. See Table 1 for a complete ALS pipeline.

8 | Magellan Rx Report | Summer 2021

Stay ahead of trend: Gene therapy management strategies 2020 ELEV ENTH

EDITION

magellanrx.com/trendreport

phase three, payers may start strategizing how to best manage the space and ensure that patients have access to the most appropriate therapy. Additionally, early research shows the opportunity for potentially curative results with gene therapy in ALS patients. As research and development progresses, this patient

population will become a higher management priority for payers. A robust landscape of treatment options, coupled with high-cost therapies, will create an urgency for payers to address the ALS space, developing creative strategies for cost management and ensuring access to proper treatment for patients.

References 1.

S myotrophic ateral Sclerosis Johns Hopkins Medicine, https://www.hopkinsmedicine.org/neurology_neurosurgery/centers_ clinics/als/conditions/als_amyotrophic_lateral_sclerosis.html.

Santaniello, riana S ana ed Care Considerations American Journal of Managed Care, u , https // ajmc com/ ie / als-managed-care-considerations.

myotrophic ateral Sclerosis ( S) act Sheet National Institute of Neurological Disorders and Stroke, une , https // ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/ Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet.

erry, ames, et al e considerations in the desi n o clinical trials or amyotrophic lateral sclerosis Clinical Investigation (London). , doi /cli Miller, R.G., et al. “Clinical trials of riluzole in patients with ALS. ALS/ Riluzole Study roup Neurology, Oct. 1996, https://pubmed. ncbi nlm nih o / /

appro es dru to treat S U.S. Food and Drug Administration, ay , https // da o /ne s-e ents/pressannouncements/fda-approves-drug-treat-als. She ner, , et al on -term edara one e cacy in amyotrophic lateral sclerosis Post-hoc analyses o Study ( C - ) Muscle & Nerve, , doi /mus

Palumbo, oseph, et al Post-hoc analyses o the edara one clinical trials Study and Study a step to ard more e cient clinical trial desi ns in amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, vol. 20, no. 5-6, 2019, pp. , doi /

“AAN Summary of Evidence-based Guideline for CLINICIANS: The care of the patient with Amyotrophic Lateral Sclerosis: Drug, Nutritional, and Respiratory herapies American Academy of Neurology, an , https // aan com/ uidelines/home/ uideline etail/

10. IPD Analytics.

Visit us online at magellanrx.com/mrxreport | 9

For your appropriate adult patients with moderately to severely active UC and CD when other therapies have not worked well enough or cannot be tolerated

Entyvio works through a gut-selective MOA by specifically binding to the α4β7 integrin and blocking its interaction with MAdCAM-1, which is mainly expressed on gut endothelial cells.1 Remission was evaluated at Week 52.1 Individual results may vary.

INDICATIONS Adult Ulcerative Colitis (UC) ENTYVIO (vedolizumab) is indicated in adults for the treatment of moderately to severely active UC. Adult Crohn’s Disease (CD) ENTYVIO (vedolizumab) is indicated in adults for the treatment of moderately to severely active CD.

IMPORTANT SAFETY INFORMATION • ENTYVIO (vedolizumab) for injection is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients. • Infusion-related reactions and hypersensitivity reactions including anaphylaxis, dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate have been reported. These reactions may occur with the first or subsequent infusions and may vary in their time of onset from during infusion or up to several hours post-infusion. If anaphylaxis or other serious infusion-related or hypersensitivity reactions occur, discontinue administration of ENTYVIO immediately and initiate appropriate treatment.

IMPORTANT SAFETY INFORMATION (continued)

• Patients treated with ENTYVIO are at increased risk for developing infections. Serious infections have been reported in patients treated with ENTYVIO, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis, and cytomegaloviral colitis. ENTYVIO is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding ENTYVIO in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice. • Progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised. One case of PML in an ENTYVIO-treated patient with multiple contributory factors has been reported in the post marketing setting (e.g., human immunodeficiency virus [HIV]

ENTYVIO is a trademark of Millennium Pharmaceuticals, Inc., registered with the U.S. Patent and Trademark Office and is used under license by Takeda Pharmaceuticals America, Inc. All other trademarks are the property of their respective owners. ©2021 Takeda Pharmaceuticals U.S.A., Inc. All rights reserved. Printed in U.S.A. US-VED-0049v2.0 02/21

For your appropriate adult patients with moderately to severely active UC and CD

ONLY ENTYVIO COMBINES

GUT SELECTIVITY

Entyvio helps address inflammation where it occurs—in the gut1 Entyvio specifically binds to the α4β7 integrin and blocks the interaction between the α4β7 integrin and MAdCAM-1, which is mainly expressed on the GI tract endothelial cells

SAFETY FOR THE LONG TERM

LONG-TERM REMISSION

2-7

1,8,9

Clinical trials evaluated safety in more than 3300 patients (UC and CD).1 A separate open-label study of up to 7 years demonstrated consistent results across safety parameters10-12*

UC and CD patients achieved remission at Week 52 vs placebo in study populations that included bio-naïve and anti-TNFα–experienced patients1,8,9 Individual results may vary

1,10-12

*In a single-arm, open-label extension study of 2243 patients who received Entyvio with a median exposure of 1072.0 days (range 1 to 3412 days).

ONLY ENTYVIO IS THE

FASTEST GROWING FIRST-LINE BIOLOGIC

FOR UC AND CD PATIENTS COMBINED 8 Biologics included Entyvio, Humira®, FOR UC AND CD PATIENTS * Remicade® (infliximab), and Stelara® (ustekinumab)‡ 13†

OFFERS RESULTS FROM

HEAD-TO-HEAD STUDY ENTYVIO HUMIRA®

OF BIOLOGICS IN MODERATE TO SEVERE UC14-16 §

(vedolizumab)

(adalimumab)

†Based on an analysis of data in SHA database comparing patient counts from year-to-year absolute growth information from December 2018 to November 2020 with "first line" defined as a new start in patients with UC or CD who had no UC or CD biologic drug claims for the past 3 years. ‡Humira® (AbbVie Inc. Chicago, IL); Remicade® (Janssen Biotech, Inc. Horsham, PA); Stelara® (Janssen Biotech, Inc. Horsham, PA). §Humira® (AbbVie Inc. North Chicago, IL). For information related to adalimumab, please see AbbVie.com.

IMPORTANT SAFETY INFORMATION (continued)

infection with a CD4 count of 300 cells/mm3 and prior and concomitant immunosuppression). Although unlikely, a risk of PML cannot be ruled out. Monitor patients for any new or worsening neurological signs or symptoms. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. If PML is suspected, withhold dosing with ENTYVIO and refer to a neurologist; if confirmed, discontinue ENTYVIO dosing permanently. • There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. ENTYVIO should be discontinued in patients with jaundice or other evidence of significant liver injury. • Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines. Patients receiving ENTYVIO may receive non-live vaccines and may receive live vaccines if the benefits outweigh the risks.

IMPORTANT SAFETY INFORMATION (continued)

• Most common adverse reactions (incidence ≥3% and ≥1% higher than placebo): nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities.

Please see Brief Summary of Full Prescribing Information on adjacent pages. CD = Crohn's disease; GI = gastrointestinal; MAdCAM-1 = mucosal addressin cell adhesion molecule-1; MOA = mechanism of action; TNFα = tumor necrosis factor alpha; UC = ulcerative colitis. References: 1. Entyvio (vedolizumab) prescribing information. Takeda Pharmaceuticals. 2. Briskin M, Winsor-Hines D, Shyjan A, et al. Am J Pathol. 1997;151(1):97-110. 3. Fedyk E, Wyant T, Yang LL, et al. Inflamm Bowel Dis. 2012;18(11):2107-2119. 4. Milch C, Wyant T, Xu J, et al. J Neuroimmunol. 2013;264:123-126. 5. Soler D, Chapman T, Yang LL, et al. J Pharmacol Exp Ther. 2009;330(3):864-875. 6. Wyant T, Fedyk E, Abhyankar B. J Crohns Colitis. 2016;10(12):1437-1444. 7. Wyant T, Leach T, Sankoh S, et al. Gut. 2015;64(1):77-83. 8. Data on file. Final CSR C13006, September 2012. Takeda Pharmaceuticals USA, Inc. 9. Data on file. Final CSR C13007, October 2012. Takeda Pharmaceuticals, USA, Inc. 10. Loftus EV Jr, Feagan BG, Panaccione R, et al. Aliment Pharmacol Ther. 2020;1-13. doi:10.1111/apt16060. 11. Data on file. Final CSR C13008, April 2020. Takeda Pharmaceuticals USA, Inc. 12. Data on file. Internal communication, October 2020. Takeda Pharmaceuticals USA, Inc. 13. Data on file. Fastest growing first-line biologic, January 2021. Takeda Pharmaceuticals USA, Inc. 14. Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al. N Engl J Med. 2019;381(13):1215-1226. 15. Data on file. AGA Abstracts 416a, May 2019. Takeda Pharmaceuticals USA, Inc. 16. Data on file. Varsity Oral Presentation, May 2019. Takeda Pharmaceuticals USA, Inc.

For more information on how you can help your patients, visit EntyvioHCP.com.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION ENTYVIO (vedolizumab) for injection, for intravenous use FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE ENTYVIO is indicated in adults for the treatment of: • moderately to severely active ulcerative colitis. • moderately to severely active Crohn’s disease. CONTRAINDICATIONS ENTYVIO is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients (such as dyspnea, bronchospasm, urticaria, flushing, rash and increased heart rate) [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Infusion-Related Reactions and Hypersensitivity Reactions Infusion-related reactions and hypersensitivity reactions have been reported, including anaphylaxis, dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate [see Adverse Reactions]. These reactions may occur with the first or subsequent infusions of ENTYVIO and may vary in their time of onset from during infusion or up to several hours post-infusion. If anaphylaxis or other serious infusion-related or hypersensitivity reactions occur, discontinue administration of ENTYVIO immediately and initiate appropriate treatment. Infections Patients treated with ENTYVIO are at increased risk for developing infections [see Adverse Reactions]. The most commonly reported infections in clinical trials occurring at a rate greater on ENTYVIO than placebo involved the upper respiratory and nasal mucosa (e.g., nasopharyngitis, upper respiratory tract infection). Serious infections have also been reported in patients treated with ENTYVIO, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis. ENTYVIO is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding treatment in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution when considering the use of ENTYVIO in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice. For progressive multifocal leukoencephalopathy (PML), see Warnings and Precautions. Progressive Multifocal Leukoencephalopathy PML, a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised. One case of PML in an ENTYVIO-treated patient with multiple contributory factors has been reported in the postmarketing setting (e.g., human immunodeficiency virus [HIV] infection with a CD4 count of 300 cells/mm3 and prior and concomitant immunosuppression). Although unlikely, a risk of PML cannot be ruled out. Monitor patients on ENTYVIO for any new onset, or worsening, of neurological signs and symptoms. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months. If PML is suspected, withhold dosing with ENTYVIO and refer to a neurologist; if confirmed, discontinue dosing permanently. Liver Injury There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. In general, the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. ENTYVIO should be discontinued in patients with jaundice or other evidence of significant liver injury [see Adverse Reactions]. Live and Oral Vaccines Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines. Patients receiving ENTYVIO may receive non-live vaccines (e.g., influenza vaccine injection) and may receive live vaccines if the benefits outweigh the risks. There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO [see Adverse Reactions].

ADVERSE REACTIONS The following topics are also discussed in detail in the Warnings and Precautions section: • Infusion-Related Reactions and Hypersensitivity Reactions [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions] • Liver Injury [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to ENTYVIO in 3,326 patients and healthy volunteers in clinical trials, including 1,396 exposed for greater than one year, and 835 exposed for greater than two years. The safety data described in Table 2 are derived from four controlled Phase 3 trials (UC Trials I and II, and CD Trials I and III); data from patients receiving open-label ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included. In these trials, 1,434 patients received ENTYVIO 300 mg for up to 52 weeks, and 297 patients received placebo for up to 52 weeks. Of these, 769 patients had ulcerative colitis and 962 patients had Crohn’s disease. Patients were exposed for a mean duration of 259 days (UC Trials I and II) and 247 days (CD Trials I and III). Adverse reactions were reported in 52% of patients treated with ENTYVIO and 45% of patients treated with placebo (UC Trials I and II: 49% with ENTYVIO and 37% with placebo; CD Trials I and III: 55% with ENTYVIO and 47% with placebo). Serious adverse reactions were reported in 7% of patients treated with ENTYVIO compared to 4% of patients treated with placebo (UC Trials I and II: 8% with ENTYVIO and 7% with placebo; CD Trials I and III: 12% with ENTYVIO and 9% with placebo). The most common adverse reactions (reported by ≥3% of patients treated with ENTYVIO in the UC Trials I and II and CD Trials I and III combined group and ≥1% higher than in combined placebo group) were nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain and pain in extremities (Table 2). Table 2. Adverse Reactions in ≥3% of ENTYVIO-Treated Patients and ≥1% Higher than in Placebo (UC Trials I and II* and CD Trials I and III*) ENTYVIO† (N=1434)

Placebo‡ (N=297)

Nasopharyngitis Headache

13% 12%

7% 11%

Arthralgia

12%

10%

Nausea

Pyrexia

Upper respiratory tract infection

6% 3%

Adverse Reaction

Fatigue

Cough

Bronchitis

Influenza

2% 3%

Back pain

Rash

Pruritus

1% 1%

Sinusitis

Oropharyngeal pain

Pain in extremities

*Data from patients receiving open-label ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included. † Patients who received ENTYVIO for up to 52 weeks. ‡ Patients who received placebo for up to 52 weeks.

