2023 Spring Prime Therapeutics Report by Prime Therapeutics

Adalimumab Biosimilars: Launch and Payer Management

Disease: New Therapies and Management Strategies

Disease: Update and Gene Therapy Pipeline

Innovative Therapies and Payer Management

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IN THIS ISSUE | Spring 2023

Published By

Magellan Rx Management

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

Tel: 401-344-1000

Fax: 401-619-5215 magellanrx.com

Editor Lindsay Speicher, J.D.

Project Manager, Specialty lspeicher@magellanhealth.com

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 Rx™ Report does not verify any claims or other information appearing in any of the advertisements contained in the publication and cannot take responsibility for any losses or other damages incurred by readers in reliance on such content. Developed by D Custom.

Contributors

Caroline Carney, M.D., M.Sc., FAPM, CPHQ CMO, Magellan Health, Magellan Rx Management

Steve Cutts, Pharm.D. SVP, Market General Manager, MRx Specialty

Haita Makanji, Pharm.D. VP, Clinical Strategy and Innovation, Specialty

Amy E. Edquist Senior Manager, Marketing

Joe Tavares SVP, Sales and Business Development, Specialty

Carole Kallas

Project Manager

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

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

Brian Kinsella, Esq.

Senior Legal Counsel

Alina Young

Associate Legal Counsel

Lilly Ackley VP, Corporate Communications

Editorial Advisory Board

Mona M. Chitre, Pharm.D., CGP hief harmacy O cer V linical nalytics, trategy Innovation, Excellus BlueCross BlueShield

Dennis Bourdette, M.D., FAAN, FANA Chair and Roy and Eulalia Swank Family Research Professor, Department of Neurology, Oregon ealth cience Uni ersity

Yousaf Ali, M.D., FACR Chief, Division of Rheumatology, Mount Sinai West; Professor of Medicine, Icahn School of Medicine at Mount Sinai

Steven L. D’Amato, B.S.Pharm. Executive Director, New England Cancer Specialists

Joseph Mikhael, M.D., M.Ed., FRCPC, FACP hief edical O cer, International yeloma oundation

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

Steve Marciniak, R.Ph. Director II, edical ene t Drug anagement, BlueCross BlueShield of Michigan

Saira A. Jan, M.S., Pharm.D. Director of Pharmacy Strategy and Clinical Integration, Horizon BlueCross BlueShield of New Jersey

A NOTE FROM OUR CEO

Dear Managed Care Colleagues,

Welcome to our spring 2023 issue of the Magellan Rx Report! Since the release of our last edition in the fall, Magellan Rx has joined forces with Prime Therapeutics to usher in the next chapter of our company's evolution. This transformational opportunity enables us to build upon our thought leadership expertise in managed care pharmacy to create a brighter future for our industry and deliver even more value to those we serve. As a result, we will continue to keep our readers informed on the latest managed care trends and treatment updates, shining a bright light on insights and opportunities for the future.

In this edition of the report, we've captured this year's momentum with the D appro al of e no el drugs and an expansive pipeline full of promising new agents across chronic conditions for the remainder of 2023. Our cover story (page 26) focuses on innovative CAR-T therapy. We review the landscape of CAR-T with a comprehensive review of the currently approved and available CAR-T therapies, as well as highlighting recent CAR-T approvals. The article also outlines the pipeline in this category as well as potential payer management strategies.

Another article (page 6) focuses on the imminent impact of adalimumab biosimilars entering the mar et. s the rst adalimumab biosimilar launched in January, with more anticipated launches throughout 2023, this space will see a

major shift in management and reimbursement for payers and manufacturers alike.

In our hemophilia article (page 10), we highlight the recent approvals of gene therapies in this category and the pipeline of gene therapies on the horizon for hemophilia. We also discuss how these innovative treatment options will impact payers, making hemophilia a high-priority management category.

Other topics in this issue include a dive into Alzheimer’s disease and recent advances (page 15), a brief rare disease update and pipeline (page 22), and an oncology update on current developments in breast cancer treatment (page 32). As always, the issue is rounded out with our pipeline update (page 38) and managed care newsstand (page 4).

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

Sincerely,

Mostafa Kamal Chief Executive Ofcer Magellan Rx Management

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MANAGED CARE NEWSSTAND

Senate Judiciary Committee Advances Drug Patent Reform, FDA-PTO Bills to Floor

The Senate Judiciary Committee voted to advance a handful of bipartisan bills that promote drug competition and biosimilar market entry:

The Interagency Patent Coordination and Improvement Act, which passed the committee in summer 2022, would establish a task force that coordinates e orts and shares information on drug patent decision making between the United States Patent and Trademark O ce U TO and the U. . ood Drug Administration (FDA), including information on patent-application evaluations, training, and FDA approvals.

The Stop STALLING Act would penalize brand drug ma ers for ling sham citi en petitions with the FDA that interfere with the approval of competing generics and biosimilars.

The Preserve Access to Afordable Generics and Biosimilars Act aims to limit the use of “pay-for-delay” agreements by making them presumptively anticompetitive, illegal, and increasingly di cult for drug ma ers to justify in court.

The Prescription Pricing for the People Act, which was reintroduced earlier this month, would require the Federal Trade Commission (FTC) to examine price

consolidations and anti-competitive practices within the entire pharmaceutical supply chain that may impact the cost of prescription drugs for consumers.

The Afordable Prescriptions for Patients Act, which passed the Senate Finance Committee in 2020, aims to stop abuse of patents via product hopping and other tactics used by brand-name drug makers to prevent generics and biosimilars from entering the market.

CMS Drug Price Negotiation Timeline 2026

The Inﬂation Reduction ct IR , signed into law in August 2022, included key healthcare provisions. One of these major provisions regarded allowing Medicare to negotiate drug prices. Centers for Medicare edicaid er ices released a Drug Price Negotiation Timeline for 2026, which outlines initial actions for the program. According to the timeline, CMS will publish the maximum fair prices for drugs selected for negotiation for 2026 with these prices going into e ect on an. , 202 .

Provision in the FY23 Omnibus Spending Bill

On Dec. 29, President Joe Biden signed the Consolidated Appropriations Act, 2023 into law, including . trillion in scal year (FY) 2023 discretionary government funding across all 12 annual spending bills. This bill included a number of other healthcare provisions, which touch on the following:

CBO Access to DIR Data: Authorizes the ongressional udget O ce O to access prescription drug payment data including rebate and Direct and Indirect Remuneration (DIR) data under Medicare Part D.

CHIP: Extends the Children’s Health Insurance Program (CHIP) until 2029; children on CHIP get one year of continuous eligibility.

Medicaid: Allows states to begin reevaluating who is still eligible for Medicaid beginning in April, while requiring states to attempt to contract bene ciaries before disenrolling them from the program; gradually phases out 6.2% increased pandemic Medicaid funding.

COVID-19 EUA Coverage: No additional COVID-19 funding, but it allows Medicare Part D plans to cover products for COVID-19 approved under an emergency use authorization (EUA) through 2024.

Mental Health Parity: Requires selffunded, nonfederal government health plans to comply with mental health parity requirements beginning six months after the date of enactment or longer, contingent on the terms of the plan agreement.

Interchangeable Biosimilars lari es the FDA’s authority to tentatively approve a subsequent interchangeable biosimilar while a rst interchangeable product’s exclusivity period is pending. Multiple interchangeable biosimilars can share a period of rst interchangeable exclusi ity if they are approved the same day.

FDA Post-Approval Studies: Adds to requirements for post-approval studies for drugs approved under accelerated approval, including targets, milestones, and dates for study completion — and clari es the D ’s authority to withdraw products where sponsors fail to conduct the studies.

FDA: Requires the FDA to make timely therapeutic equivalence evaluation for follow-on drugs approved through the 505(b)(2) pathway — a pathway in

between novel new drugs and generics — that have similar formulations as other approved pathways, and it facilitates the availability of lower-cost drugs available for automatic substitution in pharmacies.

MTM for Opioids: Eliminates a current requirement for medication therapy management (MTM) for opioid addiction that those registered to dispensecontrolled substances also apply for a separate Drug Enforcement Administration (DEA) waiver to dispense buprenorphine.

Generic Drug Labeling

: Provides that a generic drug is eligible for approval despite di erences in proposed labeling.

CMS Draft Guidance for Medicare Prescription Drug Infation Rebate Program

On Feb. 8, the Department of Health and Human Services (HHS) released an initial guidance for the Medicare Prescription Drug Inflation Rebate rogram. The program requires pharmaceutical manufacturers to pay a rebate if the prices of certain drugs are increased at a rate faster than the rate of inflation. edicare art prescription drug inflation rebates were established for single-source drugs and biologics with faster-increasing prices than the rate of inflation and pro ides lower art bene ciary cost sharing on those drugs. The guidance outlines how CMS will calculate drug inflation rebates in edicare art and D as required under the IRA.

PHE Will Expire on May 11

On Feb. 9, HHS released a COVID-19 Public Health Emergency (PHE) Transition Roadmap noting that the PHE will end on May 11. The roadmap includes an outline of what program and ﬂexibilities will and will not be a ected.

Senate Hearing on Transparency and Accountability for PBMs

The Senate Committee on Commerce, Science, and Transportation held a hearing titled “Bringing Transparency and ccountability to harmacy ene t Managers” in February to focus on the role of PBMs in how Americans access their medications as well as the operations of PBMs. The hearing addressed how the harmacy ene t anager Transparency Act will bring transparency into PBM business practices.

Proposed PBM Bills in the New Congress

The PBM Accountability Act has been reintroduced as S. 127. Sen. Maria Cantwell (D-WA) chairs the committee and is eager to move forward with the bill. Last year, the bill passed out of the committee by a wide bipartisan margin but ne er made it to the enate ﬂoor due to other priorities. The bill would regulate PBMs through the FTC.

New IQVIA Report Notes Increase in Biosimilar Spending in Next Five Years

According to the new “IQVIA Biosimilars in the United States 2023-2027” report, spending on biosimilars in the U.S. is expected to increase substantially o er the next e years. Due to expected launches and uptake in biosimilar utilization, biosimilar spending is expected to reach $129 billion by 2027. Savings associated with biosimilars are expected to increase by $180 billion in the same timeframe. In the pre ious e years, the U.S. biologics market has grown by 12.5% annually. Currently available and launched biosimilars account for 24% of the competitive volume.

Due to expected launches and uptake in biosimilar utilization, biosimilar spending is expected to reach $129 billion by 2027.

IRA: CMS Implementation Timeline

CMS released an IRA Implementation Timeline, outlining when changes brought by pro isions of the IR will go into e ect. Some notable dates in 2023 include:

April 1: Individuals with traditional Medicare may pay a lower coinsurance for some Part B drugs if the drug’s price increased faster than the rate of inﬂation in a benchmark quarter.

July 1: Individuals with traditional Medicare who take insulin through a traditional pump will not pay more than $35 for a month’s supply of insulin.

Sept. 1: CMS will announce by this date the rst 0 edicare art D drugs selected for the Drug Price Negotiation Program.

Oct. 1: Most adults with coverage from Medicaid and CHIP will be guaranteed coverage of vaccines recommended by the Advisory Committee Immunization Practices at no cost to them.

Adalimumab Biosimilars:

Launch and Payer Management

Payers should focus on assessing reimbursement agreements to ensure they are best managing this category, ensuring patients have access to appropriate therapies and both patients and payers are bene ting from cost sa ings.

Martin Burruano, R.Ph. Vice President, Pharmacy Services Independent Health

Adalimumab (HUMIRA® has been a highly pro table and utili ed drug in the U. . mar et, generating more than $20.7 billion in sales in 2021 and ranking second on a list of the top-selling drugs of all time in 2018.1 Through 2023 and 2024, an anticipated 14 or more adalimumab biosimilars may launch. At least seven adalimumab biosimilars will likely launch in 2023, which will include both the original formulation (50 mg/mL) and new high-concentration formulation (100 mg/mL) products.1 The U.S. Food Drug dministration D has appro ed se en biosimilars for adalimumab so far, with se eral more being reviewed and investigated.

Upon launch, the adalimumab biosimilars will impact the treatment landscape across several indications, including rheumatoid arthritis (RA), Crohn’s disease (CD), ulcerative colitis (UC), plaque psoriasis, psoriatic arthritis, and more.

dalimumab-atto EVIT was the rst adalimumab biosimilar to launch in the U. . on an. , 202 it was also the rst appro ed in eptember 20 .1, 2 In early uly 202 , e additional adalimumab biosimilars are set to launch: adalimumab-adbm (Cyltezo®, Boehringer Ingelheim), adalimumab-bwwd (HADLIMA®, Organon), adalimumab-fkjp (Hulio®, Mylan), adalimumab-adaz (HYRIMOZ®, Sandoz), and adalimumab-aqvh (YUSIMRY™, Coherus BioSciences).1, 3

The FDA is currently reviewing biologics license applications (BLAs) for three biosimilars and a highconcentration version of one biosimilar, which has already been approved for low-concentration formulation.

