Understanding the ABC of Epidermolysis Bullosa Treatment

Rare diseases, constituting a significant health challenge, impact around 30 million individuals in the European Union (EU) and US, each. Within this spectrum, there are more than 1000 rare skin diseases, which are often genetically rooted. Recognized by the World Health Organization (WHO) as conditions affecting fewer than 65 per 100,000 people, these rare disorders underscore a pressing demand for advanced treatments that address the root causes rather than merely alleviating symptoms. Bridging this gap remains crucial to enhance the quality of life for those grappling with these less prevalent yet profound health issues. In this article on epidermolysis bullosa treatment, we will take a closer look at the fundamentals of Epidermolysis Bullosa, a rare skin genetic disorder, and explore the landscape of both approved and clinical therapies.

Epidermolysis Bullosa: Understanding the Fundamentals of This Rare Skin Disorder

Epidermolysis bullosa (EB) is a rare genetic disorder causing various degrees of skin and mucous membrane fragility. It results from genetic mutations disrupting any one of the essential 16 skin proteins, making the skin prone to painful blisters triggered by even minor friction. Being an inherited disorder, the symptoms usually appear at birth as the proteins essential for skin integrity are absent, reduced, or abnormal. These blisters can occur both externally and internally. In mild cases, blistering may primarily affect the hands, feet, knees, and elbows. However, severe cases often involve widespread blistering and wound formation, leading to vision loss, loss or fusion of toe and fingers nails, difficulty swallowing, breathing problems and in some cases organ failure and aggressive squamous cell carcinoma. Children living with EB are often known as The Butterfly Children because their skin is as sensitive as the butterfly wings.

Depending on the layer of skin in which the formation of blisters occurs, EB is classified into four major types which have been briefly described in the table below:

Type of EB	Skin Layer Involved	Gene(s) Involved	Type of Inheritance	Number of Clinical Subtypes
EB Simplex (EBS)	Epidermis	KRT5 KRT14 PLE KLHL24 DST EXPH5 CD151	Mostly dominant but can be recessive	~14
Dystrophic EB (DEB)	Dermis Below the Basement Membrane	COL7A1	Recessive or dominant	~11
Junctional EB (JEB)	Basement Membrane	LAMA3 LAMB3 LAMC2 COL17A1 ITGA6 ITGB4 ITGA3	Recessive	~8
Kindler Syndrome	Mixed Skin Cleavage Pattern	FERMT1	Recessive	--

Epidermolysis bullosa is caused by an inherited gene. The disease gene can be inherited from one parent who has the disease (autosomal dominant inheritance) or from both parents (autosomal recessive inheritance). The various inheritance patterns have been summarized in the image below. Notably, Dystrophic EB, which has been mentioned in the table above, is divided into two major types depending on the inheritance pattern: recessive dystrophic epidermolysis bullosa (RDEB) and dominant dystrophic epidermolysis bullosa (DDEB).

Bridging the Gap: Addressing Critical Needs in the Battle Against Epidermolysis Bullosa

EB poses a significant global health care challenge, with treatment costs in the US reaching up to USD 300,000 per year for severely affected patients. Monthly wound care supplies alone are estimated at over USD 10,000. The urgency is emphasized by the short life expectancy, ranging from early infancy to around age 30. Traditional approaches to EB management are focused on symptom relief through wound care, pain management, and infection prevention, using various medications, such as antihistamines, analgesics and corticosteroids. Some companies are developing advanced wound care dressings for epidermolysis bullosa wounds. Such as Mepitel from Molnlycke Health Care, which is a non-adherent silicone dressing used in EB wounds. However, these approaches do not address the root genetic causes of EB, creating a need for innovative therapies. The industry is currently exploring pathogenesis-directed approaches, leading to the evaluation of gene therapies (gene replacement, gene editing, RNA-based therapy, natural gene therapy), cell-based therapies (fibroblasts, bone marrow transplantation, mesenchymal stromal cells, induced pluripotential stem cells), recombinant protein therapies, and small molecule and drug repurposing approaches. Some of these approaches have been successful and approved, while others are undergoing clinical trials, offering promising epidermolysis bullosa treatment avenues.