Safety data for patients (n=279) in UC Trials I and II and CD Trials I and III who received ENTYVIO at Weeks 0 and 2 and were then randomized to placebo at Week 6 for up to 52 weeks, and for patients (n=416) in CD Trial II, a 10 week Crohn’s disease trial, are similar to those listed in Table 2.

Infusion-Related Reactions and Hypersensitivity Reactions Serious infusion-related reactions and hypersensitivity reactions including anaphylaxis have been reported following ENTYVIO administration in clinical trials [see Warnings and Precautions]. In UC Trials I and II and Crohn’s Trials I and III, one case of anaphylaxis [one out of 1,434 patients treated with ENTYVIO (0.07%)] was reported by a Crohn’s disease patient during the second infusion (symptoms reported were dyspnea, bronchospasm, urticaria, flushing, rash and increased blood pressure and heart rate) and was managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone. In UC Trials I and II and CD Trials I and III, 4% of patients treated with ENTYVIO and 3% of patients treated with placebo experienced an infusion-related reaction (IRR). The most frequently observed IRR in the patients treated with ENTYVIO (reported more than twice) were nausea, headache, pruritus, dizziness, fatigue, infusion-related reaction, pyrexia, urticaria and vomiting (each of these adverse reactions occurred in <1% in all patients treated with ENTYVIO) and no individual adverse reaction reported occurred at a rate above 1%. These reactions generally occurred within the first two hours after the infusion and resolved with no treatment or following antihistamine and/or IV hydrocortisone treatment. Less than 1% of patients treated with ENTYVIO had IRRs assessed by the investigator as severe, and IRRs requiring discontinuation of study treatment occurred in <1%. In clinical trials, for patients with mild IRRs or hypersensitivity reactions, physicians were allowed to pretreat with standard medical treatment (e.g., antihistamine, hydrocortisone and/or acetaminophen) prior to next infusion. Infections In UC Trials I and II and CD Trials I and III, the rate of infections was 0.85 per patient-year in the patients treated with ENTYVIO and 0.7 per patient-year in the patients treated with placebo [see Warnings and Precautions]. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis and urinary tract infection. Two percent of patients discontinued ENTYVIO due to infections. In UC Trials I and II and CD Trials I and III, the rate of serious infections was 0.07 per patient-year in patients treated with ENTYVIO and 0.06 per patient-year in patients treated with placebo. Serious infections were more common in Crohn’s disease patients than ulcerative colitis patients, and anal abscesses were the most frequently reported serious adverse reaction in Crohn’s disease patients. Over 48 months, there was no increase in the rate of serious infections. In controlled- and open-label long-term extension trials in adults treated with ENTYVIO, serious infections have been reported, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis. In UC Trials I and II and CD Trials I and III, sepsis, including bacterial sepsis and septic shock, was reported in four of 1,434 (0.3%) patients treated with ENTYVIO and in two of 297 patients treated with placebo (0.7%). During these trials, two Crohn’s disease patients treated with ENTYVIO died due to reported sepsis or septic shock; both patients had significant comorbidities and a complicated hospital course that contributed to the deaths. In an open-label, long-term extension trial, additional cases of sepsis (some fatal), including bacterial sepsis and septic shock, were reported. The rate of sepsis in patients with ulcerative colitis or Crohn’s disease receiving ENTYVIO was two per 1,000 patient-years. In clinical trials, all patients were screened for tuberculosis. One case of latent, pulmonary tuberculosis was diagnosed during the controlled trials with ENTYVIO. Additional cases of pulmonary tuberculosis were diagnosed during the open-label trial. All of these observed cases occurred outside the United States, and none of the patients had extrapulmonary manifestations. Liver Injury There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO [see Warnings and Precautions]. In UC Trials I and II and CD Trials I and III, three patients reported serious adverse reactions of hepatitis, manifested as elevated transaminases with or without elevated bilirubin and symptoms consistent with hepatitis (e.g., malaise, nausea, vomiting, abdominal pain, anorexia). These adverse reactions occurred following two to five ENTYVIO doses; however, based on case report information it is unclear if the reactions indicated drug-induced or autoimmune etiology. All patients recovered following discontinuation of therapy with some requiring corticosteroid treatment. In controlled trials, the incidence of ALT and AST elevations ≥3x ULN was <2% in patients treated with ENTYVIO and in patients treated with placebo. In the open-label trial, one additional case of serious hepatitis was observed. Malignancies In UC Trials I and II and CD Trials I and III, malignancies (excluding dysplasia and basal cell carcinoma) were reported in six of 1,434 (0.4%) patients treated with ENTYVIO, including colon cancer (n=2), transitional cell carcinoma (n=1),

breast cancer (n=1), carcinoid tumor of the appendix (n=1) and squamous cell carcinoma (n=1). Malignancy was reported in one of 297 (0.3%) patients treated with placebo (squamous cell carcinoma). Malignancies (excluding dysplasia and basal cell carcinoma) observed during the ongoing open-label long-term extension trial included B-cell lymphoma, breast cancer, colon cancer, malignant hepatic neoplasm, malignant lung neoplasm, malignant melanoma, lung cancer of primary neuroendocrine carcinoma, renal cancer and squamous cell carcinoma. Overall, the number of malignancies in the clinical trials was small; however, long-term exposure was limited. Live and Oral Vaccines There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO. In a placebo-controlled study of healthy volunteers, 61 subjects were given a single ENTYVIO 750 mg dose (2.5 times the recommended dose), and 62 subjects received placebo followed by intramuscular vaccination with Hepatitis B surface antigen and oral cholera vaccine. After intramuscular vaccination with three doses of recombinant Hepatitis B surface antigen, those treated with ENTYVIO did not have lower rates of protective immunity to Hepatitis B virus. However, those exposed to ENTYVIO did have lower seroconversion rates and anti-cholera titers relative to placebo after receiving the two doses of a killed, oral cholera vaccine. The impact on other oral vaccines and on nasal vaccines in patients is unknown. Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to vedolizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In UC Trials I and II and CD Trials I and III, in patients who received ENTYVIO, the frequency of antibodies detected in patients was 13% at 24 weeks after the last dose of study drug (greater than five half-lives after last dose). During treatment, 56 of 1,434 (4%) of patients treated with ENTYVIO had detectable anti-vedolizumab antibody at any time during the 52 weeks of continuous treatment. Nine of 56 patients were persistently positive (at two or more study visits) for anti-vedolizumab antibody and 33 of 56 patients developed neutralizing antibodies to vedolizumab. Among eight of these nine subjects with persistently positive anti-vedolizumab antibody and available vedolizumab concentration data, six had undetectable and two had reduced vedolizumab concentrations. None of the nine subjects with persistently positive anti-vedolizumab antibody achieved clinical remission at Weeks 6 or 52 in the controlled trials. Postmarketing Experience The following adverse reactions have been identified during post-approval use of ENTYVIO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: Anaphylaxis [see Warnings and Precautions] DRUG INTERACTIONS Natalizumab Because of the potential for increased risk of PML and other infections, avoid the concomitant use of ENTYVIO with natalizumab. TNF Blockers Because of the potential for increased risk of infections, avoid the concomitant use of ENTYVIO with TNF blockers. Live Vaccines Live vaccines may be administered concurrently with ENTYVIO only if the benefits outweigh the risks [see Warnings and Precautions]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ENTYVIO during pregnancy. Information about the registry can be obtained by calling 1-877-TAKEDA7 (1-877-825-3327). Risk Summary Available pharmacovigilance data, data from the ongoing pregnancy registry, and data from published case reports and cohort studies in pregnant women have not identified an ENTYVIO associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with inflammatory bowel disease in pregnancy (see Clinical Considerations). No fetal harm was observed in

animal reproduction studies with intravenous administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and miscarriage is 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and embryo/fetal risk Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g) infants, and small for gestational age at birth. Fetal/Neonatal adverse reactions ENTYVIO administered during pregnancy could affect immune responses in the in utero exposed newborn and infant. The clinical significance of low levels of ENTYVIO in utero-exposed infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Data Animal Data A reproduction study has been performed in pregnant rabbits at single intravenous doses up to 100 mg/kg administered on gestation Day 7 (about 20 times the recommended human dosage) and has revealed no evidence of impaired fertility or harm to the fetus due to vedolizumab. A pre- and post-natal development study in monkeys showed no evidence of any adverse effect on pre- and post-natal development at intravenous doses up to 100 mg/kg (about 20 times the recommended human dosage). Lactation Risk Summary Available published literature suggests the presence of vedolizumab in human milk. The effects of local gastrointestinal exposure and expected low systemic exposure to vedolizumab on the breastfed infant are unknown. There are no data on the effects of vedolizumab on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ENTYVIO and any potential adverse effects on the breastfed infant from ENTYVIO or from the underlying maternal condition. Pediatric Use Safety and effectiveness of ENTYVIO in pediatric patients have not been established. Geriatric Use Clinical trials of ENTYVIO did not include sufficient numbers of subjects aged 65 and over (46 Crohn’s and ulcerative colitis patients aged 65 and over were treated with ENTYVIO during controlled Phase 3 trials) to determine whether they respond differently from younger subjects. However, no overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. Manufactured by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 U.S. License No. 1898 Revised: March 2020 ENTYVIO is a trademark of Millennium Pharmaceuticals Inc. and is used under license by Takeda Pharmaceuticals America, Inc. All other trademark names are the property of their respective owners. ©2014 – 2020 Takeda Pharmaceuticals America, Inc. For more information, go to www.ENTYVIO.com or call 1-877-TAKEDA-7 (1-877-825-3327). VMB245 R4_Brf04/20

Gene Therapies for Rare Diseases: Chan in

andscape and Pipeline

As the gene therapy market expands, reimbursement and payment models will have to continue to transform. The expansion of the gene therapy market in the past several years has provided exciting opportunities for treating various rare diseases. The number of these transformative therapies will continue to increase, as the U.S. Food and Drug Administration (FDA) is expected to review 10 to 20 of these drugs every year through 2025.1 The biopharmaceutical industry is increasingly investing in research and de elopment specifically ocused on ene therapy to correct rare disorders, ith ad ances ran ing from new gene-insertion methods to innovations allowing therapies to penetrate hard-to-reach tissues.2

Kimberly DornbrookLavender, Pharm.D., BCPS Director, Clinical Pharmacy Medica

Gene therapy works by modifying a patient’s genes to treat or cure a disease via agents that can replace a disease-causing gene with a functioning copy of the gene, deactivate a disease-causing gene that is mis unctionin , or introduce a ne or modified ene to help treat the disease 3 Types of gene therapy products include plasmid DNA, viral vectors, bacterial vectors, human gene-editing technology, and patient-derived cellular gene therapy products.3

Current Gene Therapies for Rare Diseases Voretigene neparvovec-rzyl (LUXTURNA®) Voretigene nerparvovec-rzyl (LUXTURNA®, Spar herapeutics), the first ene therapy appro ed in the U.S., is an adeno-associated virus vector-based gene therapy indicated for the treatment of patients ith confirmed biallelic RP mutation-associated retinal dystrophy 4 The FDA approved it in December 2017.4 Real- orld use o oreti ene nepar o ec-rzyl has sho n a si nificant benefit

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GENE THERAPIES | Continued

when treatment is initiated in early childhood. As of 2019, nine treatment centers across the U.S. were designated to administer it, with a few surgeons per site cleared to provide treatment.5 ter treatin nine children and fi e adults, Children s Hospital os n eles reported obser in the reatest benefit in youn children through enrichment of their social, motor, and cognitive development.5

Onasemnogene abeparvovec-xioi (ZOLGENSMA®) Onasemno ene abepar o ec- ioi ( O S ®, Novartis) was approved by the FDA in May 2019 for the treatment of pediatric patients under 2 years old who have spinal muscular atrophy (SMA) with biallelic mutations in the survival motor neuron 1 (SMN1) gene. As of this March, more than 1,000 children with SMA had been treated with onasemnogene abeparvovec-xioi in clinical trials, managed access programs, or in the commercial setting.7 Real- orld data su est that older children, defined as months or older, achie ed clinically meanin ul benefit ith onasemnogene abeparvovec-xioi alone, after, or in combination with another SMA drug.7 Follow-up data from the clinical trials indicate that the children treated experienced a sustained benefit in the years ollo in dosin , ith milestones achie ed years a ter treatment and sustained durability in children up to years old and more than fi e years post-treatment 7

Gene Therapy Pipeline for Rare Diseases he pipeline or ene therapies is e pansi e, specifically around innovative treatments for rare diseases. With dozens of therapies bein de eloped and researched, an in u o no el ene therapies is on the horizon. See Table 1 for the full pipeline breakdown.

