First Ever Topical Gene Therapy Approved For “Butterfly Disease” Children

The Food and Drug Administration (FDA) has approved a transformational treatment for one of the most tragic of pediatric skin diseases. The first-of-its kind topical gene therapy for Epidermolysis bullosa (EB) is expected to be available in the United States in the third quarter of 2023 under the name is VYJUVEK according to Krystal Biotech (KRYS.O). EB is a rare, debilitating skin disorder characterized by fragile skin that blisters and tears easily. The young people affected by EB are sometimes called “Butterfly Children” because of their highly fragile skin. Current treatment options primarily focus on managing symptoms and preventing infection, but the groundbreaking gene therapy offers new hope.

“This approval marks what we believe is the beginning of the end of EB. Every member of this community looks forward to the day we no longer lose loved ones to this disease,” said Emily Kubik, whose young daughter Elodie has recessive dystrophic EB, one of the more severe subtypes. “Unfortunately, the disease impacts internal organs as well, including Elodie’s mouth and esophagus, so managing her daily life can be quite complicated,” said Emily. “Knowing that we now have a tool that can actually help her gives us much hope.”

The new drug’s scientific name is Beremagene Geperpavec (B-VEC) and represents several important breakthroughs. B-VEC is the first approved gene therapy for EB. It is also the first redosable gene therapy, and the first to be applied directly to the skin. The novel treatment is an innovative topical gel gene therapy that utilizes an engineered herpes simplex virus (HSV) to target the underlying genetic cause of EB and facilitate the repair of skin collagen. This promising approach has the potential to revolutionize the treatment landscape for children suffering from this challenging condition.

“It was an exciting and emotional day for my family,” said Heather Fullmer whose son Mikey is affected by the rare severe form of the disease called dystrophic EB. “Since Mikey was about 5 years old, he has been talking about when an EB potion would be created. When we started our day, we were cautiously optimistic because as a parent of a medically fragile child, you don’t want to offer false hope to your child. So when we received the news of the approval and told Mikey, it was a very special moment.”

Epidermolysis Bullosa and Collagen Deficiency

Patients with dystrophic EB disorder suffer from open wounds, causing skin infections and are at an increased risk of vision loss, scarring and skin cancer. Most patients rarely survive beyond 30 years of age. EB is a group of inherited disorders characterized by genetic mutations that affect the proteins responsible for maintaining skin integrity. One of the key components is collagen, which provides structural support to the skin. Mutations in the genes responsible for collagen synthesis and formation result in fragile skin prone to blistering, causing significant pain, impaired wound healing, and a decreased quality of life for affected children. The topical gel gene therapy aims to address this collagen deficiency at its core, providing a transformative treatment strategy. About 9,000 to 10,000 people suffer from dystrophic epidermolysis bullosa globally, including a U.S. population of about 3,000 patients, according to Krystal Biotech.

Mechanism of Topical Gene Therapy

“The wounds heal quickly but, even more importantly, they stay closed,” Peter Marinkovich, MD, director of Stanford Medicine’s Blistering Disease Clinic has said in previous interviews. “The therapy strengthens the skin and breaks the painful and destructive cycle of wound opening and closing that patients with epidermolysis bullosa experience.”

Topical B-VEC treatment begins with the application of the specially formulated gel containing the engineered HSV. The gel facilitates the virus’s penetration through the layers of the skin, targeting the affected cells. Once inside the cells, the virus releases the corrective gene, which integrates into the patient’s cells, effectively replacing the defective gene responsible for collagen deficiency. The corrected gene then instructs the cells to produce healthy collagen, facilitating the repair and strengthening of the skin’s structure.

The gel-based gene therapy presents several advantages over traditional treatment approaches for epidermolysis bullosa. Firstly, it addresses the root cause of the disorder by delivering a corrected gene directly to the affected cells, offering the potential for long-lasting and transformative results. Moreover, the innovative topical application minimizes systemic side effects, reducing the risks associated with invasive procedures and some systemic gene therapies. The gel is stable at room temperature and can be applied without specialized expertise during routine bandage changes — key advantages for patients worldwide who have difficulty accessing specialized medical care, Dr. Marinkovich said.

Venture Philanthropy Spurred Innovation

Patient advocates such as the Fullmer family have spent years raising awareness and funds for research through work with the non-profit EB Research Partnership (EBRP), and its unique Venture Philanthropy model. EBPR leverages concepts from principal investing and applies them towards achieving patient-oriented goals. EBRP’s Venture Philanthropy business model has been highlighted for its leadership by Harvard Business School, Yale University, and MIT in helping to fast-track both potential cures for EB as well as therapies that could affect thousands of other rare diseases. EBRP has been able to generate a more than double return on its investment and reinvest that capital back into more EB projects.

“This approval shows that our model can work, and it also showed that a company was able to carve a path and demonstrate to other industry peers that it can be done. We have a reinvigorated hope that the approval will generate more interest from new industry partners,” said Fullmer.

EBRP invested in Krystal Biotech in 2017 via a private placement of common stock, and as part of the stock purchase agreement, the biotech committed to commence a Phase I clinical trial of VYJUVEK. The funding followed the highly competitive application and screening process overseen by EBRP’s Scientific Advisory Board (SAB), which is composed of leading scientists and physicians, according to EBRP Chief Executive Officer Michael Hund.

B-VEC is an engineered herpes simplex virus that restores collagen 7 expression which provides strength and integrity to the skin. The gel is applied topically and needs to remain in place for 24 hours and be applied once a week to open wounds. The therapy shows long term durable healing at 3 and 6 months. Clinical trials have shown B-VEC to be safe when applied consistently for over 3 years, and also demonstrated improved height, weight, and serum albumin, which implies better liver and kidney function and nutrient absorption.

Gene therapy using HSV as a delivery vector has been extensively studied and modified for therapeutic purposes due to its unique ability to infect and deliver genetic material to human cells. In this innovative approach, a modified HSV acts as a carrier for targeted gene delivery. The virus is engineered to carry the correct form of the mutated gene responsible for collagen synthesis and deliver it directly to the affected skin cells. The rare genetic blistering skin disease is caused by mutations in COL7A1, which encodes type VII collagen (C7). B-VEC is a unique topical herpes simplex virus type 1 (HSV-1)–based gene therapy designed to restore C7 protein by delivering COL7A1, according to researchers.

The development of the innovative “EB potion” gene therapy holds great promise for the treatment of epidermolysis bullosa and the repair of collagen deficiency in pediatric patients. By targeting the underlying genetic cause and facilitating the production of healthy collagen, this therapy offers a transformative approach that may significantly improve the lives of children affected by this challenging condition. EBRP’s uniquely successful Venture Philanthropy model has helped bring forward an innovative therapy that offers renewed hope for those living with epidermolysis bullosa, paving the way for a brighter future with improved treatment options and quality of life.