Interchangeability

The FDA designation interchangeable allows biosimilar products to be substituted for the reference product at the pharmacy level, without requiring provider permission.1 The interchangeability designation creates an ease of access to biosimilars, as the burden of pharmacists obtaining approval is removed. Cyltezo® is the only adalimumab biosimilar that is currently deemed interchangeable, although manufacturers are seeking the designation for some others currently approved or under review.1

Notably, the interchangeability designation does not indicate superiority in safety or e cacy for some biosimilars o er others, just that studies assessing patients switching between the reference and biosimilar have been conducted and completed.1 While generally interchangeable biosimilars can be dispensed in place of a reference product, some states have made restrictions as providers can request dispensing of the reference drug rather than any biosimilar regardless of interchangeability.4

Diferent Formulations

Only the reference product and HADLIMA™ currently have highconcentration formulations approved by the FDA. The vast majority of reference adalimumab prescriptions in the U.S. market, more than 80%, are for the high-concentration solution. High-concentration formulations of adalimumab reduce the number of doses required for e ecti e treatment, compared to low-concentration formulations.1

Citrate-free formulations may reduce injection site pain and allow for the use of a smaller needle during treatment administration. Of the biosimilar products approved or under FDA review, all have citratefree options, except for HYRIMOZ and low-concentration HADLIMA™.1

Impact on Treatment & Management Landscape

The launch of adalimumab biosimilars will create a burden and opportunity for all stakeholders. Providers will face the challenge

50 mg/mL

AMJEVITA™ Amgen unknown approved launched (1/31/2023)

7/1/2023

Coherus BioSciences no

7/1/2023 Hulio Mylan; Viatris; Biocon no approved 7/31/2023

7/1/2023 or after

T- Celltrion Healthcare no pending 7/1/2023 or after AVT02 Alvotech; Teva Pharmaceuticals seeking pending (12/2022) 7/1/2023 or after

HYRIMOZ HCF Sandoz unknown pending (3/2023) 4Q 2023 or after AMJEVITA™ HC (ABP 501 HC) Amgen seeking

Table 1. Adalimumab Biosimilars Status

of serving as a liaison between patients and payers, weighing payer preferences and management strategies against the needs and appropriate management of the patient. 1 Rheumatologists or other providers treating patients using adalimumab are likely already familiar with biosimilars, as biosimilars for inﬂiximab and rituximab ha e been a ailable in the treatment landscape. 5 Providers’ experience and familiarity with biosimilars will undoubtedly impact their comfortability in using biosimilars when starting new patients on adalimumab as well as switching patients from the reference to biosimilars.5 In many cases, when patients respond well to the reference drug, pro iders may feel more con dent switching them to an interchangeable biosimilar. 4

The key to uptake in biosimilar utilization will be stakeholder education, especially for patients. Payers and providers alike can provide educational materials and updates to patients so they are more comfortable and con dent in the transition to biosimilar adalimumab, where that decision is deemed appropriate.6

There are studies that show that e ecti e patient education can mitigate the nocebo e ect in biosimilar use, where an ad erse event occurs that cannot be attributed to the therapy and may be psychosomatic.7 Instances of potential nocebo e ects ha e shown to be less pre alent when patients are con dent and informed about the safety and e cacy of biosimilars.7

A 2022 Pharmacy Market Outlook report from Vizient suggests that payers will structure formulary lists using one of three strategies when adalimumab biosimilars enter the U.S. market. 8 The three strategies include: preferring the reference product, preferring at least one biosimilar, or covering the biosimilars and reference product at parity. 8 While arguments have been made for di erent approaches, the two latter strategies — preferring one biosimilar or covering biosimilars and reference product at parity — would more e ecti ely increase mar et competition and generate cost savings than preferring the reference product exclusively. A 2020 survey showed that U.S. payers preferred biosimilars on formulary in 14% of coverage decisions, and speci cally, and of U. . payers preferred reference inﬂiximab RE I DE ®) over biosimilars RENFLEXIS ® and INFLECTRA ®, respectively. 9 This may result in a loss of cost savings, according to a report from the Department of ealth uman er ices O ce of Inspector eneral, which suggests that by preferring reference products over biosimilars, Medicare Part D plans missed $84 to $143 million in savings in 2019. 10 This does not account for the potential loss in savings for commercial payers. In 2019, Health New England reported saving $1.7 million by encouraging the use of biosimilar inﬂiximab, which reached utili ing in collaboration with Magellan Rx Management. 11

Payers should evaluate potential strategies to determine which is the most appropriate for their organization, re-examining formulary tiers and savings programs. 12 Notably, some states may work toward legislation to override payer preferences, requiring coverage for biosimilars; state legislators in innesota ha e begun wor ing on such an e ort. 12, 13

According to the Magellan Rx Management Medical Pharmacy Trend Report, an increasing number of payers have been adjusting reimbursement strategies to incentivize biosimilar prescriptions, with most payers indicating biosimilar pricing as having the biggest impact on reimbursement decisions.14 The second-biggest inﬂuence in the decision process was pro ider willingness to switch patients from reference products to biosimilars.14 Payers may want to focus on assessing reimbursement agreements to ensure they are best managing this category, ensuring patients have access to appropriate therapies and patients and payers ali e are bene ting from cost sa ings.

References

1. Jeremias, Skylar. “Part 1: Biosimilars to Bring a Bumper Crop of Adalimumab Options.” The American Journal of Managed Care, 6 Sept. 2022, https://www.centerforbiosimilars.com/view/part-1biosimilars-to-bring-a-bumper-crop-of-adalimumab-options.

2. Jeremias, Skylar. “US Welcomes First Adalimumab Biosimilar, Amjevita.” The American Journal of Managed Care, 31 Jan. 2023, https www.centerforbiosimilars.com iew us-welcomes- rstadalimumab-biosimilar-amjevita.

3. “Landscape of Adalimumab biosimilars.” AmerisourceBergen, https://www.amerisourcebergen.com/manufacturer-solutions/ biosimilars/biosimilar-landscape-overview.

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

5. Hagen, Tony. “Humira Biosimilars Are Hitting the Market in 2023. Finally. But Will Prescriptions Follow?” Managed Healthcare, 7 Apr. 2022, https://www.managedhealthcareexecutive.com/view/ humira-biosimilars-are-hitting-the-mar et-in-202 - nally-but-willprescriptions-follow-.

6. “Part 3: How Adalimumab Biosimilars Will Impact Clinicians.” The American Journal of Managed Care, 20 Sept. 2022, https:// www.centerforbiosimilars.com/view/part-3-how-adalimumabbiosimilars-will-impact-clinicians.

7. agen, Tony. Nurses an ounter Nocebo E ect in iosimilar Switching.” The American Journal of Managed Care, 27 Jan. 2021, https://www.centerforbiosimilars.com/view/nurses-can-counternocebo-e ect-in-biosimilar-switching.

8. “Pharmacy Market Outlook.” Vizient, 2022, https://campaigns. i ientinc.com ﬂipboo 20220 - O .

9. Hagen, Tony. “Tufts Study: Most Payers Don’t Give Preference to Biosimilars.” The American Journal of Managed Care, 21 May 2020, https://www.centerforbiosimilars.com/view/tufts-study-mostpayers-dont-give-preference-to-biosimilars.

10. urrin, u anne. edicare art D and ene ciaries ould Reali e igni cant pending Reductions with Increased iosimilar Use. U.S. Department of Health and Human Services Ofce of Inspector General, Mar. 2022, https://oig.hhs.gov/oei/reports/OEI-05-2000480.pdf.

11. The enter for iosimilars ta . Nonpro t ayer ays it a ed . illion Through Use of Inﬂiximab iosimilars. The American Journal of Managed Care, 22 Jan. 2020, https://www.centerforbiosimilars. com iew nonpro t-payer-says-it-sa ed- -million-through-useof-inﬂiximab-biosimilars-.

12. Jeremias, Skylar. “Part 4: How Payers Can Prepare for Adalimumab Biosimilars.” The American Journal of Managed Care, 27 Sept. 2022, https://www.centerforbiosimilars.com/view/part-4-how-payers-canprepare-for-adalimumab-biosimilars.

13. “RELEASE: Rep. Schultz, Sen. Nelson introduce bill to expand access to lower-priced alternatives to brand name prescription drugs.” Minnesota House of Representatives, 24 Feb. 2021, https://www. house.leg.state.mn.us members ro le News 2 .

14. Magellan Rx Management Medical Pharmacy Trend Report 2022 Twelfth Edition, https://issuu.com/magellanrx/docs/medical_ pharmacy_trend_report_2022.

emophilia

Innovative Therapies and Payer Management

Gary Tereso, Pharm.D. Director of Pharmacy Health New England

Hemophilia is a bleeding disorder in which the blood does not clot properly, leading to spontaneous bleeding or bleeding following injuries or surgery.1 It is often inherited and is caused by a mutation or change in one of the genes that provides instructions for creating the clotting factor proteins needed to clot blood.1 emophilia is an -lin ed recessi e disorder, predominantly a ects males, and is ery rare in females due to the genes being located on the X chromosome. Females are typically asymptomatic carriers of hemophilia. Fewer than 200,000 individuals in the U.S. are living with hemophilia.1

The most common type of hemophilia is hemophilia A, which occurs in one in 5,000 male births and is caused by a lack of or decrease in clotting factor VIII (FVIII).1, 2 Hemophilia B occurs in one in 25,000 male births and is caused by lack of or decrease in clotting factor IX (FIX).1, 2

Common symptoms associated with both types of hemophilia include bleeding into the joints or skin, bleeding of the mouth and gums, bleeding after surgery or after receiving shots or injections, bleeding in urine or stool, and frequent, hard-to-stop nosebleeds. Individuals with hemophilia can be at risk for more severe bleeds, like gastrointestinal bleeds or intracranial hemorrhages.

Treatment

Hemophilia A is mainly treated via concentrated FVIII product; the two types of clotting factors are: plasma-derived, made from human plasma, and recombinant, lab-developed via DNA technology.3

Recombinant FVIII products are used about 75% of the time.1,3 For patients with severe hemophilia A, prophylactic FVIII treatment is typically used to prevent bleeds. The patient will receive treatment on a regular schedule, which can vary from every day to twice wee ly, depending on the product and how the speci c patient responds to treatment.3 The National Hemophilia Foundation’s edical and cienti c d isory ouncil recommends prophylaxis as optimal management for all individuals with severe hemophilia A.3 In February, the FDA approved ALTUVIIIO™ ([antihemophilic factor (recombinant) Fc-VWF-XTEN Fusion rotein-ehtl , ano , a rst-in-class VIII replacement therapy indicated for routine propylaxis and on-demand treatment to control bleeding episodes, as well as perioperative management for adults and children with hemophilia A.4

The main treatment for hemophilia B is FIX replacement therapy, using either recombinant FIX or plasma-derived FIX concentrates.5 Replacement therapy can be used as needed in patients with mild to moderate hemophilia B. However, regular infusions may be used to prevent bleeding in individuals with severe hemophilia B.5 In individuals with severe hemophilia B, prophylactic therapy has been shown to reduce complications associated with recurrent bleeding.5 FIX replacement therapy may be administered at home, which is key for individuals with severe disease as well as mild to moderate, as infusion is most e ecti e at limiting bleeding when administered within an hour of onset.5

In November 2022, the FDA approved etranacogene dezaparvovec (HEMGENIX®, CSL Behring) as the frst gene therapy to treat adults with hemophilia B.