Challenges Associated With Gene Therapies and Managed Care Impact Patient and Provider Awareness The National Organization for Rare Disorders (NORD) conducted a survey among healthcare professionals to identify knowledge gaps regarding gene therapies.9 he results sho ed that o respondents were unaware of current FDA-approved gene therapies, and overall, respondents reported low comfort levels in discussing gene therapies with their patients.9 More than half of respondents noted that limited healthcare professional knowledge as a top barrier to ene therapy use, and only discuss ene therapy options with patients.9 These responses indicate a major need for provider and, transitively, patient education around gene

16 | Magellan Rx Report | Summer 2021

With dozens of therapies being developed and researched, an in u o nove gene t era ies is on the horizon. therapies, especially as more enter the market. Without robust provider knowledge and comfort around gene therapies, patient access to potentially curative therapies may be limited.

Financial Burden The costs associated with the currently available gene therapies are very high. Voretigene neparvovec-rzyl has a wholesale acquisition cost (WAC) of $850,000, or $425,000 per eye damaged by an RP ene mutation he current C or onasemno ene abeparvovec-xioi is $2.125 million.10 hese hi h costs are, and ill continue to be, a si nificant challenge for payers; moving forward, navigating this space and efficiently strate izin ill be ey to ensurin that patients ha e access to potentially li esa in therapy hile mana in the financial burden payers face. The substantial burden of these high-cost therapies has resulted in some exclusionary policies relating to gene therapies.1 Some plans and employer groups have made the decision to cease coverage of any medical or prescription drug charges related to gene therapy, with or without FDA approval.1 any payers are not currently e uipped to e ecti ely mana e the cost associated ith ene therapies thus, inno ati e financial solutions will be necessary.1 Payers ha e e pressed concerns around actuarial mana ement, e ecti eness and outcomes o the therapies, and payment timing.1 inancial solutions that may be e plored to e ecti ely address payer anxiety around some of these concerns include outcomesbased performance contracts, annuities payments, and reinsurance models.1 Manufacturers and payers are often working together to develop innovative models to overcome these barriers. One model is treatment milestone-based, where the payer pays a certain amount upfront and is partially reimbursed if the therapy fails to provide the intended outcomes in a predetermined time frame.11 Another model is subscription-based, includin a fi ed ee or unlimited access to certain therapies.11 Plan members contribute a cer-

Table 1. Rare Disease Gene Therapy Pipeline8 Drug Name

Manufacturer

Route of Administration

Status

Indications

Hemophilia etranacogene dezaparvovec fidanaco ene elapar o ec (P -

)

iroctoco ene fitelpar o ec (S P )

valoctocogene roxaparvovec (Roctavian)

uniQure; CSL Behring

phase three

hemophilia B

Spar

phase three

hemophilia B

phase three

hemophilia A

phase three

hemophilia A

herapeutics Pfizer

San amo herapeutics Pfizer io arin Pharmaceutical

AskBio009

a alta a eda Pharmaceutical Company

phase two

hemophilia B

DTX201

Dimension Therapeutics; Bayer

phase two

hemophilia A

SB-FIX

Sangamo Therapeutics

phase two

hemophilia B

phase two

hemophilia A

Spark Therapeutics; Roche

phase two

hemophilia A

fordadistrogene movaparvovec (P )

Pfizer

phase three (delayed)

DMD

delandistrogene moxeparvovec (SRP)

Sarepta Therapeutics

phase two

DMD

GALGT2

Sarepta Therapeutics

injectable

phase two

DMD

SGT-001

Solid Biosciences

phase two

DMD

Krystal iotech

topical

phase three

Castle Creek Biosciences; Fibrocell Technologies

injectable

phase three

Abeona Therapeutics

other

phase three

AAV-CNGA3

MeiraGTx; Janssen Pharmaceuticals

other

phase two

achromatopsia

AAV-CNGB3

MeiraGTx; Janssen Pharmaceuticals

other

phase two

achromatopsia

elivaldogene autotemcel (Lenti-D™)

bluebird bio

phase three

adrenoleukodystrophy

lenadogene nolparvovec (GS010)

GenSight Biologics

ophthalmic

phase three

Leber’s hereditary optic neuropathy

LYS-SAF302

Lysogene; Sarepta Therapeutics

other

phase three

mucopolysaccharidosis type IIIA

simoladagene autotemcel (OTL-101)

Orchard Therapeutics

injectable

phase three

severe combined immunodeficiency (SC )

timrepi ene empar o ec (

Nightstar Therapeutics; Biogen

intravitreal

phase three

choroideremia aromatic l-amino acid decarbo ylase deficiency (AADC)

SHP

a eda Pharmaceutical Company

SPKDuchenne muscular dystrophy (DMD)

Epidermolysis bullosa (EB) berema ene eperpa ec ( -

debcoema ene autoficel ( - i) Achromatopsia

Others

-R P )

eladoca ene e upar o ec (P C-

P C herapeutics

injectable

phase two

betibe lo ene autotemcel (

O®)

bluebird bio

pending

beta thalassemia

developing

metachromatic leukodystrophy

OTL-200

Orchard Therapeutics; la oSmithKline

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GENE THERAPIES | Continued

tain monthly amount that is used to pay for these therapies if needed, with the plan taking on the risk as it guarantees to provide as much therapy as required.11 With this model, payers can potentially mana e the actuarial uctuation that occurs with the funding of gene therapies.11 Another manufactureradvanced model prices therapies solely on the intrinsic alue o the product or ho it e tends and impro es uality o li e and returns all cost o sets to the payers this approach is astly di erent rom a typical reimbursement model but ould undoubtedly ease some of the concerns payers have expressed.1 Value-based contracts currently exist in commercial markets across therapeutic areas, as well as in Medicaid programs under supplemental rebate a reements across fi e states 1 Moving forward, these reimbursement agreements based on promised outcomes may be essential in e ecti ely mana in this space The manufacturer behind voretigene neparvovec-rzyl, Spark

Therapeutics, advanced an outcomes-based rebate arrangement that ali ned ith lon er-term e cacy o the ene therapy the manufacturer will share risk with payers by paying rebates if patient outcomes ail to meet a specified threshold 12 As more gene therapies enter the market, reimbursement and payment models will have to continue to transform; currently, both payers and manufacturers have been open about concerns associated with reimbursement models, citing limitations around program complexity, the burden of information tracking, insurance, regulatory barriers, and government pricing and reporting requirements.1 As additional therapies become available, developing creative payment models through collaboration of all stakeholders will be critical in ensuring the current system works to e ecti ely mana e these treatments, the financial burdens, and the patient population.

References 1.

eumann, lrich Payin or cell and ene therapy s the future already here?” Reuters Events, 2 Nov. 2020, https://www. reutersevents.com/pharma/medical/paying-cell-and-gene-therapyfuture-already-here. Weintraub, Arlene. “The next generation of gene therapy for rare diseases forges ahead as developers weather hurdles.” Fierce Biotech, ec , https // fiercebiotech com/biotech/ next-generation-gene-therapy-for-rare-diseases-forges-ahead-asdevelopers-weather-hurdles.

“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.

“LUXTURNA.” U.S. Food & Drug Administration, uly , https // www.fda.gov/vaccines-blood-biologics/cellular-gene-therapyproducts/luxturna.

a iel, aron One ear in Perspecti es on oreti ene Retina Today, July/Aug. 2019, https://retinatoday.com/articles/2019-julyaug/one-year-in-perspectives-on-voretigene. O S U.S. Food & Drug Administration, ar www.fda.gov/vaccines-blood-biologics/zolgensma.

, https //

“New Zolgensma data demonstrate age-appropriate development hen used early, realorld benefit in older children and durability 5+ years post-treatment.” Novartis, 15 Mar. 2021, https://www. novartis.com/news/media-releases/new-zolgensma-datademonstrate-age-appropriate-development-when-used-early-realorld-benefit-older-children-and-durability- -years-post-treatment

18 | Magellan Rx Report | Summer 2021

nalytics

DonFrancesco, Valaree. “NORD and FMC’s Gene Therapy Survey: A Call to ction or Healthcare Pro essional ducation NORD, pr 2020, https://rarediseases.org/nord-and-fmcs-gene-therapy-surveya-call-to-action-for-healthcare-professional-education/.

10. Melquist, Chanttel. “Gene therapy: A promising future at a high price.” Prime Therapeutics, 10 Apr. 2020, https://www.primetherapeutics. com/en/news/Stories/2020/story-overview-gene-therapy.html. 11. Vaidya, Anuja. “Innovative payment models to support cell and gene therapies on the rise.” MedCity News, 9 Dec. 2020, https:// medcitynews.com/2020/12/innovative-payment-models-to-supportcell-and-gene-therapies-on-the-rise/?rf=1. 12.

Spar herapeutics nnounces irst-o -their- ind Pro rams to mpro e Patient ccess to R ( oreti ene nepar o ecrzyl), a One-time Gene Therapy Treatment.” Spark Therapeutics, 3 Jan. 2018, https://sparktx.com/press_releases/spark-therapeuticsannounces-first-o -their- ind-pro rams-to-impro e-patient-accessto-luxturna-voretigene-neparvovec-rzyl-a-one-time-gene-therapy-treatment/.

HER2+ Metastatic Breast Cancer: CNS Metastases and Proper Management An estimated 3.6 million women were living with breast cancer in the U.S. in 2017, with a diagnosis rate of 129.1 cases per 100,000 women per year.1 Around 13% of women will be diagnosed with breast cancer at some point throughout their lifetime; the median age of diagnosis is 62.1 While breast cancer diagnoses are not only found in women, the data around male breast cancer cases are much more limited due to the si nificantly smaller dia nosis rate amon men

Stacy Inman, Pharm.D. Senior Clinical Project Manager Magellan Method

Stage IV, or metastatic, breast cancer (MBC) occurs when the breast cancer has spread to another part of the body.2 An estimated 30% of those diagnosed with early-stage breast cancer will develop MBC.2 In breast cancer, metastases in the bones, brain, liver, and lungs are most common.3 In recent years, the rate of central nervous system (CNS) metastasis has more than doubled, from 10% to 22%; liver metastasis has increased by 46%, lung metastasis has remained stable, and bone metastasis has decreased by 32%.4 There are four main female breast cancer subtypes: HR+/HER2- (luminal A), HR-/HER2- (triple negative), HR+/HER2+ (luminal B), and HR-/HER2+ (HER2-enriched).5 Up to 14% of patients diagnosed with early breast cancer have HER2+ breast cancer, which tends to grow and spread faster than other breast cancers and is more likely to recur than HER2- breast cancer.5-8 HER2+ breast cancer is more likely to respond to treatment that targets the HER2 protein.6 In an analysis of more than 7,500 cases of MBC from the SEER database, 26% of those cases were HER2+.9 Up to 50% of patients with HER2+ MBC develop brain metastases, putting this population at a higher risk than patients with breast cancer overall.10-13 Among those with HER2+ MBC who develop brain metastases, more than 50% will be diagnosed by the second line of therapy.14 In a study of patients with

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HER2+ METASTATIC BREAST CANCER | Continued

We do it all! Learn more on every aspect of our comprehensive oncology solution.

