High-Cost Therapy Profile

April 15, 2024

Detailed information about prademagene zamikeracel Topical surgical application

High-Cost Therapy Profile

Gene therapy/Dermatology

Prademagene zamikeracel Topical surgical application

Abeona


Proposed indications

Recessive dystrophic epidermolysis bullosa (RDEB)

FDA approval timeline

May 25, 2024

  • Breakthrough Therapy
  • Orphan Drug
  • Priority Review
  • Rare Pediatric Disease (RPD)
  • Regenerative Medicine Advanced Therapy (RMAT)

Place in therapy

Prademagene zamikeracel (pz-cel) is an autologous, collagen type VII alpha 1 chain (COL7A1) gene-corrected epidermal sheet. In this ex vivo cell therapy, autologous keratinocyte grafts are created from skin biopsies that are transduced with a retrovirus containing the full-length COL7A1 gene and grown into sheets.

  • If approved, pz-cel will be the third treatment and second gene therapy approved for epidermolysis bullosa (EB).
  • Pz-cel will compete with beremagene geperpavec (Vyjuvek®) in patients with RDEB; both gene therapies provide copies of the COL7A1 gene and are administered by a health care provider (HCP).
  • Pz-cel is intended as a one-time surgical application and it is administered with anesthesia in a hospital setting, followed by a one-week hospital stay to immobilize the grafted areas. In contrast, Vyjuvek is a topical, redosable gene therapy that is applied directly to EB wounds by an HCP, which may be performed in the home setting. Vyjuvek application is repeated on a weekly basis until wound closure. It is not a curative option since a wound may reopen and require retreatment.
  • Pz-cel is also being studied in a phase 3 trial in patients with RDEB who were previously treated with pz-cel; primary study completion is anticipated in August 2024.
  • Long-term data demonstrated sustained wound healing for up to 8 years after pz-cel application.

Understanding your data

Pz-cel is a cell therapy that is developed from a patient’s own skin cells collected and genetically engineered using a retroviral vector to restore COL7A1 gene production. These modified cells are grown into cellular sheets which are then surgically grafted onto the RDEB wounds which promotes their healing. Application of pz-cel has demonstrated sustained wound healing and pain reduction in patients with RDEB. There are several ongoing clinical trials that include:

  • NCT04227106 VIITAL: A phase 3 study of pz-cel for the treatment of RDEB.
  • NCT05708677: A long-term extension study for participants previously treated with pz-cel for the treatment of RDEB.
  • NCT05725018: A phase 3b study for the treatment of RDEB in new and previously pz-cel treated patients.
  • NCT03183934: A follow-up study to evaluate the efficacy and safety for the patients with allogenic adipose-derived mesenchymal stem cells diabetic foot ulcers (ALLO-ASC-DFU) treatment in phase 1/2 clinical trial of ALLO-ASC- pz-cel.

Identification of patients would reflect the clinical trials criteria listed in the studies above, as well as diagnosis codes identified from claims data requiring among others:

Common measurable inclusion criteria:

  • Diagnosis of dystrophic epidermolysis bullosa (DEB).
  • Age ≥ 6 years.

Common measurable exclusion criteria:

  • Active infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C.
  • Pregnant or breastfeeding.
  • Active drug or alcohol addiction.

Appendix

CATEGORY PROCEDURE CODES
Dystrophic Epidermolysis Bullosa ICD-10: Q81.2
HIV, Hepatitis B or Hepatitis C ICD-10: B16x, B18x, B19x, B20x
Pregnancy and lactation ICD-10: Z34.00, Z34.8, Z34.90, Z33.1, O09.00, O09.10, O09.291, O09.40, O09.211, O09.30, O09.511, O09.521, O09.611, O09.621, O09.819, O09.821, O09.822, O09.823, O09.829, O36.80×0, O09.891, O09.892, O09.893, O09.899, Z39.0, Z39.1, Z39.2, Z36, Z37, Z37.1, Z37.2, Z37.3, Z37.4, Z37.59, Z37.69, Z37.7, Z37.9, Z64.0, Z32.01, O30.009, O30.019, O30.039, O30.049, O30.099, O30.109, O30.119, O30.129, O30.199, O30.209, O30.219, O30.229, O30.299, O30.809, O30.819, O30.829, O30.899, O20.0, O44.01, O44.02, O44.03, O10.011, O10.012, O10.013, O10.02, O10.911, O10.912, O10.913, O10.92, O10.03, O21.0, O60.12X0, O60.13X0, O60.14X0, O48.0,  O31.01X0, O31.02X0, O31.03X0, O98.111, O98.112, O98.113, O98.12, O98.13, O24.32, O24.911, O24.912, O24.913, O24.92, O24.93, O99.331, O99.332, O99.333, O99.334, O99.335, O80, O30.001, O30.002, O30.003, O32.0XX0, O33.0, O34.01, O34.02, O34.03, O34.01, O34.02, O34.03, O35.0XX0, O43.011, O36.0110, O36.0120, O36.0130, O36.0910, O36.0920, O36.0930, O36.1110, O36.1120, O36.1130, O36.1910, O36.1920, O36.1930, O68, O36.5110, O36.5120, O36.5130, O36.5910, O36.5920, O36.5930, O36.61X0, O36.62X0, O36.63X0, O43.101, O43.102, O43.103, O43.811, O43.812, O43.813, O43.91, O43.92, O43.93, O36.8910, O36.8920, O36.8930, O68, O77.0, O36.91X0, O36.92X0, O36.93X0, O40.1XX0, O40.2XX0, O40.3XX0, O41.01X0, O41.02X0, O41.03X0, O61.1, O64.9XX0, O62.0, O63.0, O70.0, O71.02, O71.03, O72.0, O43.211, O43.212, O43.213, O43.221, O43.222, O43.231, O43.232, O43.233, O73, O74.1, O89.09, O75.0, O86.89, O22.01, O22.02, O22.03, O87.4, O86.4, O88.011, O88.012, O88.013, O88.02, O88.03, O99.411, O99.412, O99.413, O99.42, O99.43, O91.011, O91.012, O91.013, O91.02, O92.011, O92.012, O92.013,O92.03, O35.8XX0, O36.8210, O36.8220, O36.8230, O75.89, Z37.0, Z37.2, Z37.3, Z37.59, Z37.69, O86.12, O85, O86.81, O86.89
Active Drug or Alcohol Addiction ICD-10: F10x, E24.4, G31.2, G62.1, I42.6, K70x, K86.0, O35.4, T40.1, T51.0x, Z71.4x