Other nonfactor replacement therapies for hemophilia A help pre ent bleeding or assist in better clotting using di erent methods. Emicizumab (HEMLIBRA®) is a FVIII mimetic, which imitates the way FVIII works — bringing together IX and X and allowing the blood to clot.3 Emicizumab was approved by the U. . ood Drug dministration D in 20 for people with hemophilia A with inhibitors and in 2018 for people with hemophilia A without inhibitors.3 MASAC concluded that individuals with hemophilia A with inhibitors experiencing spontaneous or traumatic bleeding episodes would derive signi cant bene t from emici umab prophylaxis it was gi en a recommendation for rst-line therapy.6 MASAC noted that individuals on prophylactic bypassing agent with few bleeding episodes could consider switching to emicizumab based on cost-e ecti eness, reduced administration burden, and superior hemostatic e cacy.6

Desmopressin can be used for joint and muscle bleeds, nose and mouth bleeds, and before and after surgery in patients with mild hemophilia A.3 Aminocaproic acid is used to prevent the breakdown of blood clots, often before dental procedures and to treat nose and mouth bleeds in patients with hemophilia A and B.3 MASAC recommends that a dose of clotting factor should be ta en rst to form a clot, then aminocaproic acid can be used to preserve the clot and keep it from being broken down prematurely.3

Gene Therapies

Etranacogene dezaparvovec (HEMGENIX®)

In November 2022, the FDA approved etranacogene dezaparvovec (HEMGENIX®, ehring as the rst gene therapy to treat adults with hemophilia B.7 Etranacogene dezaparvovec is an adeno-associated virus vector-based gene therapy for adults with hemophilia B who currently use FIX prophylaxis therapy, or have current or historical

life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.7 The treatment is a one-time single-dose gene therapy given by IV infusion. In one study with 54 participants, adult men ages 18 to 75 with severe or moderately severe hemophilia B, the subjects had increases in FIX activity levels, a decreased need for routine FIX replacement prophylaxis, and a 54% reduction in annualized bleeding rate (ABR) compared to baseline.7-9 Adverse reactions associated with etranacogene dezaparvovec included liver enzyme elevations, headache, mild infusion-related reactions, and ﬂu-li e symptoms.7, 9 Patients receiving the gene therapy should be monitored for adverse infusion reactions and transaminitis in their blood.7, 9

The Institute for Clinical and Economic Review (ICER) published an evidence report concluding that there is moderate certainty of a small or substantial health bene t with high certainty of at least a small net health bene t for etranacogene de apar o ec

Hemophilia Pipeline

compared with FIX prophylaxis.10 The I ER health bene t price benchmark (HBPB) for etranacogene dezaparvovec is $2.93 million to $2.96 million.10 ICER noted that the drug will become more cost-e ecti e the more durable it is.10 Etranacogene dezaparvovec will have a list price of $3.5 million.

Valoctocogene roxaparvovec (ROCTAVIAN™)

In October 2022, BioMarin announced that the FDA accepted the Biologic License Application (BLA) resubmission for valoctocogene roxaparvovec gene therapy for adults with severe hemophilia A.11 Valoctocogene roxaparvovec is an adeno-associated virus-based gene therapy vector containing a coagulation FVIII complementary DNA driven by a liver-selective promoter.12 The BLA included data from the GENEr8-1 phase 3 study. Results from the study showed stable and durable bleed control, including a reduction HEMOPHILIA

Drug Manufacturer Route of Administration Mechanism of Action Indication Status

Gene Therapy

valoctocogene roxaparvovec (ROCTAVIAN™)

giroctocogene telpar o ec - 2

danacogene elapar o ec (PF-06838435) par Therapeutics er IV

verbrinacogene setparvovec (FLT180a) Freeline injectable

SPK-8011 Spark Therapeutics/Roche IV

DTX201 Dimension Therapeutics Bayer IV

SPK-8016 Spark Therapeutics/Roche IV

ASC-618 ASC Therapeutics IV

Other Therapies

(03/31/2023)

A phase 3

B phase 3

B phase 2

A phase 2

therapy hemophilia A phase 2

A phase 2

concizumab (NN7415) Novo Nordisk; Dicerna Pharmaceuticals SC TFPI hemophilia A or B pending (3Q 2023)

GreenGene F (coagulation FVIII) GC Pharma IV coagulation FVIII (recombinant) hemophilia A phase 3

Factor VIIa marzeptacog alfa (MarzAA) Catalyst Biosciences SC coagulation FVII (recombinant) hemophilia A or B phase 3

tusiran Alnylam Pharmaceuticals/ ano SC siRNA hemophilia A or B phase 3

marstacimab (PF06741086) er SC TFPI hemophilia A phase 3

Mim8 Novo Nordisk SC FVIIIa mimetic hemophilia A phase 3

Abbreviations: FVII = factor VII; FVIII = factor VIII; FVIIIa = factor VIIIa; IV = intravenous; SC = subcutaneous; siRNA = small interfering RNA; TFPI = tissue factor pathway inhibitor

With the recent approval of etranacogene dezaparvovec for hemophilia B and more potential gene therapies in the pipeline for blood disorders, hemophilia will be a highpriority management category for payers.

in the mean ABR and mean annualized FVIII infusion rate.11 The mean annualized rate of FVIII concentrate use and treated bleeding after four weeks had decreased after infusion by 98.6% and 83.8%, respectively. All participants reported at least one adverse event; the most common adverse events were headache, nausea, and elevations in aspartate aminotransferase levels.11, 12 A decision from the FDA is expected on March 31, 2023.11

ICER noted in a November 2022 evidence report that there is moderate certainty of a comparable, small, or substantial

health bene t with high certainty of at least a comparable net health bene t for aloctocogene roxapar o ec compared to FVIII prophylaxis.10 ICER’s HBPB for valoctocogene roxaparvovec ranges from $1.958 million to $1.963 million.10

Payer Impact: Gene Therapy Strategies

With the recent approval of etranacogene dezaparvovec for hemophilia B and more potential gene therapies in the pipeline for blood disorders, hemophilia will be a high-priority management category for payers.13 This new gene therapy has set a new record for the most expensive single-use gene therapy in the U.S. However, current treatment costs, speci cally prophylactic treatment costs, are signi cant for patients with se ere hemophilia , the cost of regular infusions over a lifetime could cost up to $20 million per patient.13 Thus, despite the high list price of the gene therapy, the cost burden may not be as signi cant considering the o set cost of the regular prophylactic infusions.13 However, the durability of etranacogene dezaparvovec is not yet known. Payers also must consider the rate at which members switch payers, limiting the long-term cost bene t.

Value-based pricing arrangements, such as milestone-based reimbursement strategies, will likely be implemented, which have been used in the management of other high-cost gene and innovative therapies. These arrangements help mitigate the impact of the high upfront costs per dose.

HEMOPHILIA A & B |

References

1. “What is Hemophilia?” Centers for Disease Control and Prevention, 1 Aug. 2022, https://www.cdc.gov/ncbddd/hemophilia/facts.html.

2. emophilia , , The Three Di erent lotting actor De ciencies. Indiana Hemophilia & Thrombosis Center, https:// www.ihtc.org/types-of-hemophilia.

3. “Current Treatments.” National Hemophilia Foundation, https:// www.hemophilia.org/bleeding-disorders-a-z/treatment/currenttreatments.

4. “Press Release: FDA approves once-weekly ALTUVIIIO™, a new class of factor VIII therapy for hemophilia A that o ers signi cant bleed protection. Sanof, 23 Feb. 2023, https www.sano .com en media-room press-releas es/2023/2023-02-23-21-00-00-2614759.

5. “Hemophilia B.” National Organization for Rare Disorders, 2018, https://rarediseases.org/rare-diseases/hemophilia-b/.

6. “MASAC Document 268 - Recommendation on the Use and Management of Emicizumab-kxwh (Hemlibra®) for Hemophilia A with and without Inhibitors.” National Hemophilia Foundation, 27 Apr. 2022, https://www.hemophilia.org/healthcare-professionals/ guidelines-on-care/masac-documents/masac-document-268recommendation-on-the-use-and-management-of-emicizumabkxwh-hemlibrar-for-hemophilia-a-with-and-without-inhibitors.

7. “FDA Approves First Gene Therapy to Treat Adults with Hemophilia B.” U.S. Food & Drug Administration, 22 Nov. 2022, https://www.fda. go news-e ents press-announcements fda-appro es- rst-genetherapy-treat-adults-hemophilia-b.

8. Von Drygalski, Annette, et al. “Etranacogene dezaparvovec (AMT061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B.” Blood Advances, 12 Nov. 2019, https://www.ncbi. nlm.nih.gov/pmc/articles/PMC6855101/.

9. “Final Analysis of Pivotal HOPE-B Study Demonstrates Durable and ustained Therapeutic E ect of Etranacogene De apar o ec Gene Therapy in Hemophilia B - Data Presented at EAHAD 2022.” CSL Behring, 4 Feb. 2022, https://newsroom.csl.com/2022-02-04Final-Analysis-of-Pivotal-HOPE-B-Study-Demonstrates-Durableand- ustained-Therapeutic-E ect-of-Etranacogene-De apar o ecGene-Therapy-in-Hemophilia-B-Data-Presented-at-EAHAD-2022.

10. “ICER Publishes Evidence Report on Gene Therapies for Hemophilia A and B.” Institute for Clinical and Economic Review, 2 Nov. 2022, https://icer.org/news-insights/press-releases/icer-publishesevidence-report-on-gene-therapies-for-hemophilia-a-and-b/.

11. “FDA Accepts BioMarin’s Biologics License Application (BLA) for Valoctocogene Roxaparvovec AAV Gene Therapy for Adults with Severe Hemophilia A.” BioMarin, 12 Oct. 2022, https://investors. biomarin.com/2022-10-12-FDA-Accepts-BioMarins-BiologicsLicense-Application-BLA-for-Valoctocogene-Roxaparvovec-AAVGene-Therapy-for-Adults-with-Severe-Hemophilia-A.

12. Ozelo, Margareth, et al. “Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A.” The New England Journal of Medicine, 17 Mar. 2022, https://www.nejm.org/doi/10.1056/NEJMoa2113708.

13. Cohen, Joshua. “Despite Eye-Popping $3.5 Million Price Tag For Gene Therapy Hemgenix, Budget Impact For Most Payers Will Be Relatively Small.” Forbes, 2 Dec. 2022, https://www.forbes.com/ sites/joshuacohen/2022/12/02/despite-eye-popping-35-millionprice-tag-for-gene-therapy-hemgenix-budget-impact-for-mostpayers-will-be-relatively-small.

Alzheimer’s Disease:

New Therapies and Management Strategies

ayers and manufacturers will ha e to e ecti ely collaborate to manage costs, ensure access, and improve outcomes in this patient population.

Kathryn Canaday, Pharm.D. Vice President, Pharmacy and Clinical Drug Management

Medical Mutual of Ohio

The most common cause of dementia in older adults, Alzheimer’s disease (AD), is an irreversible, progressive brain disease that deteriorates memory and cognition.1 The cause of AD is thought to be abnormal build-up of protein around brain cells. Amyloid protein deposits form plaques around brain cells and tau protein deposits form tangles within brain cells.2

The initial symptoms of D may manifest di erently across the patient population, though memory problems are typically one of the rst signs.1 Other symptoms can include decline in other aspects of thinking, vision and spatial issues, and impaired reasoning or judgment.1 Mild cognitive impairment can be an early sign of AD; however, not all individuals with mild cognitive impairment will develop AD.1 s the disease progresses, indi iduals with D will ha e increasing di culty completing e eryday tas s and may become repetiti e, get lost easily, lose items, or nd simple concepts confusing. Emotion dysregulation may increase as AD progresses as well.1, 2

Diagnosis of AD is challenging because brain changes can occur long before clinical symptoms manifest or are detected.3 The progression of AD occurs in three phases: preclinical, mild cognitive impairment, and dementia dementia is further strati ed into mild, moderate, and se ere stages. The preclinical phase includes potential biological changes in the brain, but no symptoms. In the mild cognitive impairment phase, mild symptoms manifest that most likely do not interfere with daily activities and may go unnoticed and undiagnosed. Progression through the dementia phase is determined by the interference with everyday activities on a continuum from some to many to most being unable to be completed. actors including age, genetics, and sex can inﬂuence how uic ly patients progress through the phases of disease.3

Diagnosis of AD currently includes a combination of symptom reporting, cognitive testing, and a series of lab testing, such as CT scans, MRIs, or PET scans, that work to rule out other conditions that may potentially contribute to cognitive changes.1-3 PET scans pro ide analysis of proteins from cerebrospinal ﬂuid. While no validated blood biomarkers are currently known for AD, three cerebrospinal ﬂuid biomar ers, including β42, total tau protein, and phosphorylated tau, can be used as biomarkers for diagnosis.3

Recommended diagnosis per the International Working roup includes both the presence of biomar ers and speci c phenotypes common to D for con rmed diagnosis.3 Despite this recommendation, biomarker data is not commonly used in clinical practice. MRI is often used to show contrast between gray and white matter.1, 3

More than 6 million adults in the U.S. age 65 or older have AD. If population trends continue and the U.S. population continues to age, the number of those li ing with D will increase signi cantly over the next decade.1 The vast majority of AD cases occur in individuals 65 or older, which is described as late-onset AD. Early-onset AD occurs in individuals between ages 30 and 65 but is very rare. After initial diagnosis, the life expectancy of individuals with AD can average four to eight years; some patients with AD may live up to 20 years after diagnosis, with more than 40% of that time spent in the severe stage.1 In the late progression of AD, nonmemory symptoms such as immobility, di culty swallowing, and malnutrition become pre alent, which impact acti ities of daily li ing, correlate with signi cant morbidity, and decrease autonomy and quality of life.3 Caregiver burden in this stage is signi cant, as it is estimated that more than 11 million Americans provide unpaid care for patients with AD and associated dementias.3 AD carried a cost burden of $321 billion in 2022, in addition to an estimated $271 billion in unpaid caregiving.4