HER2+ MBC, nearly 40% developed brain metastases, and the median time rom initial C dia nosis to the first C S e ent as just over 10.8 months.14 HER2+ MBC patients have a 1.5-times-higher three-year cumulative risk for developing brain metastases when compared with HER2- patients.8, 15-17 HER2+ MBC patients with brain metastases have a median survival time of two to three years. Improvements and advances in breast cancer treatment have extended survival in patients; however, extended survival in turn results in additional time for brain metastases to develop, and there remains poor prognosis for patients with brain metastases.18 Treatment for patients who have HER2+ MBC with brain metastases is more challenging due to their reduced responsiveness to systemic therapies.19, 20

Impact of HER2+ MBC Brain Metastases Patient Outcomes, Treatment Challenges MBC disease progression greatly impacts health-related quality of life, based on patient-reported measures, including physical, functional, and emotional well-being; depression; anxiety; and global quality of life.21 Specifically, o erall breast cancer-related uality o li e as si nificantly lo er amon H R C patients ith brain metastases13; CNS metastasis is often associated with seizures,

20 | Magellan Rx Report | Summer 2021

altered mental status, headaches, visual impairment, dizziness, ataxia, nausea, and vomiting — substantially impacting physical and emotional functioning.22-24 Among patients with HER2+ MBC, low adherence or nonadherence to treatment is associated with poor quality of life and increased risk of mortality.25 Around one-third of patients with MBC reported di culties ith medication and adherence, and in a study o C patients, the number o nonadherent beha iors as si nificantly associated with a decrease in functional well-being.25 The most common patient-reported reasons for nonadherence were forgetulness and intolerance o side e ects 25 here are se eral treatment challen es associated specifically ith HER2+ MBC patients who have developed brain metastases. These patients are typically excluded from clinical trials due to poor functional status and increased risk of toxicity.26 Brain metastases often occur in C patients ho recei e adju ant chemotherapy, due to the properties of some agents that do not cross the blood-brain barrier.8 Thus, treatment plans may be complex, involving continued systemic therapies for HER2+ MBC in addition to CNS-directed treatments targeting the brain metastases.8 The standard of care for patients with HER2+ MBC with brain metastases includes CNSdirected treatment options such as surgical resection, stereotactic radiosurgery (SRS), and whole-brain radiotherapy (WBRT).27 These locally targeted treatments can be associated with short- and

re uires e ective anage ent to i rove outcomes; coordinated care is essential to address the poor prognosis resulting from disease progression in this patient population.

long-term toxicities, including cognitive defects.28, 29 A combination of systemic therapies with SRS has been shown to result in hi h rates o clinically si nificant radionecrosis in H R C patients.28 Current guidelines from the National Comprehensive Cancer Network and the American Society of Clinical Oncology recommend screening for brain metastases on the basis of suspicious CNS symptoms, including any neurologic symptoms such as new-onset headaches, unexplained nausea or vomiting, or a change in motorsensory function.27, 30 However, 43% of patients with MBC and brain metastases are asymptomatic, creating a challenge in diagnosing CNS progression.

costs for patients with CNS metastasis were four times higher than for patients without CNS metastases ($41,192 vs. $10,802, respectively).33 Additionally, patients with CNS metastases experienced more outpatient, emergency room, and inpatient visits.

Managed Care Impact H R C re uires e ecti e mana ement to impro e outcomes coordinated care is essential to address the poor prognoses resulting from disease progression in this patient population. There is a high unmet need stemming from the unique challenges these patients face, particularly tied to the occurrence of brain metastases and associated treatment obstacles. Due to the higher risk of poor outcomes and mortality among HER2+ MBC patients, proper and close management is key to improving outcomes and quality of life. Proper care coordination, addressing nonadherent behaviors, and appropriate screenings can both ease the cost burden for payers and lead to increased health-related quality of life in MBC patients. Ensuring that HER2+ MBC patients with brain metastases receive the proper treatment targeting CNS metastasis is also critical to improving outcomes, as traditional therapies for breast cancer will not penetrate the blood-brain barrier and will leave the CNS metastasis unaddressed.

References 1.

“Cancer Stat Facts: Female Breast Cancer.” National Cancer Institute, 2020, https://seer.cancer.gov/statfacts/html/breast.html.

“Metastatic Breast Cancer.” BreastCancer.org, 9 Feb. 2021, https:// www.breastcancer.org/symptoms/types/recur_metast.

Berman, Abigail, et al. “Incidence and patterns of distant metastases for patients with early-stage breast cancer after breast conservation treatment.” Clinical Breast Cancer, Apr. 2013, https://pubmed.ncbi. nlm.nih.gov/23218473/.

van den Hurk, Corina, et al. “Unfavourable pattern of metastases in M0 breast cancer patients during 1978-2008: a population-based analysis of the Munich Cancer Registry.” Breast Cancer Research and Treatment, Aug. 2011, https://pubmed.ncbi.nlm.nih.gov/21311969/.

“Cancer Stat Facts: Female Breast Cancer Subtypes.” National Cancer Institute, 2020, https://seer.cancer.gov/statfacts/html/breastsubtypes.html.

“Breast Cancer HER2 Status.” American Cancer Society, 2019, https:// www.cancer.org/cancer/breast-cancer/understanding-a-breastcancer-diagnosis/breast-cancer-her2-status.html.

Kennecke, Hagen, et al. “Metastatic behavior of breast cancer subtypes.” Journal of Clinical Oncology, July 2010, https://pubmed. ncbi.nlm.nih.gov/20498394/.

Economic Burden When compared to early-stage breast cancer, MBC has a substantially higher economic burden, as it is associated with higher shortterm and medium-term direct costs.31 Annual direct healthcare costs for patients with MBC with disease progression are 1.6 times higher than for those whose disease has not progressed; patients with progressive MBC have cost nearly $50,000 more than those without progression in the past year.32 ajor cost dri ers or H R MBC were outpatient visits and HER2-directed therapy drug costs.31 For MBC patients with brain metastases, healthcare resource use and costs are even higher. The median total cost for MBC patients with CNS metastasis was more than double the cost for those without ($112,402 vs. $50,835, respectively).33 Median outpatient

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HER2+ METASTATIC BREAST CANCER | Continued

References 8.

Musolino, Antonino, et al. “Multifactorial central nervous system recurrence susceptibility in patients with HER2-positive breast cancer: epidemiological and clinical data from a population-based cancer registry study.” Cancer, May 2011, https://pubmed.ncbi.nlm. nih.gov/21509760/.

Gong, Yue, et al. “Impact of molecular subtypes on metastatic breast cancer patients: a SEER population-based study.” Scientific Reports, Mar. 2017, https://pubmed.ncbi.nlm.nih.gov/28345619/.

10. Pestalozzi, B.C., et al. “Is risk of central nervous system (CNS) relapse related to adju ant ta ane treatments in node-positi e breast cancer? Results of the CNS substudy in the intergroup Phase III BIG 02-98 Trial.” Annals of Oncology, Nov. 2008, https://pubmed.ncbi.nlm. nih.gov/18562328/. 11. Olson, Erin, et al. “Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the posttrastuzumab era.” Breast, Aug. 2013, https://pubmed.ncbi.nlm.nih. gov/23352568/. 12. Bendell, Johanna, et al. “Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma.” Cancer, June 2003, https://pubmed.ncbi.nlm.nih. gov/12784331/. 13. Hurvitz, Sara, et al. “Central Nervous System Metastasis in Patients with HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from SystHERs.” Clinical Cancer Research, Apr. 2019, https://pubmed.ncbi.nlm.nih.gov/30593513/. 14. Brufsky, Adam, et al. “Central Nervous System Metastases in Patients with HER2-Positive Metastatic Breast Cancer: Incidence, Treatment, and Survival in Patients from registHER.” Clinical Cancer Research, , https //clincancerres aacrjournals or /content/ / / 15. Azim, Hamdy, et al. “Predicting Brain Metastases in Breast Cancer Patients: Stage Versus Biology.” Clinical Breast Cancer, Apr. 2018, https://pubmed.ncbi.nlm.nih.gov/28888580/. 16. Hun , an-Hsin, et al ect o e and iolo ical Subtype on the Risk and Timing of Brain Metastasis in Breast Cancer Patients.” PLOS One, eb , https //journals plos or /plosone/ article id /journal pone 17. Genre, Ludivine, et al. “External validation of a published nomogram for prediction of brain metastasis in patients with extra-cerebral metastatic breast cancer and risk regression analysis.” European Journal of Cancer, Feb. 2017, https://www.sciencedirect.com/science/ article/abs/pii/S0959804916325230. 18. Mounsey, Louisa, et al. “Changing Natural History of HER2-Positive Breast Cancer Metastatic to the Brain in the Era of New Targeted Therapies.” Clinical Breast Cancer, Feb. 2018, https://pubmed.ncbi. nlm.nih.gov/28867445/. 19. Frisk, G., et al. “Incidence and time trends of brain metastases admissions among breast cancer patients in Sweden.” British Journal of Cancer, 22 May 2012, https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3364124/. 20. Lin, Nancy, et al. “Brain metastases: the HER2 paradigm.” Clinical Cancer Research, Mar. 2007, https://pubmed.ncbi.nlm.nih. gov/17363517/.

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21. Marschner, Norbert, et al. “Association of Disease Progression with Health-Related Quality of Life Among Adults with Breast, Lung, Pancreatic and Colorectal Cancer.” JAMA Network Open, Mar. 2020, https://pubmed.ncbi.nlm.nih.gov/32154886/. 22. Cacho-Díaz, Bernardo, et al. “Diagnosis of brain metastases in breast cancer patients resulting from neurological symptoms.” Clinical Neurology and Neurosurgy, Oct. 2018, https://pubmed.ncbi.nlm.nih. gov/30086430/. 23. Oltean, Daniela, et al. “Brain metastases secondary to metastatic breast cancer: symptoms, prognosis and evolution.” Tumori Journal, 2009, https://pubmed.ncbi.nlm.nih.gov/20210232/. 24. Bachelot, Thomas, et al. “Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study.” The Lancet Oncology, Jan. 2013, https://pubmed.ncbi.nlm.nih. gov/23122784/. 25. daCosta DiBonaventura, Marco, et al. “Patient preferences and treatment adherence among women diagnosed with metastatic breast cancer.” American Health & Drug Benefits, Oct. 2014, https:// pubmed.ncbi.nlm.nih.gov/25525495/. 26. “Cancer Clinical Trial Eligibility: Brain Metastases.” U.S. Food and Drug Administration, 13 Mar. 2019, https://www.fda.gov/regulatoryinformation/search-fda-guidance-documents/cancer-clinical-trialeligibility-criteria-brain-metastases. 27. Ramakrishna, Naren, et al. “Recommendations on Disease Management for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases: ASCO Clinical Practice Guideline Update.” Journal of Clinical Oncology, Sept. 2018, https://pubmed.ncbi.nlm.nih.gov/29939840/. 28.

ro n, Paul, et al ect o Radiosur ery lone s Radiosur ery ith Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial.” JAMA, July 2016, https://pubmed.ncbi.nlm.nih.gov/27458945/.

29. Brosnan, Evelyn, et al. “Understanding patterns of brain metastasis in breast cancer and designing rational therapeutic strategies.” Annals of Translational Medicine, May 2018, https://pubmed.ncbi.nlm.nih. gov/29911111/. 30. “NCCN Clinical Practice Guidelines in Oncology for Breast Cancer v.6.2020.” National Comprehensive Cancer Network, 2020, https:// pubmed.ncbi.nlm.nih.gov/32259783/. 31. Sussell, Jesse, et al. “HER2-Positive Metastatic Breast Cancer: A Retrospective Cohort Study of Healthcare Costs in the TargetedTherapy Age.” Advances in Therapy, Apr. 2020, https://pubmed.ncbi. nlm.nih.gov/32172510/. 32. Reyes, Carolina, et al. “Cost of Disease Progression in Patients with Metastatic Breast, Lung, and Colorectal Cancer.” Oncologist, Sept. 2019, https://pubmed.ncbi.nlm.nih.gov/30796156/. 33. Pulgar, S., et al. “Economic burden of central nervous system metastases in human epidermal growth factor receptor 2-positive breast cancer.” Abstract for Academy of Managed Care Pharmacy, , https // jmcp or /doi/pd / /jmcp -a s

WHEN HER2+ MBC PROGRESSES

PURSUE UNPRECEDENTED TUKYSA + trastuzumab + capecitabine vs placebo + trastuzumab + capecitabine1

Reduced risk of disease progression or death by 46% 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

Extended median OS by 4.5 months Median OS: 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 The trial studied patients who had received prior trastuzumab, pertuzumab, and T-DM1 in the neoadjuvant, adjuvant, or metastatic setting.1

TUKYSAhcp.com Indication 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 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 first 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.

CI = confidence interval; HER = human epidermal growth factor receptor; HR = hazard ratio; MBC = metastatic breast cancer; OS = overall survival; PFS = progression-free survival; T-DM1 = ado-trastuzumab emtansine.

