Gene Therapy Update: New Approvals and Payer Strategy

Potentially 90 new gene and cellular therapies could be approved by 2031, representing $30 billion in healthcare spending.

Gene therapy works via agents that can replace a disease-causing gene with a functioning copy of the gene, deactivate a disease-causing gene that is malfunctioning, or introduce a new or modified gene to help treat the disease.1

Since the first U.S. Food & Drug Administration (FDA) approval of a gene therapy, KYMRIAH®, in 2017, an increasing number of gene therapies have been approved and become available. These gene therapies have been approved for a range of indications including spinal muscular atrophy, beta thalassemia, cerebral adrenoleukodystrophy, hemophilia B, inherited retinal disease, and non-muscle invasive bladder cancer.1

Amber Zuber, Pharm.D. AVP Pharmacy & Member Services

The landscape of available gene therapies as well as approved indications is expected to continue expanding. Up to 90 new gene and cellular therapies could be approved by 2031, representing $30 billion in healthcare spending.2

Recent Approvals

Etranacogene

dezaparvovec (HEMGENIX®)

In November 2022, the FDA approved etranacogene dezaparvovec (HEMGENIX®) for the treatment of adults with hemophilia B (congenital Factor IX deficiency) who currently use factor IX (FIX) prophylaxis therapy, who have current or historical life-threatening hemorrhage, or who have repeated serious spontaneous bleeding episodes. The FDA application received priority review, orphan, and breakthrough therapy designations.3

Etranacogene dezaparvovec is an adeno-associated virus vectorbased, one-time gene therapy given as a single dose by IV infusion.3 In a study of 54 adult men with severe or moderately severe hemophilia B, subjects who received the treatment showed increased FIX activity levels, a decreased need for routine FIX replacement prophylaxis, and a 54% reduction in annualized bleeding rate compared to baseline.4

Adverse reactions associated with etranacogene dezaparvovec included liver enzyme elevations, headache, mild infusionrelated reactions, and flu-like symptoms.3

In December 2022, the Institute for Clinical and Economic Review (ICER) released a report assessing the comparative clinical effectiveness and value of etranacogene dezaparvovec for hemophilia B.5 The report concluded that there is a moderate certainty of a small or substantial health benefit with high certainty of at least a small net health benefit for etranacogene dezparvovec compared with FIX prophylaxis.5

Nadofaragene firadenovec-vncg (ADSTILADRIN®)

The FDA approved nadofaragene firadenovec-vncg (ADSTILADRIN®) in December 2022 for the treatment of adult patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors.6 Efficacy was evaluated in a multicenter, single-arm trial, Study CS-003, with 157 patients with high-risk non-muscle invasive bladder cancer; 98 participants had Bacillus Calmette-Guérin — unresponsive carcinoma in situ evaluable for response.7 In the study, participants were administered nadofaragene firadenovec-vncg 75 mL intravesical instillation once every three months for up to 12 months, until unacceptable toxicity, or recurrent high-grade non-muscle invasive bladder cancer.7 Efficacy outcome measures were complete response (CR) and duration of response.7 The rate of CR was 51% and median duration of response was 9.7 months, with 46% of responding patients remaining in CR for at least one year.7

Common adverse reactions associated with nadofaragene firadenovec-vncg include increased glucose, triglycerides, and creatinine; decreased phosphate; instillation site discharge; fatigue; bladder spasm; micturition urgency; hematuria; chills; dysuria; and pyrexia.6

Beremagene Geperpavec (VYJUVEK®)

Beremagene geperpavec (VYJUVEK®) was approved by the FDA in May 2023 for the treatment of wounds in patients 6 months and older with dystrophic epidermolysis bullosa (DEB) with mutations in the collagen type VII alpha 1 chain (CO7A1) gene.8 This represents the first approved gene therapy for DEB, a genetic disorder that affects connective tissue in the skin and nails.8 Beremagene geperpavec is a genetically modified herpes-simplex virus used to deliver normal copies of the COL7A1 gene to the wounds.8 The treatment is mixed into an excipient gel prior to topical application and is administered topically by a healthcare professional once a week.8

Approval was based on a randomized, double-blinded, placebo-controlled study involving a total of 31 subjects with DEB, including 30 subjects with recessive DEB (RDEB) and one with dominant DEB (DDEB). 9 Two DEB wounds of comparable size on each patient were identified and randomized to receive either topical administration of beremagene geperpavec or placebo weekly. 9 Efficacy was established by improved wound healing, or the difference in the proportion of confirmed complete wound closure between those treated with beremagene geperpavec and those treated with placebo at 24 weeks. 9 Of wounds treated with beremagene geperpavec, 65% completely closed while only 26% of the placebo-treated wounds completely closed. 9 Common adverse reactions associated with beremagene geperpavec are itching, chills, redness, rash, cough, and runny nose. 8

Delandistrogene moxeparvovec (ELEVIDYS®)