Current Treatment Landscape

Treatment and management of AD is dynamic, multifactorial, and multidisciplinary. Currently, there are three FDA-approved cholinesterase inhibitors — donepezil, galantamine, and rivastigmine — and an N-methyl-D-aspartate-antagonist, memantine.3, 5 These approved treatments are all similarly associated with improvement above baseline on cognitive measures on the AD Assessment Scale cognitive subscale.3 Galantamine and oral rivastigmine are indicated for mild to moderate AD, while donepezil and transdermal rivastigmine are indicated for mild, moderate, or severe AD.3, 5 Memantine can be added to a treatment regimen if a patient progresses to severe AD while on these drugs,

This approval makes lecanemab the second of a new category of approved AD medications that target the pathophysiology.

and in some cases, the combination of donepezil-memantine is used as a monotherapy. Current standard treatment for AD focuses on symptom impro ement thus, e ecti eness will decrease o er time as the disease progresses.3, 5 Currently, there is no cure for AD. Two FDA-approved medications target the fundamental pathophysiology of the disease, and others are under review.5

In June 2021, the FDA approved aducanumab (ADUHELM®, a monthly intravenous immunoglobulin gamma 1 monoclonal antibody) for the treatment of AD.6 The accelerated approval of aducanumab was based on a post-hoc analysis of the EMERGE trial, which found reduction of amyloid plaques for the primary surrogate endpoint in patients treated with high-dose aducanumab. The FDA concluded that the reduction in amyloid plaques is likely to provide clinical bene t.6, 7 In July 2021, the FDA approved a label revision clarifying the indication to include initiation in patients with mild cognitive impairment or mild dementia stage of disease, as this was the population in which aducanumab was initiated in clinical trials. Along with the accelerated approval, the FDA required an additional trial to e aluate the safety and e cacy of aducanumab, to be completed by 2030.6, 7 In 2021, the Institute for Clinical and Economic Re iew I ER concluded that the health-bene t price benchmark range for aducanumab is $3,000 to $8,400 per year, compared to the list price of $56,000.8

Lecanemab (Leqembi™)

In January, the FDA approved lecanemab-irmb (Leqembi™) for the treatment of AD.9 This approval makes lecanemab the second of a new category of approved AD medications that target the pathophysiology. The FDA granted lecanemab accelerated approval based on the results of a phase 2b randomized, controlled clinical trial con rming the drug’s clinical bene t.9 In the phase 2b study of 856 patients with AD, treatment was initiated in patients with mild cognitive impairment or mild dementia disease stage and con rmed presence of amyloid beta pathology.10 The patients randomized to receive treatment with lecanemab experienced signi cant dose- and time-dependent reduction in amyloid beta plaque.10 Patients receiving 10 mg/kg of lecanemab every two

wee s had a statistically signi cant reduction in brain amyloid plaque from baseline to week 79, while those receiving placebo had no reduction of amyloid beta plaque.10 Results from a phase 3 study of 1795 patients randomized to receive lecanemab or placebo showed the mean change from baseline CDR-SB score was less in patients receiving lecanemab than placebo (1.21 vs. 1.66, respectively).11 A further sub-study of 698 patients showed greater reductions in brain amyloid burden with lecanemab, compared to placebo.11 Treatment with lecanemab comes with a warning for amyloid-related imaging abnormalities (ARIA).9

Table 1. Alzheimer’s Disease Pipeline

An expansive pipeline shows promising treatment opportunities for AD on the horizon.

Treatment Advances/Updates

An expansive pipeline shows promising treatment opportunities for AD on the horizon. In January, the FDA declined to grant accelerated approval to donanemab, which would have been the third amyloid-targeting therapy indicated for early AD.12 The FDA noted that approval would require safety data on at least 100 patients who have taken donanemab continuously for at least a year. There is an ongoing phase 3 trial (TRAILBLAZER-ALZ 2), which may provide the required data for the traditional approval pathway.12 Previously, donanemab was investigated investigated for safety and e cacy in the TR I ER- , TR I ER2, and TRAILBLAZER-ALZ 3 studies. It was assessed head-to-head with aducanumab in the TRAILBLAZER-ALZ 4 study.13 Results from TR I ER- showed signi cant reduction in the primary outcome of change in Integrated AD Rating Scale from baseline (-6.86 donanemab vs. -10.6 placebo) (32%) at 76 weeks.13 In the TRAILBLAZER-ALZ 4 trial, after six months, donanemab achieved

completed amyloid plaque clearance (<24.1 Centiloids) in 37.9% of patients versus 1.6% in aducanumab-treated patients.14

Gantenerumab, a fully human anti-amyloid antibody, failed to meet primary and secondary endpoints in the phase 3 GRADUATE clinical trials, and development of this molecule has been discontinued. The pipeline (Table 1) shows a more expansive pipeline in this category.

Payer Impact

Strategic management and policymaking by the Centers for edicare edicaid er ices will be ey mo ing forward, as analysts suggest 96% of the market for AD treatments in the pipeline are in the Medicare population.15 ost e ecti eness of new AD treatments is an important starting point for setting value-based prices. An important negotiation point for payers and manufacturers may be performance warranties, which help to apportion risk associated with initial treatment.15 Subscription payment plans may be a useful tool to address a ordability as more no el therapies for AD become available.15 As seen in other disease states with inno ati e therapies, di erent alue-based agreements may be a solution for a variety of costly treatment options in this space.15 owe er, in order to be e ecti e, they would re uire e cient care models for screening and treatment. Payers and manufacturers will ha e to e ecti ely collaborate to manage costs, ensure access, and improve outcomes in this patient population.16

References

1. “What is Alzheimer’s Disease?” National Institute of Health, 8 July 2021, https://www.nia.nih.gov/health/what-alzheimers-disease.

2. “Alzheimer’s Disease.” Cleveland Clinic, https://my.clevelandclinic. org/health/diseases/9164-alzheimers-disease.

3. Hill, Angela. “Alzheimer Disease and the Evolving Treatment Landscape.” American Journal of Managed Care, 12 Sept. 2022, https://www.ajmc.com/view/alzheimer-disease-and-the-evolvingtreatment-landscape.

4. “The Economic Costs of Alzheimer’s Disease.” Joint Economic Committee Democrats, 6 July 2022, https://www.jec.senate.gov/ public/index.cfm/democrats/issue-briefs?id=02F4CADC-954F4E3B-8409-A4213E3C0759.

5. “How is Alzheimer’s Disease Treated?” National Institute of Health, 8 July 2021, https://www.nia.nih.gov/health/how-alzheimers-diseasetreated.

6. “FDA Grants Accelerated Approval for Alzheimer’s Drug.” U.S. Food & Drug Administration, 7 June 2021, https://www.fda.gov/newsevents/press-announcements/fda-grants-accelerated-approvalalzheimers-drug.

7. “FDA’s Decision to Approve New Treatment for Alzheimer’s Disease.” U.S. Food & Drug Administration, 7 June 2021, https:// www.fda.gov/drugs/news-events-human-drugs/fdas-decisionapprove-new-treatment-alzheimers-disease.

8. “ICER Publishes Final Evidence Report and Policy Recommendations on Aducanumab for Alzheimer’s Disease.” Institute for Clinical and Economic Review, 5 Aug. 2021, https://icer.org/news-insights/ press-releases icer-publishes- nal-e idence-report-and-policyrecommendations-on-aducanumab-for-alzheimers-disease/.

9. “FDA Grants Accelerated Approval for Alzheimer’s Disease Treatment.” U.S. Food & Drug Administration, 6 Jan. 2023, https:// www.fda.gov/news-events/press-announcements/fda-grantsaccelerated-approval-alzheimers-disease-treatment.

10. Swanson, Chad, et al. “A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti- b proto bril antibody. Alzheimer’s Research & Therapy, 17 Apr. 2021, https://pubmed.ncbi.nlm.nih. gov/33865446/.

11. Van Dyck, Christopher, et al. “Lecanemab in Early Alzheimer’s Disease.” New England Journal of Medicine, 5 Jan. 2023, https:// www.nejm.org/doi/full/10.1056/NEJMoa2212948.

12. Shapiro, Lindsay. “FDA Rejects Accelerated Approval Application for Donanemab.” Alzheimer’s News Today, 24 Jan. 2023, https:// alzheimersnewstoday.com/news/accelerated-approval-deniedalzheimers-therapy-donanemab.

13. Mintun, Mark, et al. “Donanemab in Early Alzheimer’s Disease.” New England Journal of Medicine, 6 May 2021, https://www.nejm.org/ doi/full/10.1056/NEJMoa2100708.

14. “Lilly Shares Positive Donanemab Data in First Active Comparator Study in Early Symptomatic Alzheimer’s Disease.” Eli Lilly and Company, 30 Nov. 2022, https://investor.lilly.com/news-releases/ news-release-details lilly-shares-positi e-donanemab-data- rstactive-comparator.

15. Lin, Pei-Jung, et al. “Preparing the health-care system to pay for new Alzheimer’s drugs.” Alzheimer’s & Dementia, 18 Aug. 2020, https:// europepmc.org/article/med/32808733.

16. Hung, Anna, et al. “Addressing Challenges in Payment and Access to Treatments for Early-Stage Alzheimer’s Disease.” Duke Margolis Center for Health Policy, 2020, https://healthpolicy.duke.edu/sites/ default les 2020-0 du e al heimerissuebrief-2020.pdf.

What’s new in Medical Pharmacy trends?

The industry-leading source for Medical Pharmacy trends, benchmarks, strategies, and insights.

PMPM Trend

Historically, the norm was a year-over-year PMPM trend ranging from 6% to 17% across all three lines of business. In 2020 to 2021, the impact of COVID and biosimilars resulted in much smaller trends of 3.2%, 2.7%, and 0% for commercial, Medicare, and Medicaid, respectively.

Top Drug Spend Trend

The top 20 medical bene t drugs had spend trends of 0 or greater, dri en by utilization increases for commercial and Medicare, and driven evenly by both cost and utilization for Medicaid.

Oncology Trend

Oncology, a top concern for all surveyed plans, continued to be the top spend category, accounting for 39%, 53%, and 27% of commercial, Medicare and Medicaid spend, respectively.

Biosimilars Trend

Since 2019, oncology biosimilars have contributed to a dramatic estimated 7% reduction in total oncology PMPM spend for commercial markets, as well as 1.6% and 0.5% reductions in Medicare and Medicaid markets, respectively.

Rare Disease:

Update and Gene Therapy Pipeline

s an increasing number of rst-in-class medications are appro ed and become a ailable for rare disease patients, closing the gap in knowledge with all stakeholders will be key to appropriate management and utilization.

Lindsay Speicher, JD Project Manager, Specialty Magellan Rx Management

Advances in treating rare diseases continue to be a priority for those in the industry. A rare disease is de ned as one a ecting less than 200,000 people in the U. . pproximately 0 million people in the U. . li e with rare diseases, with about ,000 identi ed rare diseases.1, 2

Since the enactment of the Orphan Drug Act of 1983, more than 600 orphan drugs and biological products have been approved in the U.S.3 Exciting progress continues to be made despite challenges in researching and developing treatments for rare diseases. Challenges include the complex biology of many rare diseases, as well as variation or subtypes within a particular rare disease.3 Determining endpoints or outcome measures in trials can be di cult if nowledge of the natural history of the disease is limited.1 dditionally, populating the trials can be di cult, as rare diseases ha e small patient populations.1 Even in the face of these challenges, promising advancements continue. Some include the rst treatments directed at the underlying causes of cystic brosis, ad ances in targeted therapies for blood cancers, and therapies that prevent or slow extremely rare conditions such as pulmonary arterial hypertension, hereditary angioedema, and Gaucher disease.3 Many rare pediatric diseases, such as hypophosphatasia and neuroblastoma, now have available treatments.3

The U. . ood Drug dministration D ’s enter for Drug E aluation and Research DER is focused on facilitating the development of therapies for rare diseases.1 In 2022, more than half of CDER’s novel drug approvals were treatments for rare, or orphan, diseases. See Table 1 for a breakdown of the rare disease drug approvals in 2022.1

Gene therapies represent more innovation, with an expansive pipeline of therapies for the rare disease space. See Table 2 for a breakdown of the rare disease gene therapy pipeline.