Please see full Important Safety Information on the following pages.

RAISING THE STANDARD FOR SURVIVAL In combination with trastuzumab + capecitabine

TUKYSA extended overall survival*1 100

Patients Alive (%)

21.9 months

(95% CI: 18.3-31.0)

60 MEDIAN

17.4 months

SECONDARY ENDPOINT HR = 0.66 (95% CI: 0.50-0.87) P = 0.0048

TUKYSA arm

(95% CI: 13.6-19.9)

Control arm

NUMBER OF EVENTS TUKYSA arm: 130/410 Control arm: 85/202

IN MEDIAN OS

0 0

MONTH IMPROVEMENT

34 7

20 5

10 2

4 1

0 0

Months Since Randomization NUMBER AT RISK TUKYSA arm Control arm

410 202

388 191

322 160

245 119

178 77

123 48

80 32

51 19

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

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 first 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.

TUKYSAhcp.com In combination with trastuzumab + capecitabine

TUKYSA reduced the risk of disease progression or death PRIMARY ENDPOINT*

EXPLORATORY ANALYSIS*†

PFS

PFS AT 12 MONTHS reduction in the risk of disease progression or death1

~3x as many patients were progression-free2 TUKYSA ARM VS

• HR = 0.54 (95% CI: 0.42-0.71); P <0.00001 • Median PFS: 7.8 months (95% CI: 7.5-9.6) in the TUKYSA arm vs 5.6 months (95% CI: 4.2-7.1) in the control arm

CONTROL ARM

(33.1%; 95% CI: 26.6-39.7)

(12.3%; 95% CI: 6.0-20.9)

*Study design: HER2CLIMB was a randomized (2:1), double-blind, placebo-controlled trial of 612 patients with HER2+ MBC who received TUKYSA + trastuzumab + capecitabine (TUKYSA arm; n = 410) or placebo + trastuzumab + capecitabine (control arm; n = 202). Primary endpoint was PFS (time from randomization to documented disease progression or death from any cause) in the first 480 randomized patients. Secondary endpoints assessed in all randomized patients included OS (time from randomization to death from any cause). PFS was evaluated in accordance with RECIST criteria, version 1.1, by means of BICR.1 †This exploratory analysis is descriptive only. These are estimates and not exact numbers. HER2CLIMB was not powered to assess a statistical difference between treatment groups at this time point. BICR = blind independent central review; CI = confidence 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; RECIST = Response Evaluation Criteria in Solid Tumors.

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. The mean increase in serum creatinine was 32% within the first 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 Specific 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. Murthy RK, Loi S, Okines A, et al. Supplemental appendix for: Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609.

WARNINGS AND PRECAUTIONS

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 Modifications for Adverse Reactions The recommended TUKYSA dose reductions and dosage modifications for adverse reactions are provided in Tables 1 and 2. Refer to the Full Prescribing Information for trastuzumab and capecitabine for information about dosage modifications 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 Modifications for Adverse Reactions Severity Diarrhea1 Grade 3 without anti-diarrheal treatment Grade 3 with anti-diarrheal treatment Grade 4 Hepatotoxicity1,2 Grade 2 bilirubin (>1.5 to 3 × ULN)

TUKYSA Dosage Modification Initiate or intensify appropriate medical therapy. Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the same dose level. Initiate or intensify appropriate medical therapy. Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the next lower dose level. Permanently discontinue TUKYSA.

Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the same dose level. Grade 3 ALT or AST (> 5 to 20 × ULN) Hold TUKYSA until recovery to ≤ Grade 1, then OR Grade 3 bilirubin (> 3 to 10 × ULN) resume TUKYSA at the next lower dose level. Grade 4 ALT or AST (> 20 × ULN) Permanently discontinue TUKYSA. OR Grade 4 bilirubin (> 10 × ULN) ALT or AST > 3 × ULN AND Permanently discontinue TUKYSA. Bilirubin > 2 × ULN 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 Modifications for Severe Hepatic Impairment: For patients with severe hepatic impairment (Child-Pugh C), reduce the recommended dosage to 200 mg orally twice daily. Dosage Modifications 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.

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 first 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 findings 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 reflect 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) Grade (%) All 3 4 Gastrointestinal disorders Diarrhea 81 12 0.5 Nausea 58 3.7 0 Vomiting 36 3 0 32 2.5 0 Stomatitis 1 Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia 63 13 0 syndrome 20 0.7 0 Rash 2 Hepatobiliary disorders 42 9 0.2 Hepatotoxicity 3 Metabolism and nutrition disorders Decreased appetite 25 0.5 0

Placebo + Trastuzumab + Capecitabine (N = 197) Grade (%) All 3 4 53 44 25 21

9 3 3.6 0.5

0 0 0 0

0.5

3.6

Adverse Reaction

TUKYSA + Trastuzumab + Placebo + Trastuzumab + Capecitabine (N = 404) Capecitabine (N = 197) Grade (%) Grade (%) All 3 4 All 3 4 Blood and lymphatic system disorders 21 3.7 0 13 2.5 0 Anemia 4 Musculoskeletal and connective tissue disorders Arthralgia 15 0.5 0 4.6 0.5 0 Investigations 14 0 0 1.5 0 0 Creatinine increased5 Weight decreased 13 1 0 6 0.5 0 Nervous System Disorders Peripheral 13 0.5 0 7 1 0 neuropathy 6 Respiratory, thoracic and mediastinal disorders Epistaxis 12 0 0 5 0 0 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 All Grades Grades ≥3 % % Hematology Decreased hemoglobin Chemistry Decreased phosphate Increased bilirubin Increased ALT Increased AST Decreased magnesium Decreased potassium 2 Increased creatinine 3 Decreased sodium 4 Increased alkaline phosphatase

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

3.3

1.5

57 47 46 43 40 36 33 28

8 1.5 8 6 0.8 6 0 2.5

45 30 27 25 25 31 6 23

7 3.1 0.5 1 0.5 5 0 2

0.5

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 definition 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 definition for Grade 2 in CTCAE v.4.03.

Increased Creatinine: The mean increase in serum creatinine was 32% within the first 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 findings 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 findings 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.

pdate

reatment and

ecti e

ana ement

he pipeline or H includes methods or prophyla is, such as potential accinations ith these added pre enti e measures, payers may prioritize strate ic mana ement o the o erall H space n the S , an estimated million people are li in ith human immunodeficiency irus (H ), ith ap, there ere , pro imately , ne H in ections occurrin annually, per data 1 n deaths amon those dia nosed ith H in the S 1

Current Treatment Landscape Luke Merkel, Pharm.D., MBA Director of Pharmacy Services Avera Health

Per uidelines rom the S epartment o Health and Human Ser ices (HHS), current recommended H treatment is antiretro iral therapy ( R ), hich patients should be in as soon a ter dia nosis as possible to slow progression.2 here are se en classes o R nucleoside re erse transcriptase inhibitors ( Rs), non-nucleoside re erse transcriptase inhibitors ( R s), protease inhibitors (P s), usion inhibitors, CCR anta onists, post-attachment inhibitors, and inte rase strand trans er inhibitors ( S s)

PrEP Pre-e posure prophyla is (Pr P) is an H -pre ention strate y recommended by the S Centers or isease Control and Prevention. here are currently t o -appro ed H Pr P therapies or daily use emtricitabine and teno o ir disopro il umarate ( R or Pr P®) and emtricitabine and teno o ir ala enamide ( SCO or Pr P®) dherence to Pr P medication as prescribed can reduce the ris o contractin H ia se ual contact and ia dru injection by and , respecti ely here are three phases to appropriate care usin Pr P screenin , Pr P initiation, and ollo -up he initial screenin should include an H ris assessment, Pr P education, and an initial clinical e aluation that includes assessment o indications or Pr P, a brie medical history, and appropriate lab or Pr P initiation should occur ithin se en days o the screenin and include a re ie o Pr P basics and a prescription o Pr P or days or less ollo -up should be consistent and occur e ery three months, ith an H blood test a symptom re ie concurrent prescription o Pr P and assessment and counselin

28 | Magellan Rx Report | Summer 2021

or H ris beha ior, adherence, and pre nancy intent estin or se ually transmitted in ections and idney unction should be done e ery si months or ollo -up

Genotypic Drug-Resistance Testing ru -resistance testin helps determine i an H patient has a orm o the irus that has mutated and does not respond to R Specifically, enotypic dru -resistance testin e amines the enotype o a patient s H to analyze or the presence o specific enetic mutations that are no n to cause resistance to R

Guideline Updates n pril, HHS updated its uidelines or pediatric H treatment pdates included discussion o and uidance or the use o telehealth and telemedicine in pediatric H care an e pansion o pre erred re imen desi nation o dolute ra ir ( C ) plus t o R s to be recommended or anyone a e ee s or older, proided they ei h at least the addition o bicte ra ir, as part o bicte ra ir/emtricitabine/teno o ir ala enamide ( K R ®), in patients at least years old and ei hin at least and a distinction that R bac bone o abaca ir ( ia en) alon side either emtricitabine ( R ) or lami udine ( pi ir) is classified as

pre erred or children at least month old, despite or the dru s speci yin an a e o at least years old

appro al

HHS uidelines or the treatment o H in adults and adolescents ere most recently updated in and adjusted recommendations or first-line re imens he update added dolute ra ir/ lami udine ( O O) to the list o recommended initial re imens alon side bicte ra ir/emtricitabine/teno o ir ala enamide ( K R ®) or a treatment option in acutely or recently in ected people or hom enotypic dru -resistance testin had not yet been completed

Adherence and Single-Tablet Regimen vs. MultipleTablet Regimen dherence is critical or patients to maintain iral suppression less e ecti e iral suppression is associated ith poor treatment adherence , he adherence thresholds ary bet een di erent classes o R Ho e er, impro ed outcomes, includin iral suppression and, in some cases, reduced ris o resistance mutations, are associated ith hi her adherence le els he introduction o sin le-tablet re imen (S R) options has increased adherence or H patients and resulted in decreased

isit us online at magellanrx.com/mrxreport | 29

HIV UPDATE | Continued

Table 1. HIV Pipeline15 Drug

Manufacturer

Route of Administration

abaca ir sul ate ( R )

ii Healthcare

oral

cabote ra ir ( SK )

ii Healthcare la oSmithKline

intramuscular

islatravir ( K)

erc

oral

lenacapa ir ( S)

ilead Sciences

oral S

leronlimab (PRO )

Cyto yn

nited ioPharma

Mechanism of Action

Indication

Status

inte rase inhibitor nucleoside analogue reverse

H - in ection

phase three

prophyla is

phase three

prophyla is H in ection

phase three

H - in ection

phase three

H - in ection

phase three

H - in ection

phase three

nucleoside re erse transcriptase translocation

entry inhibitor

iral attachment bloc er

cenicri iroc ( R )

obira herapeutics a eda Pharmaceutical Company

oral

entry inhibitor

H - in ection

phase two

Remune

Immune Response ioPharma

prophyla is

phase t o (CR / / )

pharmacy costs and hospitalizations hen compared to e istin n an analysis o patients inimultiple-tablet re imens ( R) , tiatin R , patients on S R ere more than t ice as li ely to be adherent hen compared to R patients Persistence as more common amon S R patients, as R patients ere more li ely to discontinue treatment n a pilot H care-mana ement pro ram acilitated by a ellan ethod, edicaid patients prescribed at least one H medication, ith the e ception o Pr P, ere included in an outreach pro ram aimed to assess the impact o the pro ram on R adherence and the proportion o patients ho are irolo ically suppressed 11 Prior to the contact period, more than hal o the participatin patients 11 had a proportion o days co ered (P C) o less than O erall, patients on S R had hi her adherence than patients on R prior to contact, o S R patients had a P C o less than compared to o R patients Si months a ter enrollment in the pro ram, there as an increase in P C to about o erall, compared to pre-contact period 11 his data sho s an opportunity or patient en a ement in addressin patient adherence in the H patient population mpro ed adherence can lead to

30 | Magellan Rx Report | Summer 2021

accine

sustained iral suppression, better outcomes, and impro ed cost management.

Newly Approved Therapies Cabotegravir and Rilpivirine (CABENUVA) and Cabotegravir (VOCABRIA)12 n anuary, the appro ed cabote ra ir e tended-release injectable suspension and rilpi irine e tended-release injectable suspension (C , ii Healthcare), co-pac ed or intramuscular use, or H - -in ected adults t is the first -appro ed injectable complete re imen indicated or H that is administered once monthly he t o-dru co-pac a ed products include cabote ra ir, an H S , and rilpi irine, an H R t is indicated as a complete re imen to replace current antiretro iral re imen in those ho are irolo ically suppressed on a stable antiretro iral re imen ith no treatment ailure and no no n or suspected resistance to either drug.