Discover Below the Details on Current Status of Epidermolysis Bullosa Treatment and Market

This article highlights the Approved Drugs, Business Outlook and Clinical Trial Landscape within the Epidermolysis Bullosa Treatment Market.

[A] Approved Drugs for Epidermolysis Bullosa: Unlocking Hope for the EB Patients

Until recently, there were no therapies approved specifically for Epidermolysis Bullosa treatment. However, approvals of EB therapies commenced across various regions in 2022. Details on the various approved drugs has been mentioned below:

1) Drug: JACE

• Developer: Subsidiary of
• Drug Snapshot: JACE comprises of autologous epidermal cell sheets produced from keratinocytes derived from a patient's own skin tissue. This innovative approach involves grafting cultured epidermal cell sheets onto wounds, facilitating engraftment / epithelialization, and ultimately wound closure. JACE is indicated for use in patients with extensive burns when sufficient donor sites for autologous skin grafts are not available and the total area of burns is 30% or more of the total body surface area. Each container of JACE includes a single cultured epidermal cell sheet, making it a pivotal solution for addressing extensive burns.
• Region of Approval: Japan
• List of Major Events in Chronological Order:
  • March 2011: Received Orphan Medical Device Designation by Japan's Ministry of Health, Labor and Welfare (MHLW) for EB
  • May 2012: Started a clinical trial of Autologous Cultured Epidermis JACE for EB
  • March 2018: Submitted supplemental application to MHLW seeking the approval of Autologous Cultured Epidermis JACE 
  • December 2018: Received government approval to culture and sell Autologous Cultured Epidermis JACE for treating Dystrophic EB and Junctional EB in Japan

2) Drug: Filsuvez / Oleogel-S10

• Developer: Acquired by
• Drug Snapshot: Filsuvez is a topical herbal gel mixture featuring dry extracts from two bark species, namely Betula pendula and Betula pubescens, along with hybrids of both. This gel, containing birch bark extract as the active substance, assists in the growth and movement of outer skin layer cells (keratinocytes) promoting effective wound healing. Specifically designed for use in adults and children aged 6 months or older, Filsuvez is one of the few topical drugs targeting EB.
• Region of Approval: US, Europe and UK
• List of Major Events in Chronological Order (geography-wise):

1. Geography: US

• June 2021: Granted Priority Review by the FDA to Amryt Pharma’s application for seeking approval 
• February 2022: Rejection of the application by the FDA, asking the company to submit additional confirmatory data to prove the topical treatment’s efficacy
• June 2022: Filing of a formal dispute resolution request by Amryt Pharma with the FDA
• January 2023:  Chiesi Farmaceutici bought Amryt Pharma for USD 1.25 billion upfront and contingent payment of up to USD 225 million if the drug met certain milestones, including winning an FDA approval
• December 2023: Received approval from the FDA for treating Dystrophic EB and Junctional EB in the US

2. Geography: Europe and UK

• February 2011: Received Orphan Drug Designation by European Commission (EC) for EB
• April 2022: Received a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP) for the approval of the drug in Europe
• June 2022: Received approval from the European Medicines Agency (EMA) for treating dystrophic EB and junctional EB in the European Union (EU); the company started drug roll-out to Germany first
• July 2022: Partnered with ExCEEd Orphan in order to seek reimbursement, as well as distribute and market the drug in 17 Central and Eastern Europe (CEE) countries
• September 2022: Received Marketing Authorization Approval and Orphan Drug Designation from the Medical Healthcare & Products Regulatory Agency (MHRA) in Great Britain
• August 2023: Received approval from National Institute for Health Care and Excellence (NICE) to treat skin wounds associated with dystrophic EB and junctional EB

3) Vyjuvek / beremagene geperpavec-svdt / B-VEC

• Developer:
• Drug Snapshot: Vyjuvek is the first gene therapy which in intended to be applied topically to the skin, rather than infused. The treatment involves delivering two copies of COL7A1 gene directly to the wounds directly. The COL7A1 gene is crucial for the production of a protein essential in forming anchoring fibrils, which bind the dermis to the epidermis. By deploying an engineered herpes simplex virus, the drug selectively targets the epithelial cells of the wound. Given that the C7 gene isn't permanently integrated into the patient's DNA, it is eventually lost, necessitating re-treatment. As a result, unlike traditional gene therapies which are administered just once, Vyjuvek is required to be re-dosed. Recognizing its significance, both the FDA and the EMA have granted the drug Orphan Designation for the treatment of dystrophic EB.
• Region of Approval: US, Europe and Japan
• List of Major Events in Chronological Order (geography-wise):