Payer Impact and Management

s an increasing number of rst-in-class medications are appro ed and become available for rare disease patients, closing the gap in knowledge with all stakeholders — especially providers — will be key to appropriate management and utilization.2 Additionally, these therapies can be costly, which creates an increasing need for payers to closely manage and strategize in this space.2

riorities for rare disease management di er depending on the disease; for example, acute and chronic rare diseases will require di erent management priorities.2 For chronic rare diseases, cost

1. Rare Disease Drug Approvals 20224

Drug Manufacturer

Gene therapies represent more innovation, with an expansive pipeline of therapies for the rare disease space.

management strategies typically focus on policies outside of the bene t, such as stop-loss or reinsurance. eanwhile, for acute disease treatments, plans may seek ways to mitigate the cost of a one-time claim.2

Ultimately, access to appropriate therapies is crucial for patients with rare diseases. Determining the patients who can most bene t

Route of Administration Indication Status

tebentafusp-tebn (KIMMTRAK®) Immunocore injectable rst therapy for metastatic or unresectable u eal melanoma 1/26/2022 sutimlimab-jome

(PYRUKYND®) Agios oral hemolytic anemia in adults with pyru ate inase de ciency 2/17/2022 pacritinib (VONJO®) CTI BioPharma oral intermediate or high-ris primary or secondary myelo brosis in adults who have platelet levels below 50,000/uL 2/28/2022

nivolumab/relatlimabrmbw (Opdualag™) Bristol Myers Squibb injectable metastatic or unresectable melanoma in patients age 12 years or older 3/18/2022

ganaxolone (ZTALMY®) Marinus Pharmaceuticals oral rst therapy for sei ures associated with cyclin-dependent inaseli e de ciency disorder in patients age 2 or older 3/21/2022

vutrisiran (AMVUTTRA™) Alnylam Pharmaceuticals injectable polyneuropathy (damage of multiple nerves throughout the body) in adults with hereditary transthyretin-mediated amyloidosis 6/13/2022

olipudase alfa-rpcp (XENPOZYME™) ano IV rst therapy for Niemann- ic disease type , , 8/31/2022 spesolimab-sbzo (SPEVIGO®) Boehringer Ingelheim injectable rst therapy for ﬂares in patients with generali ed pustular psoriasis 9/1/2022

terlipressin (TERLIVAZ®) Mallinckrodt Pharmaceuticals injectable improve kidney function in adults with hepatorenal syndrome 9/14/2022

taurursodiol/sodium phenylbutyrate (RELYVRIO™) Amylyx Pharmaceuticals oral amyotrophic lateral sclerosis 9/29/2022 teclistamab-cqyv (TECVAYLI™) Janssen Biotech, Inc. injectable relapsed and refractory multiple myeloma in adults who have received at least four prior therapies 10/25/2022

tremelimumab-actl (IMJUDO®) AstraZeneca injectable unresectable hepatocellular carcinoma, together with IMFINZI® 11/10/2022

mirvetuximab soravtansinegynx (ELAHERE™) ImmunoGen, Inc. injectable recurrent ovarian cancer, resistant to platinum therapy 11/14/2022

mosunetuzumab-axgb (Lunsumio™) Roche injectable relapsed or refractory follicular lymphoma in adults 12/22/2022

Table

RARE DISEASE |

Table 2. Pipeline: Gene Therapies for Rare Diseases

Drug Manufacturer

Epidermolysis bullosa

Route of Administration

Beremagene geperpavec (Vyjuvek) Krystal Biotech topical epidermolysis bullosa pending

debcoemagene auto cel D- i Castle Creek Biosciences; Paragon Biosciences injectable epidermolysis bullosa phase 3

EB-101 Abeona Therapeutics other epidermolysis bullosa phase 3

Hemophilia

Valoctocogene roxaparvovec (ROCTAVIAN™) BioMarin IV hemophilia A pending (03/31/2023)

giroctocogene telpar o ec (SB-525) angamo Therapeutics er IV hemophilia A phase 3

danacogene elapar o ec06838435) par Therapeutics er IV hemophilia B phase 3

DMD

Delandistrogene moxeparvovec (SRP-9001) Sarepta Therapeutics IV

fordadistrogene movaparvovec (PF-06939926) er IV

Other

exagamglogene autotemcel (Exa-cel)

pending (05/29/2023)

phase 3

CRISPR Therapeutics/Vertex Pharmaceuticals IV beta thalassemia; SCD phase 3

timrepigene emparvovec (AAV2-REP1) Nightstar Therapeutics/Biogen intravitreal choroideremia phase 3

olenasul gene reldupar o ec (LYS-SAF302) Lysogene other mucopolysaccharidosis type IIIA phase 3

lenadogene nolparvovec (GS010) GenSight Biologics ophthalmic LHON phase 3

simoladagene autotemcel (OTL-101) Orchard Therapeutics injectable SCID phase 3

onasemnogene abeparvovec (ZOLGENSMA® IT) Novartis Gene Therapies intrathecal SMA phase 3

OTL-103 Orchard Therapeutics; GSK IV WAS phase 3

pariglasgene brecparvovec (DTX401) Ultragenyx IV von Gierke disease (glycogen storage disease type 1) phase 3

UX701 Ultragenyx IV Wilson’s disease phase 3

botaretigene sparoparvovec (AAV-RPGR) MeiraGTx; Janssen Biotech, Inc. other retinitis pigmentosa phase 3

laruparetigene zosaparvovec (AGTC-501) Applied Genetic Technologies Corporation injectable retinitis pigmentosa phase 3

atidarsagene autotemcel (OTL-200) Orchard Therapeutics; GSK IV metachromatic leukodystrophy phase 3

avolotcagene ontaparvovec (DTX301) Ultragenyx IV urea cycle disorders phase 3

bbre iations D D Duchenne muscular dystrophy IV intra enous ON eber hereditary optic neuropathy D sic le cell disease ID se ere combined immunode ciency spinal muscular atrophy; WAS = Wiskott-Aldrich syndrome

As an increasing number of frst-in-class medications are approved and become available for rare disease patients, closing the gap in knowledge with all stakeholders — especially providers — will be key to appropriate management and utilization.

from these therapies and ensuring them access and coverage are challenges that fall to payers.2 This includes determining whether these specialty drugs should be billed through medical or pharmacy bene t, pro iding le erage to pro iders to ensure treatment is covered based on the place of administration.2

Because of the high cost, input from medical specialists can help with understanding the value of certain therapies. Particularly in the space of rare diseases, informed decisions can be challenging to reach as sample sizes in trials are small, data is limited, and outcomes and impact of therapy are di cult to assess.2

In rare diseases where only one treatment is available, the top priority of payers will likely be to ensure patients are receiving the appropriate treatment for their diagnosis. Care managers can be a useful resource to guide patients through the healthcare system

Your Drug Info Digest

References

1. Cavazzoni, Patrizia. “CDER Continues to Make Rare Diseases a Priority with Drug Approvals and Programming to Speed Therapeutic Development.” U.S. Food & Drug Administration, 4 Mar. 2022, https://www.fda.gov/news-events/fda-voices/cdercontinues-make-rare-diseases-priority-drug-approvals-andprogramming-speed-therapeutic.

2. “Rare Disease: Access, Reimbursement, and Disease Management A Stakeholder Interchange Report.” American Journal of Managed Care, 3 Feb. 2022, https://www.ajmc.com/view/rare-diseaseaccess-reimbursement-and-disease-management-a-stakeholderinterchange-report.

once a diagnosis is complete. Care coordinators or managers can be particularly helpful for patients with rare diseases, or their parents and caregivers, to understand their diagnosis and the next steps, as information may be limited.2

In a roundtable of payers focusing on rare diseases, participants noted that use of high-cost agents is easier to justify if the agent targets a speci c genetic mar er associated with the disease.2 Payers also see value in manufacturers providing education and patient support. There may be opportunity for manufacturers to assist payers and providers in identifying these rare diseases, providing support in diagnosis, and accessing care.2

3. “Progress in Fighting Rare Diseases.” PhRMA, https://phrma.org/ cienti c-Inno ation rogress-in- ighting-Rare-Diseases.

4. “New Drug Therapy Approvals for 2022.” U.S. Food & Drug Administration, 10 Jan. 2023, https://www.fda.gov/drugs/newdrugs-fda-cders-new-molecular-entities-and-new-therapeuticbiological-products/new-drug-therapy-approvals-2022#raredisease.

CAR-T Therapy:

Update and Payer Impact

As currently approved CAR-T therapies expand their indications, and additional therapies move through the pipeline, this exciting opportunity and innovation will continue to create challenges and priorities for payers.

Anja Shaughnessey, Pharm.D., PRS, R.Ph.

Senior Pharmacy Program Manager

Point32Health

Chimeric antigen receptor T-cell (CAR-T) therapy is an innovative type of immunotherapy that uses a patient’s own immune system to help ght their cancer by collecting T-cells from the patient’s body and genetically modifying them to destroy cancer cells before infusing them back into the patient.1 CAR-T therapy has been an exciting and promising advancement in the oncology space.

Current CAR-T Landscape

There are currently six U. . ood and Drug dministration D -appro ed R-T therapies the rst one was approved in 2017. All of the currently approved CAR-T therapies are indicated for hematologic malignancies, in the second-line or later settings, but some experts anticipate a shift in place in treatment for CAR-T therapies in the near future.2 See Table 1 for a breakdown of approvals and indications.

Autologous vs. Allogeneic

Currently available CAR-T therapies are autologous, meaning a patient’s own immune cells are used to produce the therapy. By 2020, there were several manufacturers focusing on the development of allogeneic o -the-shelf R-T therapies, which use T-cells from healthy donor blood or umbilical cord blood. In October 2021, the FDA placed a hold on clinical trials for AlloCAR T™ (Allogene Therapeutics), which is allogeneic, after a report of chromosomal abnormality was detected after a single dose of AlloCAR T™ administration in one patient. The hold was lifted in January 2022.3 The use of allogeneic CAR-T cells may have promising advantages over autologous therapy, including immediate access to cryopreserved product for on-demand patient treatment, potential standardi ation of R-T cell product, time for multiple cell modi cations, redosing or combination of R-T cells directed against di erent targets, and lower costs using an industriali ed process.4 However, there are several concerns and challenges associated with allogenic CAR-T therapies: understanding the risk of chromosomal abnormalities, quality control, durability, T-cell exhaustion, qualifying material, and batch-to-batch variability.5

Table 1. CAR-T Therapies: Approvals and Indications

tisagenlecleucel (KYMRIAH®)

axicabtagene ciloleucel (YESCARTA®)

2017 Patients up to age 25 with B-cell precursor ALL, refractory, or in second or later relapse Yes

2018 Adult patients with relapsed or refractory LBCL after at least two lines of systemic therapy Yes

2022 Adults with relapsed or refractory follicular lymphoma after at least two lines of systemic therapy Yes

2017 Adults with relapsed or refractory LBCL after at least two lines of systemic therapy Yes

2021 Adults with relapsed or refractory follicular lymphoma after at least two lines of systemic therapy Yes

2022 dults with refractory to rst-line chemoimmunotherapy or who relapse after up to 2 months of rst-line chemoimmunotherapy

Adults with relapsed or refractory MCL*

brexucabtagene autoleucel (TECARTUS®)

Adults with relapsed or refractory B-cell

lisocabtagene maraleucel (BREYANZI™) 2021 Adults with relapsed or refractory LBCL after at least two lines of systemic therapy Yes 2022 refractory to rst-line chemoimmunotherapy or relapse within 2 months of rst-line chemoimmunotherapy OR refractory to or relapse after rst-line chemoimmunotherapy and are not eligible for HSCT due to comorbidities or age Yes

idecabtagene vicleucel (ABECMA®) 2021 Adults with relapsed or refractory multiple myeloma after at least four lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody Yes

ciltacabtagene autoleucel (CARVYKTI™) 2022

Adults with relapsed or refractory multiple myeloma after at least four lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody Yes CAR-T Therapy Approval Indication REMS Program?

