FDA approves first gene therapy for dystrophic epidermolysis bullosa (DEB)

The U.S. Food and Drug Administration (FDA) approved Krystal’s Vyjuvek for the treatment wounds in patients 6 months of age and older with dystrophic epidermolysis bullosa (DEB) with mutation(s) in the collagen type VII alpha I chain (COLA1) gene. It is applied as a gel topically once a week by a health care professional.

Drug Name:       Vyjuvek® (beremagene geperpavec-svdt)
Manufacturer:  Krystal Biotech
Condition:          Dystrophic epidermolysis bullosa

Condition overview

DEB is a rare, genetic skin-blistering disease caused by a mutation in the COL7A1 gene which is responsible for the production of protein type VII collagen (COL7) which forms anchoring fibrils that bind the dermis to the epidermis. People with DEB have fragile skin that blisters and tears easily due to lack of functional anchoring fibrils. Patients with DEB have open wounds that can lead to skin infections, fibrosis which can cause fusion of fingers and toes, and a higher risk of developing squamous cell carcinoma.^1-4

Krystal Biotech estimates about 3,000 people in the US have DEB.

Current treatment: ^3-4

• Lancing blisters
• Dressings and bathing to prevent infection
• Surgical interventions
• Analgesics and antipruritics

Before Vyjuvek, there were no FDA-approved medications for DEB.

Vyjuvek® (beremagene geperpavec) overview:

Vyjuvek is a topical, redosable gene therapy that delivers two copies of the COL7A1 gene when applied directly to DEB wounds. This gene encodes type VII collagen (COL7), which is an essential protein that helps strengthen and stabilize the outer and middle layers of the skin.

Typical application is one kit per patient per week, but it may not be possible to treat all wounds at each visit. A health care professional must compound the single-use vials together and then apply to wounds. This process is done weekly until wound closure which generally takes three to four weeks.  Vyjuvek is not curative because after closure a wound may reopen. Retreatment should be prioritized to previously treated wounds if they re-open.

Vyjuvek treatment needs will vary among individuals due to the number and size of wounds, time to wound closure, and potential retreatment. It is priced to cost about $300,000/year, although costs will vary depending on patient’s response to the treatment and reapplication.

Efficacy^1,4-7

The pivotal Phase 3, randomized, double-blind, intra-patient placebo-controlled trial evaluated complete wound healing of Vyjuvek  once weekly compared to placebo at six months. Inclusion criteria included patients with a DEB diagnosis confirmed by genetic testing aged six months or older with at least two cutaneous wounds similar in size, appearance and anatomical region. The dose was based on the patient’s age and wound size and was applied once weekly until wound closure; treatment resumed if wound reopened. More patients treated with Vyjuvek had wounds completely close at 6 months (65%) compared with those who received placebo (26%).

No drug-related serious adverse events or discontinuations due to treatment were reported. Common adverse reactions associated with Vyjuvek included itching, chills, redness, rash, cough, and runny nose.

Date approved:               June 28, 2023
Benefit/ROA:                   Medical benefit/topical application

Pipeline^8-10

FCX-007 (dabocemagene autoficel, Castle Creek Biosciences) – Autologous dermal fibroblast genetically modified to express functional COL7 using a lentiviral vector. FCX-007 is injected directly into the papillary dermis of blisters and wounds where the protein enables formation of anchoring fibrils to hold the layers of skin together.  FDA filing anticipated in 2023.

EB-101 (prademagene zamikeracel, Abeona Therapeutics) – Autologous, gene-corrected cell therapy that uses LZRSE-Col7A1 engineered epidermal sheet (LEAES) grafts. Treatment with EB101 involves using gene transfer to deliver COL7A1 genes into a patient’s own skin cells (keratinocytes and its progenitors) and transplanting them back to the patient. FDA filing anticipated in 2023.

References

1. FDA accepts Krystal Biotech’s biologics license application for dystrophic epidermolysis bullosa. Accessed in November 2022 at: FDA Accepts Krystal Biotech’s Biologics License Application for Dystrophic Epidermolysis Bullosa | Krystal Biotech
2. Krystal Biotech announces FDA’s 3-month extension of BLA PDUFA date and regulatory update for B-VEC to treat patients with dystrophic epidermolysis bullosa. Accessed in February 2023 at: Krystal Biotech Announces FDA’s 3-Month Extension of BLA PDUFA Date and Regulatory Update for B-VEC to Treat Patients with Dystrophic Epidermolysis Bullosa | Krystal Biotech
3. Dystrophic epidermolysis bullosa. Accessed in November 2022 at: Dystrophic epidermolysis bullosa – About the Disease – Genetic and Rare Diseases Information Center (nih.gov)
4. Krystal Bioteck. Data on File. September 2022.
5. Krystal Biotech announces positive topline results from GEM-3 pivotal trial of Vyjuvek in patients with dystrophic epidermolysis bullosa. Accessed in November 2022 at: https://ir.krystalbio.com/news-releases/news-release-details/krystal-biotech-announcespositive-topline-results-gem-3-pivotal
6. In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial. Nature medicine 2022; 28: 780-788.
7. Guide SV, Gonzalez ME, Bagci IS, et al. Trial of beremagene geperpavec (B-VEC) for dystrophic epidermolysis bullosa. NEJM 2022; 387; 24: 2211-2219.
8. Cortellis 2022. Search word dystrophic epidermolysis. Accessed in December 2022.
9. Castle Creek Biosciences. D-Fi Gene Therapy for dystrophic epidermolysis bullosa. Accessed in December 2022 at: Castle Creek Biosciences: D-Fi Gene Therapy : Castle Creek Biosciences, Inc.
10. Abeona Therapeutics. Abeona Therapeutics reinitiates enrollment in EB-101 pivotal Phase 3 VIITAL study in RDEB after COVID-19 related pause and announce progress in patients enrollment in MPS III studies. Accessed in December 2022 at: Abeona Therapeutics Reinitiates Enrollment in EB-101 Pivotal Phase 3 VIITAL™ Study in RDEB after COVID-19 Related Pause and Announces Progress in Patient Enrollment in MPS III Studies : Abeona Therapeutics Inc. (ABEO)
11. Krystal Biotech receives FDA approval for the first-ever redosable gene therapy, Vyjuvek (beremagene geperpavec-svdt) for the treatment of dystrophic epidermolysis bullosa. Accessed in August 2023 at: Krystal Biotech Receives FDA Approval for the First-Ever (globenewswire.com)
12. Vyjuvek (beremagene geperpavec-svdt) biological suspension mixed with excipient gel for topical application. Accessed in August 2023 at: vyjuvek-us-pi.pdf (krystallabel.com)