1. Geography: US

• August 2022: Received acceptance from the FDA for the Biologics License Application (BLA) submitted by the company, and the grant of Priority Review designation, with the Prescription Drug User Fee Act (PDUFA) action date as February 2023
• May 2023: Received approval from the FDA for the treatment of patients six months of age or older with either recessive or dominant dystrophic EB; the company raised USD 160 million through a private placement to fund the Vyjuvek launch and other future operations

2. Geography: Europe

• September 2022: Received a positive opinion from the EMA Pediatric Committee on the Pediatric Investigation Plan for Vyjuvek 
• November 2023: Received validation of its Marketing Authorization Application (MAA) for review by the Committee for Medicinal Products for Human Use (CHMP); the company is anticipating seeking approval in the region in the second half of 2024

3. Geography: Japan

• December 2023: Received Orphan Drug Designation from the MHLW; the company is anticipating seeking approval in Japan by 2025

[B] Business Outlook on Epidermolysis Bullosa: Exploring the Opportunities and Challenges

The section below highlights various trends that are shaping up the trajectory of epidermolysis bullosa treatment and market dynamics.

1) Limited Patient Pool Prompts Implementation of Governmental Incentivization Strategies, Fostering Drug Development Efforts to Address the Unmet Need in the Epidermolysis Bullosa Treatment Market

Epidermolysis bullosa, impacting 1 in 20,000 births globally with around 500,000 affected individuals worldwide, is unequivocally a rare disease. With less than 200,000 patients in the US, fewer than 5 patients per 10,000 inhabitants in the European Union and below 50,000 patients in Japan, the rarity of this disease creates challenges in recruiting participants for clinical trials. This obstacle hinders the demonstration of drug efficacy and safety. Recognizing this, governments across the globe provide incentives to encourage the development of drugs for rare disorders. For instance, the FDA’s Orphan Drug Act provides vital incentives, including tax credits (50% off the clinical drug testing cost awarded upon approval), 7 years of market exclusivity, and waiver of NDA / BLA application fee for companies developing drugs for patients suffering from rare disorders in the US. In addition, it awards a Priority Review Voucher (PRV) to players developing drugs for rare indications. The PRV can either be sold to another drug sponsor or can be redeemed later to receive priority review from FDA with a targeted review time of 6 months, rather than the 10-month standard review, for a selected drug application. The potential for additional revenue from either selling the PRV or marketing a drug about 4 months sooner could provide an incentive for drug sponsors to develop drugs for uncommon medical conditions. Notably, in August 2023, Krystal Biotech's sale of a PRV for USD 100 Million underscored the significance of this incentive.

2) Unaffordability Caused by High Costs of Disease Modifying Therapies Prompts Drug Developers to Adopt Price Capping and Discounting Strategies

Since therapies targeting rare disorders serve smaller patient populations, their cost of development is shared by fewer patients. As a result, the drug developers generally price them high to ensure profitability. Further, novel modalities, specifically gene therapies, incur relatively higher expenses owing to the complexity of producing, handling, and controlling viral vectors. It is interesting to note that Krystal Biotech has set the annual cost of Vyjuvek, a gene therapy, at USD 630,500 per patient, assuming an average usage of 26 vials per year priced at USD 24,250 each. In order to drive the adoption of this expensive therapy, Krystal is implementing an innovative payment model, offering commercial payer clients a cap of USD 900,000 annually per patient. This volume based incentivization is likely to be indirectly beneficial for patients requiring a larger quantity of vials. In contrast to gene therapies, the list price for Filsuvez, a topical small molecule drug, is only around USD 350 per 23.4g in the UK. To drive adoption, the company offers a discounted access scheme for the National Health Service (NHS), although the specific discount remains confidential according to National Institute for Health and Care Excellence (NICE).