Abbrevations: ALL = acute lymphoblastic leukemia; HSCT = hematopoietic stem cell transplantation; LBCL = large B-cell lymphoma; MCL = mantle cell lymphoma; REMS = Risk Evaluation and Mitigation Strategy due to cytokine release syndrome and neurologic toxicities ppro ed under accelerated appro al continued appro al may be contingent upon eri cation and description of clinical bene t in con rmatory trial

Recent CAR-T Approvals

Ciltacabtagene autoleucel (CARVYKTI™)

In February 2022, the FDA approved ciltacabtagene autoleucel (cilta-cel) (CARVYKTI™; Janssen Biotech Inc.) for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.6 Cilta-cel is a B-cell maturation antigen (BCMA)-directed, genetically modi ed autologous R-T therapy, with each dose customi ed using collected and modi ed T-cells from the patient that are then infused back into the patient.6 CARTITUDE-1 was an open-label, multicenter clinical trial evaluating the safety and e cacy of cilta-cel.7 The trial evaluated cilta-cel in 97 patients with relapsed or refractory multiple myeloma who received at least three prior lines of therapy, including a proteasome inhibitor,

an immunomodulatory agent, and an anti-CD38 monoclonal antibody and who had disease progression on or after the last chemotherapy regimen.7 Overall response rate and duration of response established e cacy, as e aluated by an Independent Review Committee (IRC) using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.7 Results showed the overall response rate was 97.9%, and among the 95 patients who responded, median duration of response was 21.8 months with a median duration of follow-up of 18 months.7 Cilta-cel comes with a boxed warning for cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis/macrophage activation syndrome, Immune E ector ell- ssociated Neurotoxicity Syndrome, Parkinsonism and Guillain-Barré syndrome and their associated complications, and prolonged and/or recurrent cytopenia.6 Janssen is required by the FDA to conduct a postmarketing observational study of patients treated with cilta-cel to evaluate and assess long-term safety.6

CAR-T THERAPY

Axicabtagene ciloleucel (YESCARTA®)

The FDA approved axicabtagene ciloleucel (axi-cel) (YESCARTA®, Kite Pharma Inc.) for adult patients with large B-cell lymphoma, refractory to rst-line chemoimmunotherapy or relapses within 2 months of rst-line chemoimmunotherapy in pril 2022.8 E cacy was established in the U - randomi ed, openlabel, multicenter trial of adult patients with primary refractory large B-cell lymphoma or relapse within 12 months following completion of rst-line chemoimmunotherapy.9 In the trial, 359 patients were randomized to receive a single infusion of axicel after ﬂudarabine and cyclophosphamide lymphodepleting chemotherapy or to second-line standard therapy (two or three cycles of chemoimmunotherapy followed by high-dose therapy and autologous hematopoietic stem cell transplantation [HSCT] in patients attaining complete remission or partial remission).9 The primary e cacy measure, e ent-free sur i al, was signi cantly longer in the axi-cel arm with a hazard ratio of 0.40; estimated 18-month event-free survival was 41.5% in the axi-cel arm compared to 17% for standard therapy.8 Estimated median event-free survival was longer for patients on axi-cel compared to standard therapy (8.3 months vs. 2 months).9 The best ob ecti e response rate was statistically signi cantly higher for

patients on axi-cel compared to standard therapy (83% vs. 50%, respectively).9 About 35% of patients receiving standard therapy received on-protocol HSCT, and lack of response to chemotherapy was the most common reason for not receiving the HSCT.9 The axicel label carries a warning for CRS and neurologic toxicities.8

Previously, axi-cel was approved by the FDA in 2017 for the treatment of adult patients with certain types of large B-cell lymphoma who had not responded to or who had relapsed after at least two other kinds of systemic treatment.10 Subsequently, in 2021, the FDA granted accelerated approval to axi-cel for the treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.11

Tisagenlecleucel (KYMRIAH®)

Tisagenlecleucel (tisa-cel) (KYMRIAH®, Novartis Pharmaceutical Corporation) was granted accelerated approval in May 2022 for the treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.12 In the primary e cacy analysis, the E R trial e aluated tisacel in 90 adult patients who were refractory or relapsed within

tabelecleucel (ATA129) Atara Biotherapeutics

autoleucel (CT053)

Status

PHE885 Novartis autologous BCMA-directed CAR-T therapy multiple myeloma phase 2

obecabtagene autoleucel (AUTO1) Autolus autologous CAR-T therapy ALL phase 2

Descartes-08 Cartesian Therapeutics autologous D R-T cell therapy multiple myeloma; myasthenia gravis phase 2

lisocabtagene maraleucel (BREYANZI®) Bristol Myers Squibb autologous CAR-T therapy NHL phase 1-2

lisocabtagene maraleucel (BREYANZI®) Bristol Myers Squibb autologous CAR-T therapy follicular lymphoma/MZL phase 2

PBCAR269A Precision Biosciences allogeneic T-cell therapy multiple myeloma phase 1-2

CTX110 CRISPR Therapeutics allogeneic CRISPR/Cas9 geneedited CAR-T therapy B-cell malignancies phase 1-2

UCART123 Cellectis allogeneic CAR-T therapy acute myeloid leukemia phase 1 Name Manufacturer

Abbreviations: ALL = acute lymphocytic leukemia; CMV = cytomegalovirus; IV = intravenous; MZL = marginal zone lymphoma; NHL = non-Hodgkin’s lymphoma; PTLD = post-transplant lymphoproliferative disorder

Table 2. Pipeline

six months after completion of two or more lines of systemic therapy (including an anti-CD20 antibody and an alkylating agent) or relapsed after HSCT.13 Tisa-cel was administered after lymphodepleting chemotherapy as a single intravenous infusion with a target dose of 0.6 to 6.0 x 108 CAR-positive viable T cells.13 The main e cacy endpoints, o erall response rate and duration of response, were determined by an IRC.13 Results showed an overall response rate of 86% with a complete response rate of 68%. Median duration of response was not reached with 75% of responders still within response at nine months.13 The most common adverse reactions were CRS, infection, fatigue, musculoskeletal pain, headache, and diarrhea.12 Like axi-cel, tisacel carries a boxed warning for CRS and neurologic toxicities and is available only through a restricted program under a REMS.

In 20 , tisa-cel was the rst R-T therapy the D appro ed, indicated forthe treatment of patients up to age 25 with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.14 The FDA granted tisa-cel supplemental approval in 2018 to treat adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including di use large -cell lymphoma D not otherwise speci ed, high-grade -cell lymphoma, and D arising from follicular lymphoma.15

Lisocabtagene maraleucel (BREYANZI®)

In June 2022, the FDA approved lisocabtagene maraleucel (lisocel) (BREYANZI®, Bristol Myers Squibb) to treat adult patients with large B-cell lymphoma who have refractory disease to rst-line chemoimmunotherapy or relapse within 2 months of rst-line immunotherapy refractory to or relapse after rstline chemoimmunotherapy and are not eligible for HSCT due to comorbidities or age.16 ppro al was based on e cacy results from two studies, TRANSFORM and PILOT. TRANSFORM was a trial for adult patients with primary refractory large B-cell lymphoma or relapse within 12 months of achieving complete response to rst-line therapy.17 In TRANSFORM, 184 patients were randomized to receive a single infusion of liso-cel following ﬂudarabine and cyclophosphamide lymphodepleting chemotherapy or to receive second-line standard therapy (three cycles of chemoimmunotherapy followed by high-dose therapy and autologous HSCT in patients who attained complete or partial response).17 E ent-free sur i al, the primary e cacy measure was signi cantly longer in the liso-cel arm, with a ha ard ratio of 0.34.17 In the liso-cel arm, estimated one-year event-free survival was 45% compared to 24% in the standard therapy arm.17 Estimated median event-free survival was 10.1 months for lisocel, compared to 2.3 months for standard therapy.17 About 47%

of patients receiving standard therapy received HSCT as planned; lack of response to chemotherapy was the most common reason for not recei ing T. rogression-free sur i al was signi cantly longer in the liso-cell arm, with a hazard ratio of 0.41.17

The I OT study e aluated e cacy in transplant ineligible patients with relapsed or refractory large B-cell lymphoma after one line of chemoimmunotherapy.18 The study included patients who were ineligible for high-dose therapy and HSCT due to organ function or age but who had adequate organ function for CAR-T therapy.18 Complete response rate and duration of response were the primary e cacy measures. Of the patients who received liso-cel, 54% achieved complete response, and the median duration of response was not reached in patients who achieved complete response.18 Median duration of response was 2.1 months in patients with a best response of partial response.18

Liso-cel carries a boxed warning for CRS and neurologic toxicities and is available only through a REMS because of these risks.16 CRS occurred in 45% of patients in studies of liso-cel as a secondline therapy for large B-cell lymphoma and neurologic toxicities occurred in 27%.16

Previously, the FDA approved liso-cel in 2021 to treat adult patients with certain types of large B-cell lymphoma who had not responded to, or who had relapsed after, at least two other types of systemic treatment.19

ICER Reviews

The Institute for Clinical and Economic Review (ICER) previously published a report on CAR-T therapies for treatment of B-cell malignancies in 2018 highlighting that although the pricing of axi-cel and tisa-cel aligned with patient bene t at the time, changes were needed in future pricing, payment, and delivery mechanisms to ensure patient access without threatening health system a ordability.20 In May 2021, ICER released its nal e idence report e aluating se eral treatments for multiple myeloma, including CAR-T therapies cilta-cel and idecabtagene vicleucel (ide-cel) (ABECMA®, Bristol Myers Squibb).21 ICER gave cilta-cel an e idence rating of , meaning there is moderate certainty of a small or substantial net health bene t, with high certainty of at least a comparable net health bene t.21 Both idecel and cilta-cel were determined to pro ide a net health bene t when compared to usual care. For ide-cel, the only CAR-T agent having gained FDA approval for multiple myeloma at the time of the report, a majority of panelists from ICER’s independent appraisal committee voted that it represents “low” long-term value for money at current pricing.21

CAR-T THERAPY

PEOPLE

a e The Di erence

SEE HOW!

Payer Management

Because of the high cost and complexity of CAR-T therapy, proper and e ecti e management is ey for payers. oremost, communication is essential between all stakeholders — providers, payers, and patients — to ensure utilization is appropriate and safe.

As currently approved CAR-T therapies broaden their indications, and additional therapies move through the pipeline to expand CAR-T use into treatment of solid cancers, such as lung and breast cancer, and o -the-shelf R-T therapies become reality, this exciting opportunity and innovation will continue to create challenges and priorities for payers.22 Key to proper management in this space will be determining the appropriate patients for these therapies.22 Payers need to assess the full treatment landscape to properly identify which patients are CAR-T therapy candidates; deference to providers in these instances is important, but establishing appropriate policy will also be essential.22 Policies shifts may include medical necessity criteria in order to ensure these high cost therapies will be utilized

by the appropriate patients. Key opinion leaders may also be a useful resource in providing second opinions in patient selection.

With currently available CAR-T therapies, organizations will typically coordinate payment by using customized agreements on a perpatient basis, making the billing and reimbursements for these therapies complicated and burdensome.23 Yet, as more CAR-T options become available, payers have been approving and allowing access to these therapies more expeditiously.23 However, payers will still need to take time to negotiate and customize these per-patient agreements in order to optimize management in this space.23

Continued strategizing and management will be required moving forward. rafting policy that appropriately identi es populations and ensures access to new innovative therapies, whether on a patient-by-patient basis or through broader management, will be ey to payers’ ability to e ecti ely manage the cost burden of CAR-T therapy while ensuring access to the patients who may bene t most.

References

1. “CAR T-Cell Therapy for Cancer.” OHSU Knight Cancer Institute, https:// www.ohsu.edu/knight-cancer-institute/car-t-cell-therapy-cancer.

2. Doherty, Kyle. “CAR Therapy Era Moves Forward With Much Excitement, Lingering Questions.” OncologyLive, 16 Nov. 2022, https://www.onclive.com/view/car-therapy-era-moves-forwardwith-much-excitement-lingering-questions.

References (cont.)

3. Stanton, Dan. “CAR-T at the Crossroads: Is Allogeneic the Way to Go?” BioProcess International, 31 Jan. 2020, https://bioprocessintl. com/manufacturing/emerging-therapeutics-manufacturing/car-tcell-therapies-is-allogeneic-the-way-to-go/.

4. Depil, ., et al. ’O -the-shelf’ allogeneic R T cells de elopment and challenges.” Nature Reviews Drug Discovery, Mar. 2020, https:// pubmed.ncbi.nlm.nih.gov/31900462.

5. Litchman, Manuel. “Autologous Vs. Allogeneic CAR-T Therapies: Time For A Second Look.” Cell & Gene, 14 Feb. 2022, https://www. cellandgene.com/doc/autologous-vs-allogeneic-car-t-therapiestime-for-a-second-look-0001.

6. “FDA D.I.S.C.O. Burst Edition: FDA approval of CARVYKTI (ciltacabtagene autoleucel) for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.” U.S. Food & Drug Administration, 30 Mar. 2022, https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-disco-burst-edition-fda-approvalcarvykti-ciltacabtagene-autoleucel-treatment-adult-patients.

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

8. “FDA D.I.S.C.O. Burst Edition: FDA approval Yescarta (axicabtagene ciloleucel) for adult patients with large B-cell lymphoma that is refractory to rst-line chemoimmunotherapy or relapses within 2 months of rst-line chemoimmunotherapy. U.S. Food & Drug Administration, 25 Apr. 2022, https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-disco-burst-edition-fda-approvalyescarta-axicabtagene-ciloleucel-adult-patients-large-b-cell.

9. Locke, Frederick, et al. “Axicabtagene Ciloleucel as SecondLine Therapy for Large B-Cell Lymphoma.” The New England Journal of Medicine, 17 Feb. 2022, https://pubmed.ncbi.nlm.nih. gov/34891224/.

10. “FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma.” U.S. Food & Drug Administration, 18 Oct. 2017, https://www.fda.gov/news-events/press-announcements/ fda-approves-car-t-cell-therapy-treat-adults-certain-types-large-bcell-lymphoma.

11. “FDA grants accelerated approval to axicabtagene ciloleucel for relapsed or refractory follicular lymphoma.” U.S. Food & Drug Administration, 8 Mar. 2021, https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-grants-accelerated-approvalaxicabtagene-ciloleucel-relapsed-or-refractory-follicular-lymphoma.