In June 2023, the FDA approved delandistrogene moxeparvovec-rokl (ELEVIDYS®, Sarepta Therapeutics) via accelerated approval pathway; this is the first gene therapy to treat Duchenne muscular dystrophy (DMD).10 The therapy is approved for the treatment of ambulatory pediatric patients aged 4 through 5 years with DMD who have a confirmed mutation in the DMD gene.10 Approval was supported empirical and biologic evidence as well as efficacy data from two clinical studies (SRP-9001-102 and SRP-9001-103) and safety data from SRP 9001-101.10 A confirmatory, global, randomized, doubleblind, placebo-controlled phase 3 trial, EMBARK, is fully enrolled with top-line results anticipated late in 2023.10 Adverse reactions associated with delandistrogene moxeparvovec-rokl were vomiting, nausea, liver function test increased, pyrexia, and thrombocytopenia.10

Valoctocogene roxaparvovec (ROCTAVIAN®)

The FDA approved the first gene therapy for adults with severe hemophilia A, valoctocogene roxaparvovec (ROCTAVIAN®, BioMarin Pharmaceutical Inc.) in June 2023.11 Valoctocogene roxaparvovec is an adeno-associated virus vector-based gene therapy, now approved for the treatment of adults with severe hemophilia A without pre-existing antibodies to adeno-associated virus serotype 5 detected by an FDA-approved test.11 A multinational study in adult men 18 to 70 years of age with severe hemophilia A evaluated safety and effectiveness.12 Participants were previously treated with Factor VIII replacement therapy and effectiveness was established based on results from a cohort of 112 patients followed up for at least three years after treatment with the gene therapy.12 Mean annualized bleeding rate decreased from 5.4 bleeds per year at baseline to 2.6 bleeds per year following infusion.12 A majority of patients who received valoctocogene roxaparvovec received corticosteroids as an immune system suppressant for the gene therapy to be effective and safe.12 The treatment response may decrease over time.11 Common adverse reactions associated with treatment were mild changes in liver function, headache, nausea, vomiting, fatigue, abdominal pain and infusion-related reactions.11

Payer Management

As the gene therapy landscape continues to expand with more options and approved indications, payer management of the space will become increasingly important considering the high price tag associated with these treatments. A May 2023 survey of benefit leaders at employers and health plans from the Pharmaceutical Strategy Group outlined findings and concerns regarding gene therapy and specialty drug benefit design.13 About half of the payers reported gene therapy affordability as a major challenge in the next few years and 25% anticipated a major challenge from the drugs.13 Only 25% of payers surveyed reported using value-based contracts for specialty drugs with only 5% of employers reporting the same.13 About 14% of employers and 7% of payers use alternative payment models, like grant and manufacturer patient programs, to pay for specialty drugs.13 Site of care carboplatin programs are utilized by half of payers and a quarter of employers surveyed, in an effort to reduce specialty drug costs.13 The top challenge concerning specialty drug cost for health plans was cost parity across medical and pharmacy benefits and, for employers, was affordability for members.13 Despite concerns around the financial burden and cost associated with these therapies, there is consensus that ensuring access to potentially life-saving therapies for the appropriate patient population is important.2

In February 2023, the U.S. Department of Health and Human Services (HHS) announced a new payment and service delivery model for testing by the Center for Medicare & Medicaid Innovation (CMS Innovation Center).14 Under the voluntary Cell and Gene Therapy Access Model, state Medicaid agencies would have the option to direct CMS to coordinate and administer multistate, outcomes-based agreements with manufacturers for certain cell and gene therapies, giving CMS the responsibility of implementing, monitoring, reconciling, and evaluating the financial and clinical outcomes.14 The objective of the model would be to allow CMS to pool bargaining power to obtain discounted pricing, tie the cost of cell and gene therapies to outcomes, and shift the burden of administering complex outcomes-based agreements from state Medicaid agencies to CMS.9 The model development is slated to begin this year with a launch as early as 2026.14

Overall, alternative payment models may prove critical in financing and allowing access to gene therapies where appropriate. These models, including outcomes- or milestone-based agreements,

Pipeline Rare Diseases lovotibeglogene autotemcel (Lovo-cel) mortgage-like mechanisms, subscription payment models, risk pools, and orphan reinsurer benefit managers, can help finance high-cost gene therapies. There are ongoing concerns around current reimbursement models, such as the burden of information tracking, regulatory barriers, and pricing and reporting requirements. Thus, collaborative development of creative payment models by all stakeholders will be key to effectively manage these treatments, allow access, and ease the financial burdens. bluebird bio IV SCD pending (1H 2024) exagamglogene autotemcel (Exa-cel) CRISPR Therapeutics; Vertex IV beta thalassemia; SCD phase 3 giroctocogene fitelparvovec (SB-525) Sangamo Therapeutics; Pfizer IV hemophilia A phase 3 fidanacogene elaparvovec (PF-06838435) Spark Therapeutics; Pfizer IV debcoemagene autoficel (D-Fi)

EB-101 fordadistrogene movaparvovec (PF-06939926)

Hemophilia B phase 3

Castle Creek Biosciences; Fibrocell Technologies injectable epidermolysis bullosa phase 3

Abeona Therapeutics other epidermolysis bullosa phase 3

Pfizer IV DMD phase 3 timrepigene emparvovec (AAV2-REP1) Nightstar Therapeutics; Biogen intravitreal choroideremia phase 3 olenasufligene relduparvovec (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 brecaparvovec (DTX401)