Focused measures to increase treatment adherence in HIV patients can lead to lower costs overall, including pharmacy and hospitalizations.

recei in the placebo, and a ter day , all participants recei ed ostemsa ir alon ith other antiretro iral dru s i ty-three percent o participants achie ed iral suppression a ter ee s o ostemsa ir plus other antiretro iral dru s inally, a ter ee s, o participants continued to ha e iral suppression he most common side e ect as nausea ho e er, more se ere ad erse e ents included ele ations in li er enzymes amon participants also in ected ith hepatitis or C irus and chan es in the immune system

Payer Implications he also appro ed cabote ra ir m tablets ( OC R ) indicated to be ta en in combination ith oral rilpi irine or one month prior to starting treatment with the two-drug extendedrelease injectable to ensure the medications are ell tolerated beore s itchin o phase-three randomized, multicenter, acti e-controlled, parallel-arm, open-label, non-in eriority trials e aluated the e cacy o C n the R trial, H -in ected, R -na e subjects recei ed dolute ra ir S -containin re imen or ee s, and subjects ho ere irolo ically suppressed ere randomized to recei e either a cabote ra ir plus rilpi irine re imen or remain on the current R re imen n ebruary, HHS determined C injections can be used to optimize treatment in patients ith H ho are currently on oral R ith documented iral suppression or at least three months and ho ha e no baseline resistance to either medication, prior irolo ic ailures, or acti e hepatitis irus are not pre nant or plannin to become pre nant and are not recei in medications ith si nificant interactions n patients ho may be dra n to monthly injection o er daily pills, C may become the pre erence

Fostemsavir (Rukobia)14 n uly , the appro ed ostemsa ir (Ru obia, ii Healthcare), indicated or adults li in ith H ho ha e tried multiple H medications and hose in ection cannot be successully treated ith other therapies due to resistance, intolerance, or sa ety considerations trial o hea ily treatment-e perienced adult participants ith hi h irus le els as conducted ith participants in the main trial arm and an additional participants recei in ostemsa ir in a di erent arm o the trial Participants in the main trial arm recei ed either ostemsa ir or a placebo t ice daily or ei ht days in addition to the pre iously ailin antiretroiral re imen On day , participants recei in ostemsa ir had a si nificantly reater decrease in irus le els compared to those

Research sho s that ith the e pansion o edicaid under the ordable Care ct ( C ) came an increase in the identification o undia nosed H in ections and use o H -pre ention ser ices an estimated increase in H dia noses as associated ith edicaid e pansion, accordin to data rom the ni ersity o llinois. his shi t, alon ith accompanied appropriate treatment and use o pre enti e ser ices, as lin ed directly to the impro ed access to care throu h edicaid, as dia noses ere most common in populations li ely a ected by edicaid e pansion, includin lo -income indi iduals en a ed in injection dru use rom rural counties ith hi h uninsured rates prior to the C

Research shows that with the expansion of Medicaid under ACA came an increase in the identification o undiagnosed HIV infections and use of HIV-prevention services; an estimated 13.9% increase in HIV diagnoses was associated with Medicaid expansion. isit us online at magellanrx.com/mrxreport | 31

HIV UPDATE | Continued

MRx PIPELINE

Our latest quarterly report on anticipated specialty and traditional drugs in the pipeline

A VIEW INTO UPCOMING SPECIALTY & TRADITIONAL DRUGS JANUARY 2021

magellanrx.com/pipeline

he data su ests access to health insurance and proper care impro ed H testin rates and use o pre enti e care, leadin to hi her rates o indi iduals li in ith H ccess to care and proper mana ement or patients ith H are critical in impro in outcomes ith se eral enerics enterin the mar et or on the horizon, there is potential or cost mana ement in this cate ory Combination therapies ha e created the opportunity or combinin se eral eneric therapies here brand-only therapies ere preiously utilized Stron policy ill be ey in dri in eneric utilization in this space dditionally, by prioritizin the H population, payers can better mana e this space ocused measures to increase treatment adherence in H patients can lead to lo er costs o erall, includin pharmacy and hospitalizations 11

32 | Magellan Rx Report | Summer 2021

he pipeline or H includes methods or prophyla is, such as potential accinations ith these added pre enti e measures, payers may prioritize strate ic mana ement o the o erall H space, includin identi yin appropriate populations and ensurin access to prophylactic therapies Proper pre enti e care, coupled ith e ecti e mana ement o populations ith H , could lead to impro ed lon -term outcomes and cost mana ement ith an e pandin pipeline, payers may strate ize to achie e cost sa in s by incenti izin and steerin patients to ard lo ercost eneric alternati es

References 1.

S Statistics HIV.gov, ar , https // basics/o er ie /data-and-trends/statistics

o /hi -

H reatment O er ie HIV.gov, ar , https // hi o /hi -basics/stayin -in-hi -care/hi -treatment/hi -treatmentoverview. Pre-e posure Prophyla is (Pr P) Care System U.S. Centers for Disease Control and Prevention, Sept , cdc o /hi / e ecti e-inter entions/pre ent/prep/inde html H ru Resistance estin Stanford Health Care, https // stan ordhealthcare or /medical-conditions/se ual-and-reproducti ehealth/hi -aids/treatments/hi -dru -resistance-testin html Hel and, yles hat s e in S H Clinical reatment uidelines TheBodyPro, pr , https // thebodypro com/article/ hats-ne -in-the-us-hi -clinical- uidelines

10.

an ness, acob, et al Comparison o adherence rates or antiretro iral, blood pressure, or mental health medications or H -positi e patients at an academic medical center outpatient pharmacy Journal of Managed Care and Specialty Pharmacy, https //pubmed ncbi nlm nih o / /

11. Kan ethe, nne, et al nalysis o a Pilot H Care ana ement Pro ram Academy of Managed Care Pharmacy, , https // ma ellanr com/documents/ / /analysis-o -a-pilot-hi -caremana ement-pro ram pd / 12.

ppro es Cabenu a and ocabria or the reatment o H n ection U.S. Food and Drug Administration, an , da o /dru s/human-immunodeficiency- irus-hi / da-appro escabenu a-and- ocabria-treatment-hi - -in ection

Schaecher, Kenneth he mportance o reatment dherence in H American Journal of Managed Care, Sept , https // ajmc com/ ie /a sep schaecher s

HHS dults and dolescents ntiretro iral uidelines Panel Recommendation or the on - ctin njectable ntiretro iral Re imen o Cabote ra ir and Rilpi irine Clinical Info, eb , https //clinicalin o hi o /en/ uidelines/adult-and-adolescent-ar / hhs-adults-and-adolescents-antiretro iral- uidelines-panel

Hines, ionne, et al reatment dherence and Persistence mon H - Patients e ly Startin reatment Patient Preference and Adherence, o , https // ncbi nlm nih o /pmc/articles/ P C /

ppro es e H reatment or Patients ith imited reatment Options U.S. Food and Drug Administration, uly , https // da o /ne s-e ents/press-announcements/ daapproves-new-hiv-treatment-patients-limited-treatment-options.

Cohen, Cal in, et al ssociation bet een daily antiretro iral pill burden and treatment adherence, hospitalization ris , and other healthcare utilisation and costs in a S edicaid population ith H BMJ Open, , https //bmjopen bmj com/content/ / / e

nalytics

elson, Hannah edicaid pansion Helped etect ndia nosed H n ections Health Payer Intelligence, an , https // healthpayerintelli ence com/ne s/medicaid-e pansion-helpeddetect-undia nosed-hi -in ections

Sa , Paul, et al dherence to antiretro iral treatment and correlation ith ris o hospitalization amon commercially insured H patients in the nited States PloS One, , https //pubmed ncbi nlm nih o / /

isit us online at magellanrx.com/mrxreport | 33

Kite, a Gilead Company, is dedicated to achieving one of the most ambitious goals of the 21st century: curing cancer. This mission is at the heart of everything we do from early research to product development. W W W.K ITEPH ARMA.COM

P R O U D

T O

S U PP ORT

THE

MAGELLAN

REPORT

CAR-T Update: Expanding Landscape and Payer Impact ith se eral C R- therapies in the pipeline, the oncolo y space e ecti e mana ement mo in or ard

ill re uire strate izin and

The oncology management landscape is ever-evolving. The approval and pipeline of innovative new therapies coupled with the way the ongoing COVID-19 pandemic has changed care delivery will create new challenges for payers to navigate in managing members with cancer moving forward. Chimeric antigen receptor T-cell (CAR-T) therapy represents an exciting recent advancement in oncology treatment. CAR-T therapy is a type of immunotherapy that works by modifying a patient’s T-cells to attack cancer cells.1 Currently, it is used in the treatment of certain blood cancers; it is also being in esti ated or e cacy in treatin se eral other types o cancer, ith a robust pipeline on the horizon 1, 2 Mona Chitre, Pharm.D., CGP ie ar ac cer Clinical Analytics, Strategy and Innovation Excellus BlueCross BlueShield

Recent Approvals Idecabtagene Vicleucel (ABECMA®)3 n arch, the S ood and ru dministration ( ) appro ed the first C R- therapy or the treatment of multiple myeloma in adult patients. Idecabtagene vicleucel (ABECMA®, Celene) is specifically indicated or adult patients ith multiple myeloma ho ha e not responded to, or whose disease has returned after, at least four prior lines of therapy. Idecabtagene icleucel is a -cell maturation anti en ( C )-directed enetically modified autolo ous C R- therapy. In a study of 127 patients with relapsed myeloma and refractory myeloma who had received at

Visit us online at magellanrx.com/mrxreport | 35

CAR-

DA E | Continued

Brexucabtagene Autoleucel (TECARTUS®)5 Brexucabtagene autoleucel (TECARTUS®, Kite Pharma) received FDA approval in July 2020 for the treatment of adult patients diagnosed with mantle cell lymphoma (MCL) who have not responded to or who have relapsed following other treatments. This is the first appro ed C R- therapy or the treatment o C trial o 60 adults with refractory or relapsed MCL showed a complete response rate of 62% after treatment with brexucabtagene autoleucel, with an objective response rate of 87%. The most common associated side e ects include serious in ections, lo blood cell counts, and a weakened immune system; more serious potential side e ects include CRS and neurolo ic to icities

least three prior antimyeloma lines of therapy, 72% of patients partially or completely responded to treatment with idecabtagene vicleucel. Overall, 28% showed complete response, and 65% of that group remained in complete response for at least 12 months. Severe associated adverse reactions include cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis/macrophage activation syndrome, neurologic toxicity, and prolonged cytopenias more common side e ects include in ections, ati ue, musculoskeletal pain, and a weakened immune system.

Currently, CAR-T is used in the treatment of certain blood cancers; it is also being investigated or e cac in treating several other types of cancer, with a robust pipeline on the horizon.

Lisocabtagene Maraleucel (BREYANZI®)4

ICER De er

The FDA approved lisocabtagene maraleucel (BREYANZI®, Juno Therapeutics) in February for the treatment of adult patients with certain types of large B-cell lymphoma who have not responded to or have relapsed after at least two other types of systemic treatment. Lisocabtagene maraleucel is the third CAR-T therapy approved for certain types of non-Hodgkin lymphoma, including di use lar e -cell lymphoma ( C ) n a trial o more than adult patients with refractory or relapsed large B-cell lymphoma, patients treated with lisocabtagene maraleucel showed a complete response rate o Se ere associated side e ects include CRS and neurolo ic to icities other side e ects include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system.