12. “FDA approves tisagenlecleucel for relapsed or refractory follicular lymphoma.” U.S. Food & Drug Administration, 31 May 2022, https:// www.fda.gov/drugs/resources-information-approved-drugs/fdaapproves-tisagenlecleucel-relapsed-or-refractory-follicular-lymphoma.

13. Fowler, Nathan Hale, et al. “Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial.” Nature Medicine, 17 Dec. 2021, https://www.nature.com/articles/s41591021-01622-0.

14. “FDA approves tisaganlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome.” U.S. Food & Drug Administration, 7 Sept. 2017, https://www.fda.gov/drugs/resources-information-approveddrugs/fda-approves-tisagenlecleucel-b-cell-all-and-tocilizumabcytokine-release-syndrome.

15. “FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma.” U.S. Food & Drug Administration, 3 May 2018, https://www.fda.gov/drugs/resources-informationapproved-drugs/fda-approves-tisagenlecleucel-adults-relapsed-orrefractory-large-b-cell-lymphoma.

16. “FDA D.I.S.C.O. Burst Edition: FDA approval of Breyanzi (lisocabtagene maraleucel) for second-line treatment of large B-cell lymphoma.” U.S. Food & Drug Administration, 21 July 2022, https://www.fda.gov/drugs/resources-information-approved-drugs/ fda-disco-burst-edition-fda-approval-breyanzi-lisocabtagenemaraleucel-second-line-treatment-large-b.

17. Kamdar, Manali, et al. “Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, andomized, phase 3 trial.” The Lancet, 18 June 2022, https://www.thelancet.com/journals/lancet/ article/PIIS0140-6736(22)00662-6/fulltext.

18. Sehgal, Alison, et al. “Lisocabtagene maraleucel as secondline therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study.” The Lancet Oncology, Aug. 2022, https://pubmed.ncbi.nlm.nih.gov/35839786/.

19. “FDA Approves New Treatment For Adults with Relapsed or Refractory Large B-Cell Lymphoma.” U.S. Food & Drug Administration, 5 Feb. 2021, https://www.fda.gov/news-events/ press-announcements/fda-approves-new-treatment-adultsrelapsed-or-refractory-large-b-cell-lymphoma.

20. “Leukemia and Lymphoma: An assessment of CAR-T Therapies (tisagenlecleucel and axicabtagene ciloleucel).” Institute for Clinical and Economic Review, Mar. 2018, https://icer.org/assessment/ leukemia-and-lymphoma-2018.

21. “Anti B-Cell Maturation Antigen CAR T-cell and Antibody Drug Conjugate Therapy for Heavily Pre-Treated Relapsed and Refractory Multiple Myeloma.” Institute for Clinical and Economic Review, 11 May 2021, https://icer.org/wp-content/uploads/2020/10/ICER_ Multiple-Myeloma_Final-Report_Unredacted_112222.pdf.

22. Minemyer, Paige. “Optum: How payers can prepare now for wave of CAR-T therapies.” Fierce Healthcare, 22 Sept. 2020, https://www. ercehealthcare.com payer optum-how-payers-can-prepare-nowfor-wave-car-t-therapies.

23. Cryts, Aline. “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-celltherapy-how-payers-are-responding-huge-price-tags.

Oncology Update: Advances in Breast Cancer Management

With the potential approval of a second oral SERD later in 2023, competition in this space could lead to better cost management.

Simone Ndujiuba, Pharm.D., BCOP Director, Clinical Strategy and Innovation, Oncology Magellan Rx Management

New approvals and a broad pipeline promise advances in the treatment of breast cancer. The treatment landscape continues to shift with targeted therapies for breast cancers with di erent biomar ers.

Recent Approvals

Olaparib (LYNPARZA®)

The U. . ood Drug dministration D appro ed olaparib YN R ®, AstraZeneca) in March 2022 for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) human epidermal growth factor receptor 2 (HER2)-negative high-risk early breast cancer, who have been treated with neoadjuvant or adjuvant chemotherapy.1 An FDA-approved companion diagnostic for olaparib must be used to select patients for therapy.1

Approval of olaparib was based on OlympiA, a randomized, double-blind, placebo-controlled, international study of patients with gBRCAm HER2-negative high-risk early breast cancer who completed de niti e local treatment and neoad u ant or ad u ant chemotherapy.2 The 1,836 patients were randomized 1:1 to receive either 12 months of olaparib tablets, 300 mg orally twice daily, or placebo. They were required to have completed at least six cycles of neoadjuvant or adjuvant chemotherapy containing anthracyclines, taxanes, or both.2 Per local guidelines, patients with hormone receptor positi e R breast cancer were allowed to continue concurrent treatment with endocrine therapy.2 Therapy continued for up to one year, or until disease recurrence or unacceptable toxicity.2

In asi e disease-free sur i al ID — the time from randomi ation to date of rst recurrence, de ned as invasive loco-regional, distant recurrence, contralateral invasive breast cancer, new cancer, or death from any cause — was the primary e cacy endpoint.2 For patients receiving olaparib, IDFS was 86%, compared to 77% for those receiving placebo.2 There was statistically signi cant impro ement in ID and overall survival observed in the olaparib arm compared to the placebo arm.2

Adverse reactions associated with olaparib in the trial included nausea, fatigue, anemia, vomiting, headache, diarrhea, leukopenia, neutropenia, decreased appetite, dysgeusia, dizziness, and stomatitis.1

Fam-trastuzumab deruxtecan-nxki (ENHERTU®)

In May 2022, the FDA approved fam-trastuzumab deruxtecan-nxki (ENHERTU®) for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and who have developed disease recurrence during or within six months of completing therapy.3 Famtrastuzumab deruxtecan-nxki was previously approved by the FDA under accelerated approval in December 2019 for adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.4 Approval was based on DESTINY-Breast03, the con rmatory trial for DE TINY-0 , a multicenter, open-label, randomized trial that enrolled 524 patients with HER2-positive, unresectable, and/or metastatic breast cancer who received prior trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within six months of completing neoadjuvant or adjuvant therapy.4 Patients received either fam-trastuzumab deruxtecan-nxki or ado-trastuzumab emtansine by intravenous (IV) infusion every three weeks until unacceptable toxicity or disease progression.4 The primary e cacy outcome was progression-free survival (PFS), with overall survival and con rmed ob ecti e response rate as secondary outcome measures.4 While PFS was not reached in the fam-trastuzumab deruxtecan-nxki arm, it was reached 6.8 months in the adotrastuzumab emtansine arm. In the fam-trastuzumab deruxtecan-

Elacestrant (Radius Health, Eisai) is an oral selective estrogen receptor degrader currently under FDA review for the treatment of breast cancer.

nxki arm, objective response rate was 82.7%, compared to 36% in patients receiving ado-trastuzumab emtansine.4

Then, in August 2022, fam-trastuzumab deruxtecan-nxki received further FDA approval for adult patients with unresectable or metastatic HER2-low breast cancer who had received prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy.5 The DESTINYBreast04 randomized, multicenter, open-label clinical trial included 55-year-old patients with unresectable or metastatic HER2-low breast cancer, with ha ing R disease.6 Patients were randomized 2:1 to receive either fam-trastuzumab deruxtecan-nxki or physician’s chemotherapy choice (PCC).6 in patients with R breast cancer was the primary e cacy measure, with secondary measures of and o erall sur i al in the R and R- groups combined and o erall sur i al in R patients.6 In the R cohort, was 0. months for patients on fam-trastuzumab deruxtecan-nxki, compared to 5.4 months for patients receiving PCC; PFS in the overall population was 9.9 months and 5.1 months for the fam-trastuzumab deruxtecan-nxki arm and PCC arm, respectively.6 Overall survival for patients receiving fam-trastuzumab deruxtecan-nxki was 23.9 months and 23.4 months in the R cohort and the o erall population, respecti ely.6 For patients recei ing , o erall sur i al was . months for the R group and 16.8 months for the overall population.6

Elacestrant

In January 2023, elacestrant (ORSERDU™, Stemline Therapeutics, Inc.) was approved by the FDA for postmenopausal women or adult men with estrogen receptor (ER)-positive, HER2-negative, estrogen receptor 1 gene (ESR1)-mutated advanced or metastatic breast cancer (MBC) with disease progression following at least one line of endocrine therapy.7 In the EMERALD randomized, open-label, phase trial, the e cacy of elacestrant in men and women with ER-positive/HER2-negative advanced breast cancer was evaluated.7 Participating patients previously had one or two lines of endocrine therapy, one line of a cyclin dependent kinase

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4/6 inhibitor and may have received one line of chemotherapy in the advanced or metastatic setting.7 A total of 477 patients were enrolled, with 228 having ESR1 mutations. Patients were randomized to receive either elacestrant 345 mg orally once daily or standard of care (SOC) endocrine monotherapy.7

The ma or e cacy outcome was with o erall sur i al as an additional measure. Comparison of the PFS for the intention to treat and the E R groups showed a statistically signi cant di erence, demonstrating the magnitude of the bene t seen in the ESR1-mutated population.8 peci cally, in patients with the ESR1 mutation taking elacestrant, the median PFS was 3.8 months compared to 1.9 among SOC patients, representing a 45% risk reduction of progression.7 Overall, 22.3% of the elacestrant group achieved 12-month PFS compared to 9.5% of the SOC group.7

Common adverse events associated with elacestrant were musculoskeletal pain; increased cholesterol, AST, creatinine and triglycerides; decreased sodium, hemoglobin, and appetite; and fatigue, nausea, vomiting, diarrhea, headache, constipation, abdominal pain, hot ﬂash, and dyspepsia.7

Pipeline Outlook

There are many exciting advancements and expanded approvals in the breast cancer category. See Table 1 for an expanded

pipeline. Imminent approval decisions by the FDA of oral selective estrogen receptor degraders ERD o er particularly interesting opportunities for shifts in the treatment of breast cancer.

Vic-trastuzumab duocarmazine

An intravenous anti-HER2 antibody-drug conjugate, victrastuzumab duocarmazine, is currently under review by the FDA with an expected approval decision in May 2023.8 A Biologics License Application (BLA) was accepted for vic-trastuzumab duocarma ine for the treatment of patients with ER2 unresectable locally advanced or MBC.8 Data from the phase 3 TULIP trial supported the BLA. TULIP was a multi-center, open-label, randomized clinical trial comparing vic-trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated ER2 unresectable locally advanced or metastatic breast cancer (MBC) with at least two previous MBC regimens or previous MBC treatment with ado-trastuzumab emtansine.9 Patients were randomized to receive either 1.2 mg/kg of vic-trastuzumab duocarmazine every three weeks or physician’s choice chemotherapy (lapatinib/ capecitabine, trastuzumab/capecitabine, trastuzumab/vinorelbine, or trastuzumab/eribulin mesylate).9

For patients in the vic-trastuzumab duocarmazine group, median PFS was seven months compared to 4.9 months in the physician’s choice group.9 Median overall survival was 20.4 months and 16.3

months for vic-trastuzumab duocarmazine and physician’s choice chemotherapy, respectively.9 This endpoint did not meet statistical signi cance. d erse e ents associated with treatment with ictrastuzumab duocarmazine were conjunctivitis, keratitis, and fatigue; interstitial lung disease, or pneumonitis, was reported for 7.5% of patients in the vic-trastuzumab duocarmazine group.9

This therapy is potentially a third-line treatment for MBC. Currently, the National omprehensi e ancer Networ lists tucatinib trastu umab capecitabine as the ategory preferred thirdline treatment for stage IV R or R- ER2 . inal o erall survival results are needed for vic-trastuzumab duocarmazine to determine whether it will provide improved outcomes over current preferred regimens.

Management Impact

The recent approval of oral SERDs for breast cancer will cause shift in the management of breast cancer. Elacestrant is the rst oral SERD for the treatment of breast cancer. Currently, fulvestrant (Faslodex®) injection is the only available SERD to treat breast

cancer. Endocrine therapy is so crucial in the treatment for ER breast cancer ERDs remain e ecti e in treating some E Rbearing breast cancers that can be resistant to some anti-estrogen therapy.10 Increasing treatment options in this space will provide alternative opportunities for all stakeholders.

Elacestrant could potentially become a preferred endocrine monotherapy regimen in second- or third-line ER-positive/HER2negative advanced metastatic breast cancer. An oral alternative could shift the treatment landscape for breast cancer. Patients could avoid the administrative burden of the three initial fulvestrant injections and follow-up monthly injection doses. Elacestrant could present a more e ecti e and con enient option to intramuscular ful estrant, speci cally in patients with E Rmutation. With the potential approval of a second oral SERD later in 2023, competition in this space could lead to better cost management.