3) Government Backed Reimbursement of Epidermolysis Bullosa Treatment Therapies to Catalyze the Adoption of Expensive Therapies

Governments globally are crucially involved in facilitating reimbursement for life-saving medications, ensuring not only patient access to essential treatments but also enabling companies to market their high-priced drugs to those who may face affordability challenges. For instance, the US government is actively backing reimbursement of Vyjuvek for dystrophic EB patients. Medicaid, designed for low-income individuals, ensures Vyjuvek is attainable at a discounted rate of USD 485,000. The Centers for Medicare and Medicaid Services (CMS) implemented a permanent J-code (J3401) on January 1, 2024, simplifying billing and reimbursement processes to foster efficient and accurate support for patients and rare drug development companies alike.

4) With Vyjuvek’s Approval, The Prospect of Expanding Gene Therapy to Outpatient Care May Now be More Attainable Than Ever Envisioned

Bringing gene therapy to outpatient care is a game-changer in healthcare, giving patients the chance for personalized treatment outside the hospital. Currently, Vyjuvek’s administration requires a healthcare provider who applies the gel to the open wounds and wraps the area with a hydrophobic dressing. This is because the administration process involves an intricate syringe filling step, although the therapy is applied in a droplet pattern without penetrating the skin. In the future, there is a possibility that administration of Vyjuvek would be done in an outpatient setting as more patients become comfortable with self-administering the product. The potential self-application of this epidermolysis bullosa treatment, which requires frequent administration, would translate to substantial time and cost savings for the patient, thereby driving adoption.

5) With Few Molecules Advancing to Late Stages of Clinical Trials, the Quest for More Transformative Epidermolysis Bullosa Treatment Continues

There are approximately over 20 companies which are evaluating therapies for epidermolysis bullosa across various stages of development. The table below highlights some notable players with pipeline drugs undergoing advanced-phase trials.

Company	YoE	HQ	Employee Count	Drug	POD	NCT
Abeona Therapeutics	2015		51-200	EB-101/ LZRSECol7A1 engineered autologous epidermal sheets (LEAES)	Phase III	NCT05725018
Castle Creek Biosciences	2020		11-50	FCX-007/D-Fi/ dabocemagene autoficel	Phase III	NCT04213261
RHEACELL	2003		51-200	allo-APZ2-OTS injection/ allogeneic ABCB5-positive dermal mesenchymal stromal cells	Phase III	NCT05838092
Holostem	2008		11-50	Epidermal stem cells transduced with a LAMB3-gamma retroviral vector	Phase II/III	NCT05111600

In addition to the aforementioned epidermolysis bullosa treatment, several other drugs are being evaluated in phase II trials. An inexhaustive list of such drugs, along with their developer names, has been presented below:

• S-005151 (Redasemtide Trifluoroacetate), being developed by StemRIM and Shionogi 
• PTR-0, being developed by BridgeBio and Phoenix Tissue Repair 
• VPD-737, being developed by Vyne Therapeutics (formerly Menlo Therapeutics) 
• Adipose stem cell therapy, being developed by Anterogen
• INM-755 Cannabinol cream, being developed by InMed Pharmaceuticals

Developing drugs for rare disorders is inherently challenging due to limited patient populations, a lack of prior research, regulatory complexities, economic viability concerns, and the scientific intricacies involved. Consequently, companies invest substantial resources in research, development and clinical trials. Unfortunately, discontinuation in advanced stages, often due to unforeseen challenges or insufficient efficacy, can result in substantial losses for the companies involved. It is worth highlighting that RGN-137 by Regenrx / Lenus Therapeutics was discontinued after phase II trial study and SD-101 cream by Scioderm was discontinued after phase III clinical investigation.

At Roots Analysis, we can provide in-depth research and analysis on the business outlook within the epidermolysis bullosa treatment market.

[C] Clinical Trial Landscape: Taking a Closer Look at the Ongoing R&D Efforts

In order to analyze the pipeline activity within this domain in detail, we downloaded the completed and ongoing interventional clinical trials from clinicaltrials.gov. 15 terminated and withdrawn trials were removed from the list. Currently, 68 clinical trials are active for epidermolysis bullosa treatment. The count of trials does not correspond to the number of drugs, as a single drug may have been evaluated across different phases of a trial. The image below presents insights on the clinical trials that have been conducted / are being conducted for epidermolysis bullosa treatment:

We have briefly summarized some insights related to the clinical landscape for epidermolysis bullosa treatment below.