In April, the Institute for Clinical and Economic Review (ICER) released an evidence report that assessed the comparative clinical e ecti eness and alue o idecabta ene icleucel and ciltacabtagene autoleucel, which is currently under FDA review. The report noted that both therapies appear to deli er relati ely sizeable gains in both progression-free survival and overall survival for triple class refractory multiple myeloma patients exposed to three or more prior lines of treatment, with higher rates of response and longer survival than treatment with current therapies,” concluding there is “high certainty that both therapies provide at least a small net health benefit compared to usual care, ith the possibility o substantial benefit Ho e er, C R noted that idecabta ene icleucel ould re uire a discount o the currently an-

36 | Magellan Rx Report | Summer 2021

e 1 CAR Drug

e ne6 Manufacturer

Route of Administration

Mechanism of Action

Status

ciltacabtagene autoleucel (JNJ4528)

Janssen Pharmaceuticals; Legend Biotech

multiple myeloma

pending

axicabtagene ciloleucel (YESCARTA)

Kite Pharma; Gilead Sciences

mar inal zone lymphoma di use lar e -cell lymphoma

pending; phase three

CEA CAR-T

Sorrento Therapeutics

injectable

pancreatic cancer

phase three

tabelecleucel (ATA129)

Atara Biotherapeutics

post-transplant lymphoproliferative disease

phase three

ATA230

Atara Biotherapeutics

cytomegalovirus infection

phase two

AUTO1

Autolus Therapeutics

acute lymphocytic leukemia

phase two

Descartes-08

Cartesian Therapeutics

injectable

multiple myeloma; myasthenia gravis

phase two

Descartes-11

Cartesian Therapeutics

injectable

multiple myeloma

phase two

With several CAR-T therapies in the pipeline, the oncology space will require strategizing and e ective anage ent moving forward. nounced wholesale acquisition cost (WAC) of $419,500 in order to all in the recommended health-benefit price-benchmar ran e

e C re I

In September 2020, the U.S. Centers for Medicare & Medicaid Serices (C S) finalized its proposal to establish a edicare Se erity

Diagnosis Related Group for CAR-T services, with a national, unadjusted payment amount for this new group of $239,929.8 Notably, this amount is less than the recommended amount from the American Society of Clinical Oncology (ASCO) as well as the sales price of CAR-T, which is $373,000.8 ith the e citin opportunity and inno ation o ered by C Rtherapies come high costs. Determining the appropriate patients for these therapies will be key in properly managing the space.9 While CAR-T is an exciting option, payers need to assess the full treatment landscape and properly identify for which patients CAR-T is appropriate; deference to providers in these instances is important, but proper policy will also be key.9 With currently a ailable C R- therapies, or anizations ill typically coordinate payment by usin customized a reements on a per-patient basis, making the billing and reimbursement for these therapies complicated and burdensome.10 However, as more CAR-T options become available, payers are approving and allowing access to these therapies expeditiously.10 Still, it will take payers time to negotiate and customize these per-patient a reements in order to optimize management in the space.10

Visit us online at magellanrx.com/mrxreport | 37

CAR-

DA E | Continued

With several CAR-T therapies in the pipeline, the oncology space ill re uire strate izin and e ecti e mana ement mo in orard Cra tin policy that appropriately identifies populations and ensures access to new innovative therapies, whether on a patient-by-patient basis or through broader management, will be critical to payers ability to e ecti ely mana e the cost burden o CAR-T therapies as these options become increasingly available.

Stay ahead of trend: CAR-T management strategies

2020 ELEVENTH EDITION

magellanrx.com/trendreport

References 1.

“CAR-T cell therapy.” National Cancer Institute, https://www.cancer. gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy.

Huang, Ruihao, et al. “Recent advances in CAR-T cell engineering.” Journal of Hematology & Oncology, 2 July 2020, https://jhoonline. biomedcentral.com/articles/10.1186/s13045-020-00910-5.

“FDA Approves First Cell-Based Gene Therapy for Adult Patients with Multiple Myeloma.” U.S. Food and Drug Administration, 27 Mar. 2021, https://www.fda.gov/news-events/press-announcements/ da-appro es-first-cell-based- ene-therapy-adult-patients-multiplemyeloma.

“FDA Approves New Treatment For Adults With Relapsed Or Refractory Large-B-Cell Lymphoma.” U.S. Food and Drug Administration, 5 Feb. 2021, https://www.fda.gov/news-events/pressannouncements/fda-approves-new-treatment-adults-relapsed-orrefractory-large-b-cell-lymphoma.

“FDA Approves First Cell-Based Gene Therapy For Adult Patients with Relapsed or Refractory MCL.” U.S. Food and Drug Administration, 24 July 2020, www.fda.gov/news-events/press-announcements/fdaappro es-first-cell-based- ene-therapy-adult-patients-relapsed-orrefractory-mcl.

38 | Magellan Rx Report | Summer 2021

IPD Analytics. “CAR-T Therapy Pipeline.”

“ICER Publishes Evidence Report on Therapies for Multiple Myeloma.” Institute for Clinical and Economic Review, 5 Apr. 2021, https://icer. org/news-insights/press-releases/icer-publishes-evidence-report-ontherapies-for-multiple-myeloma/.

edicare Reimbursement pdate or C R- inalized American Society of Clinical Oncology, 4 Sept. 2020, https://www.asco.org/ practice-policy/policy-issues-statements/asco-in-action/medicarereimbursement-update-car-t.

Minemyer, Paige. “Optum: How payers can prepare now for wave of CAR-T therapies.” Fierce Healthcare, 22 Sept. 2020, https://www. fiercehealthcare com/payer/optum-ho -payers-can-prepare-no for-wave-car-t-therapies.

10. Cryts, Aine. “CAR T-cell Therapy: How Payers are Responding to Huge Price Tags.” Managed Healthcare Executive, 5 Nov. 2018, https://www. managedhealthcareexecutive.com/view/car-t-cell-therapy-howpayers-are-responding-huge-price-tags.

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COVID-19 and Oncology Care: Long-Term Implications Decreased Screenings and Delayed Diagnoses

Lindsay C. Speicher, J.D. Project Manager Magellan Method

Since the be innin o the CO - pandemic, oncolo y dia nosis and care ha e been si nificantly impacted.1, 2 Hospital outpatient evaluation and management visits, new patient visits, established patient visits, and billing for physician-administered oncology products have been similarly lower.1, 2 The current global health crisis has undoubtedly delayed diagnosis and treatment, which can lead to major challenges downstream, potentially increasing cancer morbidity and mortality rates. A physician survey showed a shift away from prescribing immune checkpoint inhibitors, monoclonal antibodies, and corticosteroids during the COVID-19 pandemic.3 In April 2020, when COVID-19 cases were surging in the U.S., breast, colon, prostate, and lung cancer screenings were massively reduced by 85%, 75%, 74%, and 56%, respectively.1, 2 Data indicates a si nificant decline in ne ly identified patients ith common types o cancer this could lead to a potential increase in cancer deaths of nearly 34,000.4 Delays in cancer diagnoses, surgery, radiation, and chemotherapy as well as a trend in treatment strategies toward less-intensive approaches could increase cancer mortality by 10,000 deaths from breast and colorectal cancers in the next decade.1-2, 4

Changing Oncology Care Overall, the healthcare system has relied on alternate delivery models to mitigate the impact of reduced in-person care. There has been an emphasis on using telehealth and home care to continue pro idin care e ecti ely and sa ely durin the pandemic

40 | Magellan Rx Report | Summer 2021

Oncology care has been increasingly delivered in the home setting as a response to the ongoing pandemic. Telehealth Telehealth visits increased 135% from March to April 2020 and have been a preferred method of care delivery for many during the pandemic.5 The types of in-person visits that can be appropriately deli ered ia telehealth must be identified or this modality to be successful. The American Society of Clinical Oncology (ASCO) published a report on care during the pandemic, identifying visits for positive COVID-19 infections, nonurgent highrisk patient populations, and symptom management as eligible for telehealth visits.5 ASCO recommended optimizing the use of telehealth during the COVID-19 pandemic, noting that providers should recei e additional trainin and education specifically regarding telehealth and its appropriate use.6 A study evaluating the use of telehealth among patients with cancer during the COVID-19 pandemic showed most participatin patients ere satisfied ith and are becomin increasin ly com ortable ith telehealth ideo isits a majority o physicians ere satisfied and li ely to use it in the uture 7 elehealth is not ithout challen es healthcare pro iders ha e cited several concerns, including inadequate patient interactions and acquisition of medical data, increased potential for missing si nificant clinical findin s, decreased uality o care, and potential medical liability.7 Additionally, challenges surrounding the equitable delivery of telehealth must be addressed as this modality is used moving forward. Vulnerable older, lower-income, and un- or underinsured communities may not have equal access to the technology necessary to receive this type of care.7

Trend Toward Home Care Oncology care has been increasingly delivered in the home setting as a response to the ongoing pandemic.8 Delaying care to reduce risk of exposure would also increase probability of death. Thus, there was a critical need to identify ways to avoid risk of exposure while continuing to provide care.8

Prior to the pandemic, in an e ort to demonstrate sa e oncolo y care delivery at home, Penn Medicine launched its Cancer Care at Home program, which was accelerated in light of the COVID-19 pandemic.9 Over a period in late March and April 2020, home infusion referrals for patients with cancer increased 700%.9 Additionally, other health systems had been working to move patients from infusion centers to home care prior to the pandemic to improve patient convenience and free up space.10 As the COVID-19 outbreak and pandemic increased the need, home care became more used where appropriate, which helped decrease exposure for already vulnerable and at-risk patients.10 here are si nificant concerns relatin to home care and in usions, however. Oncologists have expressed concerns over safety issues such as urgent reactions and the potential for the spread of COVID-19 in the home setting.20 Notably, ASCO reported that it does not support the routine use of home infusion for oncology treatment, citing concerns for “increased waste and the loss of valuable patient toxicity assessment during an infusion visit in the clinic.”6

Visit us online at magellanrx.com/mrxreport | 41

COVID-19 AND ONCOLOGY CARE | Continued

Managed Care Implications Payer management strategies will likely adjust to address the increase in use of telehealth and a shift toward home care. Moving forward, there will potentially be a shift away from delivering care in person where possible. Certain factors informing the decision to deliver care in the home setting will include capacity at sites of care, clinical considerations, drug pricing, labor and building costs, and insurer co era e and benefit desi n 9 Payers may strate ize ho to e ecti ely include home care and telehealth options in the management of patients with cancer while ensuring patients continue receiving appropriate care. The oncology space ill re uire strate izin and e ecti e mana ement in order to address the growing need stemming from a period of delayed dia noses and care Re isitin benefit desi n or patients ith cancer to increase access to di erent modalities o care deli ery, including telehealth and home care, can improve outcomes and help provide patients a level and setting of care that promotes additional comfort.

42 | Magellan Rx Report | Summer 2021

Certain factors informing the decision to deliver care in the home setting will include capacity at sites of care, clinical considerations, drug pricing, labor and building costs, and insurer coverage and benefit design.

References 6.

ennett, Christina CO nspires Recommendations to Improve Cancer Care and Research.” Cancer Therapy Advisor, 21 Dec. 2020, https://www.cancertherapyadvisor.com/home/cancertopics/general-oncology/asco-covid19-coronavirus-cancer-careimprovements-guidelines/.

“Cancer Care During the COVID-19 Pandemic.” Pharmacy Times, 18 Dec. 2020, https://www.pharmacytimes.com/view/cancer-careduring-the-covid-19-pandemic.

Darcourt, Jorge, et al. “Analysis of the Implementation of Telehealth Visits for Care of Patients with Cancer in Houston During the COVID-19 Pandemic.” JCO Oncology Practice, 7 Oct. 2020, https:// ascopubs.org/doi/full/10.1200/OP.20.00572.

Kaufman, Harvey, et al. “Changes in the Number of US Patients With e ly dentified Cancer e ore and urin the Corona irus isease 2019 (COVID-19) Pandemic.” JAMA Network Open, 2020, https:// jamanetwork.com/journals/jamanetworkopen/fullarticle/2768946.

Chakraborty, Mainak, et al. “Caring for cancer patients in the Covid pandemic: choosing between the devil and deep sea.” World Journal of Surgical Oncology, 22 Aug. 2020, https://wjso. biomedcentral.com/articles/10.1186/s12957-020-02002-7.

Laughlin, Amy, et al. “Accelerating the Delivery of Cancer Care at Home During the Covid-19 Pandemic.” NEJM Catalyst, 7 July 2020, https://catalyst.nejm.org/doi/full/10.1056/cat.20.0258.

Patt, Debra, et al. “Impact of COVID-19 on Cancer Care: How the Pandemic Is Delaying Cancer Diagnosis and Treatment for American Seniors.” JCO Clinical Cancer Informatics, 30 Nov. 2020, https:// ascopubs.org/doi/full/10.1200/CCI.20.00134.

McNulty, Rose. “Cancer Care Delays in COVID-19 Could Lead to Higher Morbidity and Mortality.” American Journal of Managed Care, 22 Oct. 2020, https://www.ajmc.com/view/cancer-care-delays-incovid-19-could-lead-to-higher-morbidity-mortality.

Nguyen, Ryan, et al. “Telehealth Is Here to Stay: Opportunities and Challenges for Cancer Care.” OncologyLive, 29 Oct. 2020, https:// www.onclive.com/view/telehealth-is-here-to-stay-opportunitiesand-challenges-for-cancer-care.

10. “At-Home Cancer Care, Infusions Widespread Amid Pandemic.” Clinical Oncology News, 14 Dec. 2020, https://www.clinicaloncology. com/Community-Oncology/Article/12-20/At-Home-Cancer-CareInfusions-Widespread-Amid-Pandemic-/61420.