Clinical deep dive

Disease state overview

Epidermolysis bullosa (EB) is an ultra-rare, inherited, genetic skin disorder characterized by formation of painful blisters after minor friction or trauma to the skin or mucosa. Dystrophic epidermolysis bullosa (DEB) is 1 of the 4 main types of EB (EB simplex, dystrophic EB, junctional EB, Kindler EB). It is caused by mutation in the COL7A1 gene that is responsible for making collagen VII (C7), a protein that strengthens and stabilizes the adhesion of the epidermis and dermis. There are two major subtypes of DEB, dominant DEB (DDEB) and recessive DEB (RDEB). RDEB is typically more generalized and severe than DDEB. Common manifestations of RDEB include scarring, malnutrition, anemia, esophageal strictures, growth retardation, webbing or fusion of the fingers and toes, contractures, teeth malformation, microstomia, and corneal abrasions. Patients with severe cases are also at increased risk of aggressive squamous cell carcinoma (SCC), which typically occurs in the second decade of life and can be fatal.

Epidemiology

EB affects an estimated 1 in every 50,000 live births. While EB simplex accounts for majority of the EB cases (70%), dystrophic EB accounts for 25% of all EB cases. DEB has a prevalence of 1.35 cases per 1 million live births.

Treatment

There is no cure for EB. Current management for this genetic disorder includes reduction of skin trauma, nutritional support, and pain management. The gene therapy Vyjuvek was FDA approved in May 2023 for use in patients ≥ 6 months of age with DEB and confirmed COL7A1 mutation. It is a herpes-simplex virus type 1 (HSV-1) vector-based gene therapy topical gel that is applied to wounds once weekly by an HCP. In clinical trials, it resulted in complete healing of 67% of wounds compared to 22% with placebo gel (p=0.002). In addition, birch triterpene topical gel (Filsuvez®) was approved in December 2023 for the treatment of wounds associated with dystrophic and junctional EB in patients ≥ 6 months of age. The botanical product is applied at home to wound surfaces at each dressing change (every 1 to 4 days) until the wound has healed. Clinical trials demonstrated that 41.3% of patients treated with the Filsuvez achieved wound closure within 45 days compared to 28.9% who received placebo.

Drug and clinical trial overview

The open-label, controlled, phase 3 VIITAL study evaluated pz-cel in patients ≥ 6 years of age with RDEB and two confirmed C7 mutations. Pz-cel treatment was administered to 11 patients with a total of 43 large (> 20 cm2) chronic wound pairs that had remained open for ≥ 6 months (mean, 6.2 years). Pz-cel was administered as a one-time surgical application on up to six chronic, RDEB wounds. Each pz-cel sheet can treat a wound area up to 40 cm2. Up to six sheets were applied to each patient, depending on the area of existing wounds. Patients received adequate general anesthesia during pz-cel application. Top-line data revealed that, at the 6-month assessment, a significantly greater proportion of wounds achieved ≥ 50% healing from baseline (co-primary endpoint) when treated with pz-cel (81.4%) compared to untreated control wounds (16.3%; p<0.0001). In addition, at 6 months, pz-cel resulted in significantly greater pain reduction associated with wound dressing changes compared to untreated wounds (mean pain reduction from baseline, 3.07 versus 0.9, respectively; p=0.0002; based on a 0 to 10 pain severity scale). Pz-cel was well tolerated. TEAEs included procedural pain, muscle spasms and pruritis. No cases of positive replication-competent retrovirus (RCR), systemic immunologic responses or squamous cell carcinoma (SCC) were reported. Patients were allowed to enroll in a long-term follow-up study.