1. An Average of 25 Patients in EB Clinical Trials Highlight the Need for Better Patient Recruitment in Epidermolysis Bullosa Treatment Trials

As of now, a total of 1,673 patients have been enrolled or are currently undergoing recruitment in interventional trials for EB. Apart from the challenge of a limited patient pool, various factors may hinder EB patients' participation in clinical trials, including study duration, competition with ongoing trials, exclusion criteria, travel costs, additional clinical tests, family commitments, and misconceptions about cell and gene therapies. Facilitating patient recruitment can be achieved through collaboration with clinical-network partners, with organizations like EB Client serving as mediators, and entities such as DEBRA International actively contributing to the development of long-term clinical practice guidelines (CPGs) for EB. Notably, Amryt Pharma’s phase III study of Oleogel-S10, completed in 2022, achieved the highest patient enrollment to date, with 223 participants. More than 40% of the trials have enrolled less than 10 EB patients, highlighting the need for a better patient recruitment process to evaluate the therapies for this rare disorder.

2. Repurposing Emerging as a Potential Therapeutic Approach to Provide Symptomatic Relief to EB Patients

Drug repurposing involves discovering new applications for existing treatments, offering a quicker and more cost-effective way to expand treatment options for individuals with EB compared to developing entirely new treatments. Demonstrating the effectiveness of these repurposed drugs necessitates well-designed clinical trials before they can be officially licensed for use in the EB patient population. Several non-industry entities are actively engaged in conducting such clinical trials. For example, the University of Southern California is investigating the antibiotic Gentamicin, which is already approved for treating various bacterial infections such as meningitis, blood infections, and serious urinary tract infections. Additionally, Stanford University is exploring the potential of Sirolimus, a drug approved for lymphangioleiomyomatosis, and Northwestern University is evaluating Dupilumab, an approved treatment for moderate-to-severe atopic dermatitis. These initiatives signify collaborative efforts beyond the pharmaceutical industry to repurpose existing drugs for the benefit of individuals with EB.

3. Companies in Pursuit of Elevating Competitiveness by Dual-region Clinical Validation

Demonstrating safety and efficacy in both Europe and the USA can provide a competitive advantage over drugs that have only been tested in one region. It may also position the company as a global player in the rare disease treatment space. Currently, over 95% of trials are being conducted in a single region, such as the US or Europe, since players want to test the waters before expanding globally. However, some pioneers are venturing beyond. Notably, RHEACELL (NCT03529877) and Amryt Research (NCT03068780) are actively conducting clinical trials in both North America and Europe, showcasing a strategic move toward broader geographical reach.

4. Envisioning the Future Clinical Trials with Potential Progress on Gene Editing Approaches

In November 2023, Healiva and C4U Corporation joined forces to develop CRISPR-Cas3-based therapeutic solutions for Epidermolysis Bullosa. C4U Corporation, a Japanese biotech company, specializes in gene therapies for rare diseases, utilizing its CRISPR-Cas3 gene editing platform, which has been validated in vitro and in vivo. Healiva's proprietary technology platform focuses on acute and chronic wound therapies, employing an affordable end-to-end approach that combines cell therapies, autologous (EpiDex®), and allogeneic cell therapy for personalized and precision medicine in wound care. The future of Epidermolysis Bullosa treatment holds great promise with ongoing advancements in gene editing and other innovative therapeutic approaches anticipated to transform the landscape of care for individuals affected by this condition.

At Roots Analysis, we can provide in-depth analysis on active, ongoing, completed and discontinued clinical trials for epidermolysis bullosa treatment. For personalized assistance in identifying the most relevant solutions based on your specific criteria, please don't hesitate to reach out to us at sales@rootsanalysis.com.

Sources

Source 1: https://www.drugs.com/condition/dystrophic-epidermolysis-bullosa.html
Source 2: https://www.debra.org/about-eb/approved-treatments-eb
Source 3: https://clinicaltrials.gov/
Source 4: https://epidermolysisbullosanews.com/news/new-partners-using-technology-develop-eb-gene-editing-therapy/
Source 5: https://www.cgtlive.com/view/bvec-vyjuvek-gene-therapy-approved-dystrophic-epidermolysis-bullosa
Source 6: https://www.debra.org/