Krystal Biotech has announced the successful clinical validation of its experimental drug Vyjuvek (beremagene geperpavec) being developed to treat dystrophic epidermolysis bullosa.
Vyjuvek gene therapy, which targets the direct cause of the disease, has demonstrated proper efficacy and safety.
Krystal, which completed an initial public offering (IPO) in August 2017, intends to submit a Biologics License Application (BLA) for Vyjuvek to the U.S. Food and Drug Administration (FDA) in the first half of 2022. By mid-2022, a Marketing Authorization Application (MAA) will go to the European Medicines Agency (EMA).
On the backdrop of good news, Krystal stock quotes jumped by 140%.
What Is Dystrophic Epidermolysis Bullosa
Dystrophic epidermolysis bullosa (DEB) is a rare (1–9 cases per million) and severe genetic disorder in which the skin tissue is so tender and fragile that blisters and tears form at the slightest mechanical impact. This is why patients are called “butterfly children”.
The cause of the disease is a mutation in the COL7A1 gene encoding type VII collagen (COL7), which is responsible for producing the anchor fibrils that bind the epidermis to the underlying dermis. Even light friction of the skin (e.g., from clothing) results in blisters followed by painful separation of the skin.
Open wounds in the skin heal slowly or do not heal at all, often leaving extensive scars and high susceptibility to infection. Chronic inflammation leads to errors in the DNA of the affected skin cells, which in turn causes squamous cell carcinoma. Most patients die before the age of 30, either from the latter or from other complications.
Because type VII collagen is associated with the epithelium of the esophageal lining, patients with dystrophic epidermolysis bullosa may experience chronic scarring, webbing, and esophageal obstruction. Because of trauma to the oral mucosa and esophagus, patients are often severely malnourished and require an artificial feeding tube. Patients suffer from iron deficiency anemia of unclear origin, leading to chronic fatigue.
The most severe form of dystrophic epidermolysis bullosa is recessive, which is caused by homozygous null mutations in the COL7A1 gene (its complete disabling). The pathology also occurs in the dominant form, which is considered milder. Currently, there are no treatments affecting the outcome of both forms of the disease: the therapy standards are limited to palliative care.
Vyjuvek: Mechanism of Action of Beremagene Geperpavec
Beremagene geperpavec gene therapy delivers the functional COL7A1 gene directly to dividing and non-dividing skin cells.
Beremagene geperpavec, made into a topical gel formulation to be applied to the skin, transduces keratinocytes and fibroblasts. After entering the cell nucleus, the vector genome is episomally deposited. Next, COL7A1 transcripts are generated, allowing the cells to produce and secrete the functional protein COL7. The latter assembles into anchoring fibrils that hold the epidermis and dermis together.
Beremagene geperpavec is built on the proprietary Skin TARgeted Delivery (STAR-D) gene therapy platform, which carries out viral vector transfer of copies of working genes based on herpes simplex virus type 1 (HSV-1) for the treatment of dermatological diseases. The HSV-1 used has no replication capability, is not capable of being inserted into the human genome, and allows multiple administrations into the body.
Vyjuvek: Efficacy and Safety of Treatment for Dystrophic Epidermolysis Bullosa
The GEM-3 (NCT04491604) phase 3 (randomized, double-blind, placebo-controlled, multicenter) clinical trial enrolled patients (n=31) aged 6 months or older with a clinical diagnosis of dystrophic epidermolysis bullosa.
Participants were administered beremagene geperpavec and placebo simultaneously. Each subject provides at least one pair of primary target wounds, with one wound from each pair being treated with beremagene geperpavec and the other wound with placebo.
The primary endpoint was complete wound healing after 6 months of treatment.
It was demonstrated that 67% of wounds treated with Vyjuvek were completely healed — versus 22% of wounds treated with placebo: the absolute difference was 45.8% (95% CI: 23.6–68.0; p<0.005).
Vyjuvek similarly outperformed placebo for complete wound healing after 3 months: 71% — vs. 20%: the absolute difference was 51.0% (95% CI: 29.3–72.6; p<0.005).
Vyjuvek administration was characterized by acceptable tolerability. No serious adverse events or discontinuation of treatment were reported.
The immunogenic profile of beremagene geperpavec did not result in a significant change in antibody levels against HSV-1 or COL7.
The fact that between three and six months of treatment of dystrophic epidermolysis bullosa with Vyjuvek recorded a discrepancy in the percentage of closed wounds indicates a subsequent reopening of them. However, the data provided by Krystal are not yet sufficient to draw any definite conclusions.
Krystal hopes that eventually the regulator will allow Vyjuvek to be used in patient-friendly home settings.
According to industry estimates, Vyjuvek’s sales will be slightly short of half a billion dollars by 2026.
Competitors include Filsuvez (oleogel-S10, AP101) from British Amryt Pharma, which is a betulin extract topical gel and is waiting until late February 2022 for the FDA to decide on its approval.
Alternative approaches to the treatment of dystrophic epidermolysis bullosa appear to be less convenient, although no less effective. For example, Abeona Therapeutics deals with the gene therapy prademagene zamikeracel (EB-101): keratinocytes taken from the patient are cultured ex vivo, then transduced with an adeno-associated virus vector carrying the functional COL7A1 gene, and then grown until an epidermal leaf-graft is formed, followed by transplantation.
Castle Creek Biosciences is trying its hand with the gene therapy dabocemagene autoficel (FCX-007): fibroblasts taken from the patient are transduced ex vivo with a lentiviral vector carrying the functional gene COL7A1 and then injected intradermally.
Italian Holostem Terapie Avanzate develops an autologous epidermal graft, Hologene 7, containing epidermal stem cells taken from a patient and transduced ex vivo with a gammaretroviral vector carrying complementary DNA of COL7A1.
BridgeBio Pharma and Phoenix Tissue Repair are working on intravenous replacement therapy in the form of BBP-589 (PTR-01), a recombinant type VII collagen.
Krystal Biotech. GEM-3 phase 3 topline data presentation. November 29, 2021. [PDF]
Krystal Biotech. Corporate presentation. November 2021. [PDF]