An open-label, single-site, phase 1/2 trial included seven participants with RDEB, 18 to 45 years of age, with chronic wounds that were present for a mean of 11.2 years (range, 3 to 20 years). Each patient received six grafts with pz-cel. Patients were followed for 4 to 8 years (mean, 5.9 years). Based on investigator global assessment (IGA), at 5 years, 70% of sites treated with pz-cel achieved ≥ 50% wound healing compared to baseline. In addition, no sites with ≥ 50% wound healing were painful or pruritic, compared to 67% of sites with < 50% wound healing (p<0.001) at 5 years.

Pipeline (late-stage development)

NAME MANUFACTURER ROUTE OF ADMINISTRATION MECHANISM OF ACTION PROPOSED/STUDIED

INDICATION

STATUS
Allantoin Amicus Topical Anti-inflammatory agent All subtypes of EB Phase 3
allo-APZ2-OTS Rheacell IV Stem cell therapy RDEB Phase 3
Dabocemagene autoficel (D-Fi) Castle Creek Injected into EB wounds during at least 2 treatment sessions An autologous dermal fibroblast genetically modified with a full-length COL7A1 gene RDEB Phase 3
PTR-01 BridgeBio IV Collagen type VII (C7) (recombinant) RDEB Phase 2

 

References
  1. Abeona Therapeutics announces FDA accepts and grants Priority Review for Pz-cel biologics license application (BLA). November 27, 2023. Available at: https://investors.abeonatherapeutics.com/press-releases/detail/268/abeona-therapeutics-announces-fda-accepts-and-grants. Accessed March 5, 2024.
  2. Centers for Medicare & Medicaid Services (CMS). ICD-10 Coordination and Maintenance Committee Meeting. March 19, 2024. Available at: https://www.cms.gov/files/document/march-19-2024-final-agenda-and-materials.pdf. Accessed March 15, 2024.
  3. ClinicalTrials.gov. A phase 3 study of pz-cel for the treatment of RDEB. Available at: https://clinicaltrials.gov/search?intr=NCT04227106. Accessed March 15, 2024.
  4. ClinicalTrials.gov. A long-term extension study for participants previously treated with pz-cel for the treatment of RDEB. Available at: https://clinicaltrials.gov/search?intr=NCT05708677. Accessed March 15, 2024.
  5. ClinicalTrials.gov. A phase 3b study for the treatment of RDEB in new and previously pz-cel treated patients. Available at: https://clinicaltrials.gov/search?intr=NCT05725018. Accessed March 15, 2024.
  6. ClinicalTrials.gov. A follow-up study to evaluate the efficacy and safety for the patients with allogenic adipose-derived mesenchymal stem cells diabetic foot ulcers (ALLO-ASC-DFU) treatment in phase 1/2 clinical trial of ALLO-ASC- pz-cel. Available at: https://clinicaltrials.gov/search?intr=NCT03183934. Accessed March 15, 2024.
  7. Filsuvez [package insert]. Wahlstedt, Germany; Lichtenheldt GmbH; December 2023.
  8. Johnson V. Second gene therapy for epidermolysis bullosa up for priority review. November 28, 2023. Available at: https://www.cgtlive.com/view/second-gene-therapy-pz-cel-epidermolysis-bullosa-priority-review. Accessed March 13, 2024.
  9. Khanna D, Bardhan A. Epidermolysis bullosa. Updated January 11, 2024. StatPearls [Internet]. Treasure Island, FL: 2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK599531/. Accessed March 13, 2024.
  10. Pfender EG, Lucky AW. Dystrophic Epidermolysis Bullosa. August 21, 2006 [Updated September 13, 2018]. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1304/. Accessed on May 25, 2020.
  11. Shapiro L. FDA approval decision expected in May on RDEB cell therapy pz-cel. November 4, 2023. Available at: https://epidermolysisbullosanews.com/news/fda-decision-expected-may-pz-cel-cell-therapy-rdeb-was-eb-101/?cn-reloaded=1. Accessed March 5, 2024.
  12. Vyjuvek [package insert]. Pittsburgh, PA; Krystal Biotech; May 2023.

Related news

Perspectives

May 20, 2024

Preventing opioid overdoses with naloxone

As prescription opioid overdoses rise in the U.S., the Prime/MRx Special Investigations Unit (SIU) shares how to identify if someone has overdosed and how you can help save a life

Perspectives

May 15, 2024

High-Cost Therapy Profile

Detailed information about Fidanacogene elaparvovec-dzkt Intravenous (IV)

Perspectives

May 15, 2024

June 2024 decisions expected from the FDA

Your monthly synopsis of new drugs expected to hit the market