Provider education will be crucial to help inform the process of selecting the appropriate population for treatment.11 Additionally, biomarker testing will be key to identifying the patients who will most bene t from treatment with these particular agents.11

bbre

Table 1. Pipeline: Breast Cancer Management

1. “FDA approves laparib for adjuvant treatment of high-risk early breast cancer.” U.S. Food & Drug Administration, 11 Mar. 2022, https://www.fda.gov/drugs/resources-information-approved-drugs/ fda-approves-olaparib-adjuvant-treatment-high-risk-early-breastcancer.

2. Tutt, Andrew, et al. “Adjuvant Olaparib for Patients with BRCA1or BRCA2-Mutated Breast Cancer,” The New England Journal of Medicine, 24 June 2021, https://www.nejm.org/doi/full/10.1056/ NEJMoa2105215.

3. “FDA D.I.S.C.O. Burst Edition: FDA approval of Enhertu (famtrastuzumab deruxtecan-nxki) for adult patients with unresectable or metastatic HER2-positive breast cancer.” U.S. Food & Drug Administration, 24 May 2022, https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-disco-burst-edition-fda-approvalenhertu-fam-trastuzumab-deruxtecan-nxki-adult-patients.

4. Cortés, Javier, et al. “Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer.” The New England Journal of Medicine, 24 Mar. 2022, https://www.nejm.org/doi/10.1056/ NEJMoa2115022.

5. “FDA D.I.S.C.O. Burst Edition: FDA approvals of Enhertu (famtrastuzumab deruxtecan-nxki) for unresectable or metastatic HER2-low breast cancer, and Nubeqa (darolutamide) in combination with docetaxel for metastatic hormone-sensitive prostate cancer.” U.S. Food & Drug Administration, 7 Sept. 2022, https://www.fda. gov/drugs/resources-information-approved-drugs/fda-disco-burstedition-fda-approvals-enhertu-fam-trastuzumab-deruxtecan-nxkiunresectable-or.

6. Modi, Shanu, et al. “Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.” The New England Journal of Medicine, 7 July 2022, https://www.nejm.org/doi/10.1056/ NEJMoa2203690.

7. “FDA approves elacestrant for ER-positive, HER2-negative, ESR1mutated advanced or metastatic breast cancer.” U.S. Food and Drug Administration, 27 Jan. 2023, https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-approves-elacestrant-er-positiveher2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer.

8. ADC Review Editorial Team, “Following Positive Results of Phase III TULIP Trial: FDA Accepts Byondis’ BLA for [Vic-] Trastuzumab Duocarma ine in ER m , ADC Review, 12 July 2022, https:// www.adcreview.com/news/following-positive-results-of-phaseiii-tulip-trial-fda-accepts-byondis-bla-for-vic-trastuzumabduocarmazine-in-her2-mbc/.

9. Saura Manich, Cristina, et al. “LBA 15- Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer,” Annals of Oncology, 19 Sept. 2021, https://oncologypro. esmo.org/meeting-resources/esmo-congress-2021/primaryoutcome-of-the-phase-iii-syd985.002-tulip-trial-comparing-victrastuzumab-duocarmazine-to-physician-s-choice-treatment-inpatients-with-p.

10. Wang, Yating, et al. “The race to develop oral SERDs and other novel estrogen receptor inhibitors: recent clinical trial results and impact on treatment options.” Cancer and Metastasis Review, 14 Oct. 2022, https://link.springer.com/article/10.1007/s10555-022-10066-y.

11. Fernando, Surani. “Pipeline Report 2022: Patient experience takes center stage,” MM+M, 7 Dec. 2022, https://www.mmm-online.com/ home/channel/features/pipeline-report-2022-patient-experiencetakes-center-stage/.

tro netide

Acadia Pharmaceuticals Rett syndrome oral NDA; fast track; orphan drug; priority review; rare pediatric disease 3/12/2023

efgartigimod/hyaluronidase Argenx myasthenia gravis SC orphan drug priority review 3/20/2023

rezafungin Melinta Therapeutics candidemia/invasive candidiasis IV NDA; fast track; orphan drug; priority review; QIDP 3/22/2023

leniolisib Pharming/Novartis activated PI3K delta syndrome oral NDA; orphan drug; priority review 3/29/2023

naloxone (NARCAN®) Emergent BioSolutions opioid overdose intranasal sNDA for Rx-to-OTC; priority review 3/29/2023

evinacumab-dgnb (EVKEEZA®) Regeneron

homozygous familial hypercholesterolemia (ages 5-11 years, adjunct) IV sBLA; breakthrough therapy; orphan drug; priority review 3/30/2023

valoctocogene roxaparvovec BioMarin hemophilia A (severe) IV BLA; breakthrough therapy; orphan drug; RMAT 3/31/2023

mirikizumab Eli Lilly and Company UC (moderate to severe)

Olaparib (LYNPARZA®) AstraZeneca prostate cancer (mCRPC, combination with prednisone abiraterone)

polatuzumab vedotin-piiq (POLIVY®) Genentech

DLBCL (1st-line, in combination with rituximab/cyclophosphamide or doxorubicin/prednisone)

adalimumab 100 mg/mL (biosimilar to AbbVie’s HUMIRA®) Alvotech RA; AS; PSO; PsA; JIA; CD; UC SC

breakthrough therapy; priority review March 2023

breakthrough therapy; orphan drug 4/2/2023

ri atriptan lm Gensco migraine treatment oral transmucosal 505(b)(2) NDA 4/17/2023

atogepant (QULIPTA™) AbbVie migraine prevention oral sNDA 4/21/2023

enfortumab vedotin-ejfv (PADCEV®) Astellas Pharma urothelial cancer (advanced, 1stline)

breakthrough therapy; priority review 4/21/2023

quizartinib Daiichi Sankyo acute myeloid leukemia oral NDA; breakthrough therapy; fast track; orphan drug; priority review 4/24/2023

tofersen Biogen ALS (superoxide dismutase 1) intrathecal

SER-109 Seres Therapeutics clostridium di cile-associated diarrhea prevention of recurrence

NDA; seeking accelerated approval; orphan drug; priority review 4/25/2023

breakthrough therapy; orphan drug; priority review 4/26/2023

PIPELINE

PIPELINE DRUG LIST CONT.

aripiprazole 2-month H. Lundbeck bipolar disorder; schizophrenia IM 505(b)(2) NDA 4/27/2023

elexacaftor/tezacaftor/ ivacaftor (TRIKAFTA®) Vertex cystic brosis ages 2- oral sNDA; breakthrough therapy; fast track; orphan drug; priority review 4/28/2023

durvalumab (IMFINZI®) AstraZeneca hepatocellular carcinoma (unresectable) IV sBLA; orphan drug 4/30/2023

palopegteriparatide Ascendis Pharma hypoparathyroidism (adults) SC NDA; orphan drug; priority review 4/30/2023

anthrax vaccine, absorded Emergent BioSolutions anthrax infection (post-exposure prophylaxis) IM BLA; fast track April 2023

cobimetinib (COTELLIC®) Genentech histiocytosis oral sNDA; breakthrough therapy April 2023

pneumococcal conjugate vaccine candidate (20-valent) (PREVNAR®) er invasive pneumococcal disease pre ention related otitis media (ages 6 weeks-17 years) IM sBLA; breakthrough therapy; fast track; orphan drug; priority review April 2023

omidubicel Gamida Cell HSCT (allogeneic) IV BLA; breakthrough therapy; orphan drug; priority review 5/1/2023

RSV pre-fusion protein, adjuvanted vaccine (GSK3844766A) GSK RSV prevention (older adults) IM BLA; fast track; priority review 5/3/2023

phenylephrine/tropicamide (2.5%/1%) Eyenovia mydriasis in-o ce ophthalmic 505(b)(2) NDA 5/8/2023

brexpiprazole (REXULTI®) Otsuka Alzheimer’s disease oral sNDA; fast track; orphan drug 5/10/2023 (vic-)trastuzumab duocarmazine Byondis breast cancer ER2 , unresectable locally advanced or metastatic) IV BLA; fast track 5/12/2023

beremagene geperpavec Krystal Biotech epidermolysis bullosa (dystrophic) topical BLA; fast track; orphan drug; priority review; rare pediatric disease; RMAT 5/19/2023

foscarbidopa/foslevodopa AbbVie Parkinson’s disease motor ﬂuctuations SC NDA 5/20/2023

epcoritamab Genmab/AbbVie DLBCL (R/R, >3rd-line) SC BLA; priority review 5/21/2023

dengue tetravalent vaccine, live, attenuated Takeda dengue fever prevention (ages 4-60 years) SC BLA; fast track; priority review 5/22/2023

buprenorphine ER (weekly, monthly dosing) Braeburn opioid use disorder (moderate to severe) SC 505(b)(2) NDA; fast track 5/23/2023

nogapendekin alfa inbakicept ImmunityBio

bladder cancer (BCG-unresponsive, non-muscle invasive carcinoma situ, in combination with BCG) intravesical BLA; breakthrough therapy; fast track 5/23/2023

upadacitinib (RINVOQ®) AbbVie CD (moderate to severe) oral sNDA 5/26/2023

nirmatrelvir/ritonavir (PAXLOVID™) er COVID-19 treatment (high-risk individuals) oral NDA 5/28/2023

delandistrogene moxeparvovec Sarepta Therapeutics/ Genentech DMD (ambulatory patients) IV BLA; seeking accelerated approval; fast track; orphan drug; priority review; rare pediatric disease 5/29/2023

durlobactam/sulbactam Innoviva acinetobacter baumannii infection IV NDA; fast track; priority review; QIDP 5/29/2023

sotagliﬂo in Lexicon Pharmaceuticals heart failure (with or without T2DM) oral NDA 5/31/2023

RSV pre-fusion protein vaccine (PF-06928316) er RSV prevention (ages > 60 years) injectable BLA; breakthrough therapy; fast track; priority review May 2023

landiolol Eagle Pharmaceuticals supraventricular tachycardia (shortterm reduction of ventricular rate) IV NDA 6/1/2023

cyclosporine A Novaliq DED ophthalmic 505(b)(2) NDA 6/8/2023

mavacamten (CAMZYOS®) Bristol Myers Squibb cardiomyopathy (reduce need for septal reduction therapy) oral sNDA; breakthrough therapy; orphan drug 6/16/2023

momelotinib GSK myelo brosis oral NDA; fast track; orphan drug 6/16/2023

oloro m F2G fungal infections (invasive)

obeticholic acid (OCALIVA®) Intercept N pre-cirrhotic li er brosis

perﬂuorohexyloctane Bausch Health DED-associated with meibomian gland

carbidopa/levodopa Amneal Pharmaceuticals Parkinson’s disease

bimekizumab

ritlecitinib er alopecia areata (ages > 12 years)

sNDA; breakthrough therapy 6/23/2023

505(b)(2) NDA 6/30/2023

tocilizumab (biosimilar to Genentech’s ACTEMRA) Fresenius Medical Care RA; polyarticular JIA; systemic JIA IV; SC BLA

natalizumab (biosimilar to Biogen’s TYSABRI®) Polpharma/ Novartis CD; multiple sclerosis IV

atezolizumab (TECENTRIQ®) Genentech

PIPELINE

glo tamab Genentech DLBCL (after > 3rd-line)

rucaparib (Rubraca®) Clovis Oncology ovarian cancer; 1st-line, post 1stline platinum) oral sNDA; breakthrough therapy; orphan drug 7/12/2023

brentuximab vedotin (ADCETRIS®) Seagen Hodgkin’s lymphoma (untreated advanced)

epinephrine

sofpironium

nirsevimab AstraZeneca RSV prevention (newborns/infants in 1st RSV season, ages > 24 months at risk through 2nd RSV season)

nirogacestat SpringWorks Therapeutics desmoid tumors oral

sBLA: breakthrough therapy; fast track; orphan drug July 2023

2023

2023 hypericin Soligenix cutaneous T-cell lymphoma (early stages)

ustekinumab (biosimilar to Janssen’s STELARA) Alvotech PSO; PsA; CD; UC

2023

bbre iations amyotrophic lateral sclerosis acillus almette- uerin iologics icense pplication D rohn’s disease DED dry eye disease D di use large B-cell lymphoma; DMD = Duchenne muscular dystrophy; HSCT = haematopoietic stem cell transplantation; IM = intramuscular; IV = intravenous; JIA = juvenile idiopathic arthritis; LPAD = Limited Population Pathway for Antibacterial and Antifungal Drugs; NASH = nonalcoholic steatohepatitis; NDA = new drug application; PsA = psoriatic arthritis; PSO = psoriasis; RA = rheumatoid arthritis; RMAT = regenerative medicine advanced therapy; R/R = relapsed or refractory; RSV = respiratory syncytial virus; RTOR = Real-Time Oncology Review; sBLA = supplemental biologics license application; SC = subcutaneous; sNDA = supplemental new drug application; T2DM = Type 2 diabetes mellitus; UC = ulcerative colitis