FDA Issues CRL to Abeona for Potential RDEB Cell Therapy

As reported by sister publication CGTLive Monday night, the US Food and Drug Administration (FDA) issued a complete response letter (CRL) to Abeona Therapeutics for the company’s biologic license application (BLA) for prademagene zamikeracel (pz-cel).¹ The novel cell-based therapy is under development for the treatment of recessive dystrophic epidermolysis bullosa (RDEB), a rare, inherited, debilitating skin disease associated with severe outcomes including increased risk of skin cancer and death.

Abeona stated on Monday the CRL entailed an FDA request for additional information regarding Chemistry Manufacturing and Control (CMC) requirements being “satisfactorily resolved” prior to a potential approval for pz-cel. The company stated they submitted plans to the FDA with the commitment to provide the relevant CMC data prior to a potential BLA approval.²

“The information needed to satisfy the CMC requests in the CRL pertains to validation requirements for certain manufacturing and release testing methods, including some that were captured in the observations during the FDA’s pre-license inspection,” they wrote. “The CRL did not identify any deficiencies related to the clinical efficacy or clinical safety data in the BLA, and the FDA did not request any new clinical trials or clinical data to support the approval of pz-cel.”

Abeona chief executive officer Vish Seshardri expressed surprise and disappointment with the CRL, but said the company is working to remediate the issue all the same.

“We are already hard at work generating the additional CMC information, and we expect that all of FDA’s requests will be addressable in a reasonable timeframe,” Seshandri said in a statement. “We anticipate completing the BLA resubmission in the third quarter of 2024 with necessary updates to fully satisfy all the deficiencies outlined in the CRL.”

Earlier this year, HCPLive spoke with a trio of experts regarding pz-cel, its supporting phase 3 data from the VIITAL trial, and the novel therapy’s potential role in the treatment of RDEB.

Joyce Teng, MD, PhD, professor of dermatology at Stanford University, explained how the use of genetically corrected cells derived from patients could create for the opportunity to provide a “true, personalized approach” to managing RDEB. “The genetically corrected keratinocytes will be growing into a sheet of skin without the genetic defect, then grafted back onto the individual where the initial cells were derived from, to correct the area where the disease is affected,” Teng said.³

That said, skin graft procedures with pz-cel will have to be performed in skilled tertiary centers, she explained.

“But the advantage of that kind of approach to some of these data are already in the public domain—that the durability of these skin grafts are quite good compared to other products,” Teng said. “It can probably tailor to patients that have, for instance, a chronic wound in a particular location of their body that's really, really difficult to heal.”

The potential application of pz-cel to treat patients with RDEB comes at a time when gene therapy beremagene geperpavec (B-VEC; VYJUVEK) was recently approved to treat DEB; Amy Paller, MD, chair of dermatology at Northwestern Medicine, discussed with HCPLive how they may be used in unique ways.⁴

“Aging, older individuals and those maybe a little bit slower in general to heal, those who have more of these larger (wound) areas, maybe are really who we would more readily designate for these (pz-cel) transplants,” Paller said. “And obviously, there may be those who can't be putting on (the topical) every week, because it's complicated, right?”

Paller explained that patients will experience more inflammation and a slower healing process as they age; the properties of pz-cel’s clinical benefit may be especially pronounced in the older RDEB patient population.

“The deficiency in type VII collagen affects both the adhesive properties of skin—because it is a major component of the anchoring fibrils...but also collagen VII can be involved as an extracellular matrix component that cells can migrate on,” Paller said. “There's so many reasons why it's problematic.”

In the event the BLA is eventually approved by the FDA, there will likely be a rollout phase to ensure the grafting procedure is handled optimally, explained investigator Peter Marinkovich, MD, director of the Stanford Bullous Disease and Psoriasis Clinics.⁵

“You want to have very good EB surgeons and anesthesiologists who understand EB patients, who know how to manage their fragile airways effectively to try to minimize the risk,” he explained. “And then you also want the patients to be hospitalized and treated during their medical care by people who are familiar with EB, who will handle the skin gently and not incur blistering and try to give the patient as good a hospital experience as possible. “

References

1. ^{Stansfield N. FDA Issues CRL for Abeona's Epidermolysis Bullosa Gene Therapy Pz-Cel. CGTLive. Published April 22, 2024. https://www.cgtlive.com/view/fda-issues-crl-abeona-epidermolysis-bullosa-gene-therapy-pz-cel}
2. ^{Abeona. Abeona Therapeutics Provides Regulatory Update on Pz-cel. Press release. Published April 22, 2024. https://investors.abeonatherapeutics.com/press-releases/detail/276/abeona-therapeutics-provides-regulatory-update-on-pz-cel}
3. ^{Kunzmann K. Comparing New Therapies for Dystrophic Epidermolysis Bullosa. HCPLive. Published March 6, 2024. https://www.hcplive.com/view/comparing-therapies-dystrophic-epidermolysis-bullosa}
4. ^{Kunzmann K. Amy Paller, MD: What Pz-cel, B-VEC Each Bring to Recessive DEB. HCPLive. Published March 6, 2024. https://www.hcplive.com/view/amy-paller-pz-cel-b-vec-recessive-deb}
5. ^{Kunzmann K. The Prospect of Pz-cel in RDEB Treatment, with Peter Marinkovich, MD. HCPLive. Published March 6, 2024. https://www.hcplive.com/view/pz-cel-rdeb-treatment-peter-marinkovich-md}