UX701 botaretigene sparoparvovec (AAV-RPGR)

Ultragenyx IV Von Glerke disease phase 3

Ultragenyx IV Wilson’s disease phase 3

MeiraGTx; Janssen other retinitis pigmentosa phase 3 afidarsagene autotemcel (OTL-200) Orchard Therapeutics; GSK IV metachromatic leukodystrophy phase 3 laruparetigene zosaparvovec (AGTC-501) avalotcagene ontaparvovec (DTX301)

Common diseases alferminogene tadenovec (Generx)

RGX-314

LBP-EC01 donaperminogene seltoplasmid (Engensis)

Applied Genetic Technologies injectable retinitis pigmentosa phase 3

Ultragenyx IV urea cycle disorders phase 3

Angionetics; Gene Biotherapeutics other angina pectoris phase 3

Regenxbio; AbbVie ophthalmic wAMD phase 3

Locus Biosciences oral

UTI caused by certain organisms phase 3

ViroMed; Helixmith intramuscular chronic diabetic foot ulcers; diabetic neuropathy phase 3

Abbreviations: DMD = Duchenne muscular dystrophy; IV = intravenous; LHON = Leber hereditary optic neuropathy; SCD = Sickle cell disease; SCID = severe combined immunodeficiency; SMA = spinal muscular atrophy; UTI = urinary tract infection; wAMD = wet age-related macular degeneration; WAS = Wiskott Aldrich syndrome

References

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

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

3. “FDA Approves First Gene Therapy to Treat Adults with Hemophilia

B.” U.S. Food & Drug Administration, 22 Nov. 2022, https://www.fda. gov/news-events/press-announcements/fda-approves-first-genetherapy-treat-adults-hemophilia-b.

4. Pipe, Steven W., et al. “Adults with Severe or Moderately Severe Hemophilia B Receiving Etranacogene Dezaparvovec in the HOPE-B Phase 3 Clinical Trial Continue to Experience a Stable Increase in Mean Factor IX Activity Levels and Durable Hemostatic Protection after 24 Months’ Follow-up.” Blood, 15 Nov. 2022, https://ashpublications.org/ blood/article/140/Supplement%201/4910/490589/Adults-withSevere-or-Moderately-Severe-Hemophilia.

5. “ICER Publishes Final Evidence Report on Gene Therapies for Hemophilia A and B.” Institute for Clinical and Economic Review, 22 Dec. 2022, https://icer.org/news-insights/press-releases/icer-publishesfinal-evidence-report-on-gene-therapies-for-hemophilia-a-and-b/.

6. “FDA D.I.S.C.O. Burst Edition: FDA Approval of Adstiladrin (nadofaragene firadenovec-vncg) for patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors.” U.S. Food & Drug Administration, 20 Jan. 2023, https://www.fda.gov/drugs/resources-informationapproved-drugs/fda-disco-burst-edition-fda-approval-adstiladrinnadofaragene-firadenovec-vncg-patients-high-risk.

7. Boorjian, Stephen A., et al. “Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.” The Lancet Oncology, Jan. 2021, https://pubmed.ncbi.nlm.nih. gov/33253641/.

8. “FDA Approves First Topical Gene Therapy for Treatment of Wounds in Patients with Dystrophic Epidermolysis Bullosa.” U.S. Food & Drug Administration, 19 May 2023, https://www.fda.gov/news-events/pressannouncements/fda-approves-first-topical-gene-therapy-treatmentwounds-patients-dystrophic-epidermolysis-bullosa.

9. Guide, Shireen V., et al. “Trial of Beremagene Geperpavec (B-VEC) for Dystrophic Epidermolysis Bullosa.” The New England Journal of Medicine, 15 Dec. 2022, https://pubmed.ncbi.nlm.nih. gov/36516090/.

10. “Sarepta Therapeutics Announces FDA Approval of ELEVIDYS, the First Gene Therapy to Treat Duchenne Muscular Dystrophy.” Sarepta Therapeutics, 22 June 2023, https://investorrelations.sarepta. com/news-releases/news-release-details/sarepta-therapeuticsannounces-fda-approval-elevidys-first-gene.

11. “FDA Approves First Gene Therapy for Adults with Severe Hemophilia A.” U.S. Food & Drug Administration, 29 June 2023, https://www.fda.gov/news-events/press-announcements/fdaapproves-first-gene-therapy-adults-severe-hemophilia.

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

13. Wilson, Rylee. “Payers are concerned about gene-therapy drug costs: 5 things to know.” Becker’s Payer Issues, 5 May 2023, https:// www.beckerspayer.com/payer/payers-are-concerned-about-genetherapy-drug-costs-5-things-to-know.html.

14. “New U.S. Drug Pricing Models Target Cell and Gene Therapies, Accelerated Approval Drugs, and Generics.” Sidley, 23 Feb. 2023, https://www.sidley.com/en/insights/newsupdates/2023/02/ new-us-drug-pricing-models-target-cell-and-gene-therapiesaccelerated-approval-drugs-and-generics.