Visit us online at magellanrx.com/mrxreport | 43

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PI PE LI N E D RU G LIST

PIPELINE DRUG LIST

Name

Manufacturer

Clinical Use

Dosage Form

Approval Status

Expected FDA Approval

coagulation factor VIIa (recombinant)-jncw (SEVENFACT®)

Hema Pharmaceuticals

hemophilia A and B (prevention of bleeding related to surgery or invasive procedure)

sBLA

mid-2021

15-valent pneumococcal conjugate vaccine

Merck

invasive pneumococcal disease

BLA; breakthrough therapy; priority review

07/16/2021

narsoplimab

Omeros

HSCT-associated thrombotic microangiopathy

BLA; breakthrough therapy; orphan drug; priority review

07/16/2021

odevixibat

Albireo Pharma

progressive familial intrahepatic cholestasisrelated pruritus

oral

NDA; fast-track; orphan drug; priority review; rare pediatric disease

07/20/2021

retifanlimab

Incyte

anal cancer (squamous cell, locally advanced/ metastatic, failed on/ intolerant to platinumbased chemotherapy)

BLA; orphan drug; priority review

07/23/2021

sulopenem etzadroxil/probenecid

Iterum Therapeutics

uncomplicated UTI (quinolone-resistant)

oral

NDA; fast-track; priority review; QIDP

07/23/2021

tenapanor (IBSRELA®)

Ardelyx

hyperphosphatemia

oral

sNDA

07/29/2021

selexipag (UPTRAVI®)

Janssen Pharmaceuticals

PAH (as temporary alternative to oral formulation)

sNDA; orphan drug

07/30/2021

levonorgestrel 52 mg intrauterine device (Mirena®)

Bayer

contraception duration up to 6 years

sNDA

July 2021

abrocitinib

Pfizer

atopic dermatitis (moderate-severe)

oral

NDA; breakthrough therapy; priority review

July-August 2021

baricitinib (Olumiant®)

Eli Lilly and Company

atopic dermatitis (moderate-severe)

oral

sNDA

July-August 2021

mepolizumab (NUCALA)

GlaxoSmithKline

nasal polyposis

sBLA

July-August 2021

tofacitinib (Xeljanz®/Xeljanz XR®)

Pfizer

ankylosing spondylitis

oral

sNDA

July-August 2021

upadacitinib (RINVOQ™)

AbbVie

atopic dermatitis (moderate-severe, ages >12 years)

oral

sNDA; breakthrough therapy

July-August 2021

tick-borne encephalitis vaccine

Pfizer

tick-borne encephalitis

BLA; priority review; rare pediatric disease

August 2021

treosulfan

Medac

allogeneic-HSCT conditioning

IV; oral

NDA; orphan drug

August 2021

tretinoin/benzoyl peroxide

Sol-Gel

acne vulgaris

topical

505(b)(2) NDA

08/01/2021

Visit us online at magellanrx.com/mrxreport | 45

PI PE LI N E D RU G LIST

PIPELINE DRUG LIST CONT.

Name

Manufacturer

Clinical Use

Dosage Form

Approval Status

Expected FDA Approval

topiramate oral solution

Azurity Pharmaceuticals

partial seizures

oral

505(b)(2) NDA

08/06/2021

sodium oxybate (XYWAV™)

Jazz Pharmaceuticals

idiopathic hypersomnia

oral

sNDA; fast-track; orphan drug; priority review

08/12/2021

Amgen

NSCLC (KRAS G12 mutation, locally advanced/metastatic, >1 prior systemic therapy)

oral

sNDA: breakthrough therapy; fast-track; orphan drug; priority review; RTOR

08/16/2021

enfortumab vedotin-ejfv (PADCEV™)

Astellas Pharma

bladder cancer (locally advanced/metastatic, after PD-1/L1 inhibitor therapy, cisplatin ineligible)

sBLA; priority review; Project Orbis; RTOR

08/17/2021

avalglucosidase alfa

Sanofi

Pompe disease

BLA; breakthrough therapy; fast-track; orphan drug; priority review

08/18/2021

oportuzumab monatox

Sesen Bio

bladder cancer (BCG-unresponsive, nonmuscle-invasive)

intravesical

BLA; fast-track; priority review

08/18/2021

dextromethorphan/bupropion

Axsome Therapeutics

MDD

oral

505(b)(2) NDA; breakthrough therapy; fasttrack; priority review

08/20/2021

difelikefalin

Cara Therapeutics

pruritus (hemodialysisrelated)

NDA; breakthrough therapy; priority review

08/23/2021

lenvatinib (LENVIMA®)

Eisai

RCC (first-line, in combination with pembrolizumab)

oral

sNDA; breakthrough therapy; priority review

08/25/2021

pembrolizumab (KEYTRUDA®)

Merck

RCC (first-line, in combination with lenvatinib)

sBLA; breakthrough therapy; priority review

08/25/2021

rivaroxaban (XARELTO®)

Janssen Pharmaceuticals

peripheral arterial disease (post-recent lower-extremity revascularization)

oral

sNDA

08/26/2021

belumosudil

Kadmon

GVHD (chronic)

oral

NDA; breakthrough therapy; orphan drug; priority review; Project Orbis; RTOR

08/30/2021

adalimumab (biosimilar to HUMIRA®)

Alvotech

RA; AS; PsO; PsA; JIA; CD; UC

BLA

September 2021

ivosidenib (TIBSOVO®)

Les Laboratoires Servier

biliary tract cancer (previously treated, IDH1 mutated)

oral

sNDA; fast track; orphan drug; priority review

09/01/2021

paliperidone palmitate 6-month injectable

Janssen Pharmaceuticals

schizophrenia

NDA

09/02/2021

Lenvatinib (LENVIMA®)

Eisai

endometrial carcinoma (advanced, in combination with pembrolizumab)

oral

sNDA; breakthrough therapy; priority review

09/03/2021

sotorasib (LUMAKRAS™)

46 | Magellan Rx Report | Summer 2021

PI PE LI N E D RU G LIST

PIPELINE DRUG LIST CONT.

Name

Manufacturer

Dosage Form

Clinical Use

Approval Status

Expected FDA Approval

nivolumab (OPDIVO®)

Bristol Myers Squibb

bladder cancer (adjuvant, high-risk muscle-invasive)

sBLA; breakthrough therapy; priority review

09/03/2021

pembrolizumab (KEYTRUDA®)

Merck

endometrial carcinoma (advanced, in combination with lenvatinib)

sBLA; breakthrough therapy; priority review

09/03/2021

dihydroergotamine mesylate

Impel NeuroPharma

migraine

intranasal

505(b)(2) NDA

09/06/2021

pembrolizumab (KEYTRUDA®)

Merck

squamous cell carcinoma (locally advanced)

sBLA

09/09/2021

daratumumab/hyaluronidase-fihj (Darzalex Faspro™)

Janssen Pharmaceuticals

multiple myeloma (relapsed/refractory, in combination with pomalidomide and dexamethasone)

sBLA

09/10/2021

belzutifan

Merck

RCC

oral

NDA; breakthrough therapy; orphan drug; priority review

09/15/2021

budesonide (long-acting)

Calliditas Therapeutics

IgA nephropathy (Berger’s disease)

oral

505(b)(2) NDA; seeking accelerated approval; orphan drug; priority review

09/15/2021

risperidone long-acting in situ microparticle

Rovi

schizophrenia

505(b)(2) NDA

09/24/2021

udenafil

Dong-A Socio Holdings

single-ventricle heart defects (post-Fontan operation)

oral

NDA; orphan drug

09/29/2021

reltecimod

Atox Bio

NSTI-related organ dysfunction/failure (ages >12 years)

NDA; seeking accelerated approval; fast-track; orphan drug

09/30/2021

ranibizumab (biosimilar Lucentis®)

Biogen/Samsung

wet AMD

intravitreal

BLA

SeptemberOctober 2021

maralixibat

Mirum Pharmaceuticals

Alagille syndrome

oral

NDA; breakthrough therapy; orphan drug; priority review; rare pediatric disease

10/01/2021

RVT-802 (cultured human thymus tissue)

Enzyvant

DiGeorge syndrome (congenital athymia)

BLA; breakthrough therapy; orphan drug; RMAT

10/08/2021

tisotumab vedotin

Seagen

cervical cancer (recurrent, metastatic)

BLA; seeking accelerated approval; priority review

10/08/2021

sodium oxybate

Avadel Pharmaceuticals

narcolepsy-related excessive daytime sleepiness and cataplexy

oral

505(b)(2) NDA; orphan drug

10/15/2021

varenicline

Oyster Point Pharma

dry-eye syndrome

intranasal

505(b)(2) NDA

10/18/2021

Visit us online at magellanrx.com/mrxreport | 47

PI PE LI N E D RU G LIST

PIPELINE DRUG LIST CONT.

Name

Manufacturer

Clinical Use

Dosage Form

Approval Status

Expected FDA Approval

zanubrutinib (BRUKINSA®)

BeiGene

Waldenstrom macroglobulinemia

oral

sNDA; fast-track; orphan drug; priority review

10/18/2021

dupilumab (DUPIXENT®)

Sanofi

asthma (moderatesevere, adjunct, ages 6-11 years)

sBLA

10/21/2021

mobocertinib

Takeda Pharmaceutical Company

NSCLC

oral

NDA; breakthrough therapy; orphan drug; priority review

10/26/2021

phenylephrine/tropicamide

Eyenovia

pharmacologic mydriasis

ophthalmic

505(b)(2) NDA

10/29/2021

testosterone undecanoate

Marius Pharmaceuticals

hypogonadism

oral

505(b)(2) NDA

10/29/2021

andexanet alfa (Andexxa®)

Alexion Pharmaceuticals

acute intracranial hemorrhage while taking an oral Factor Xa inhibitor, including edoxaban and enoxaparin

sBLA; breakthrough therapy; orphan drug

October 2021

dexamethasone insert (DEXTENZA®)

Ocular Therapeutix

allergic conjunctivitis

intraocular

sNDA

October 2021

somatrogon

Pfizer/OPKO Health

growth hormone deficiency (pediatrics)

BLA; orphan drug

October 2021

tacrolimus (PROGRAF®)

Astellas Pharma

lung transplant rejection prevention

IV; oral

sNDA

October 2021

SH-111

Shorla Pharma

T-cell leukemia (adult)

N/A

NDA; priority review

OctoberNovember 2021

abemaciclib (Verzenio®)

Eli Lilly and Company

breast cancer (highrisk HR+, HER2-, early disease)

oral

sNDA

OctoberDecember 2021

Janssen Pharmaceuticals

NSCLC (EGFR exon 20 insertion mutations, progressed on or after platinum-based chemotherapy)

BLA; breakthrough therapy

OctoberDecember 2021

amivantamab

AMD = age-related macular degeneration; ANCA = antineutrophil cytoplasmic antibody; AS = ankylosing spondylitis; BCG = Bacillus Calmette-Guerin; BLA = biologics license application; CD = Crohn’s disease; GVHD = graft versus host disease; HSCT = hematopoietic stem cell transplantation; IDH1 = isocitrate dehydrogenase 1; IgA = immunoglobulin A; IM = intramuscular; IU = intrauterine; IV = intravenous; JIA = juvenile idiopathic arthritis; MDD = major depressive disorder; NDA = new drug application; NSCLC = non-small cell lung cancer; NSTI = necrotizing soft-tissue infections; PAH = pulmonary arterial hypertension; PsA = psoriatic arthritis; PsO = psoriasis; RA = rheumatoid arthritis; RCC = renal cell carcinoma; sBLA = supplemental biologics license application; sNDA = supplemental new drug application; SQ = subcutaneous; T1DM = Type 1 diabetes mellitus; UC = ulcerative colitis; UTI = urinary tract infection This information is up to date as of July 9, 2021.

48 | Magellan Rx Report | Summer 2021

Advancing the Limits. Targeting ALS. Actor portrayal.

We are taking on the challenges of complex and debilitating conditions and are committed to meeting the needs of people suffering from serious and often life-threatening illnesses. Today, MTPC group companies are focused on driving scientific discovery in many areas, including amyotrophic lateral sclerosis (ALS).

The corporate symbol of Mitsubishi Tanabe Pharma America is a registered trademark of Mitsubishi Tanabe Pharma Corporation. For US audiences only. Mitsubishi Tanabe Pharma America, Inc. 525 Washington Boulevard, Suite 400 Jersey City, NJ 07310 © 2021 Mitsubishi Tanabe Pharma America, Inc. All rights reserved.

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Magellan Rx Report - Summer 2021

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