Epidermolysis Bullosa (EB) is a rare genetic skin disorder that causes extreme skin fragility leading to recurrent blister formations or erosions in response to little or no apparent trauma. People born with this disease have defective or lack the anchoring filaments that facilitate the adhesion of the epidermis, the outer layer of the skin to the inner dermal layers of the skin. Any skin trauma that creates friction between the skin layers results in painful blister formation and open wounds. Mild form of the disease may be limited to the hands and feet and the severe forms can affect generalized areas of the skin resulting in deformities and disability. The condition is also associated with significant pain and pruritus in most patients. More severe forms of EB are often lethal during childhood, typically because of overwhelming infection. Those who survive into adulthood are at high risk of developing squamous cell carcinomas, which can prove fatal. There are three main types of inherited EB (Simplex, Dystrophic, and Junctional) and, based on the type, the symptoms can range from mild to disabling or life threatening. EB is estimated to affect 20,000 to 50,000 people in the United States (U.S.), mostly children and is acknowledged as an orphan disease by the U.S. Food and Drug Administration (FDA). There is currently no cure or effective treatment; care is supportive and palliative. Better treatments producing clinically significant benefits are desperately needed for this serious disease. Scioderm, Inc. is developing SD-101 (proprietary cream formulation containing various concentrations of allantoin) for EB. In this grant application, Scioderm is proposing to conduct a Phase 2B open-label extension (OLE), multi-center study (SD-004) to assess the continued effectiveness and long-term safety of SD-101 cream (SD-101-6.0) use in the treatment of lesions in subjects with EB. This study is an open label roll-over study, for which all patients who complete the ongoing Phase 2B Study (SD-003), are eligible to participate. The primary purpose of this study is assessment of long-term safety of use of SD-101-6.0 in EB patients. The investigators expect SD-101 to be clinically safe and effective based on results obtained from two clinical studies: (1) a compassionate use study involving 44 EB patients using SD-101-1.5 (containing 1.5% allantoin), and (2) an open-label FDA approved study in 8 pediatric EB patients using SD-101-3.0. The compassionate use study, involving 44 EB patients using SD-101-1.5 treatment, showed a reduction in coverage of blisters and lesions and a reduction in formation of new blisters in EB patients. In the open-label FDA approved Phase 2 study at Northwestern University with SD-101-3.0, complete closure of chronic target lesions was seen in the majority of patients within the first month (88%), with 5 of 7 lesions (71.4%) closed within a period of 3 to 10 days after initiation of application of cream to the lesions. SD-101-3.0 was also shown to significantly reduce body surface area (BSA) coverage of blisters and lesions across all EB subtypes. In addition, topical use of SD-101-3.0 was shown to have the potential to improve both pain and pruritus associated with the blisters and open wounds. A recently completed Phase 1 double blinded, parallel, vehicle-controlled study local tolerance study with SD-101-3.0, SD-101-6.0, and SD-101-9.0 revealed that the cream is well tolerated at all doses. For effective topical, locally delivered pharmaceutical products, both the active ingredient and the formulation are equally important. Scioderm has developed an innovative proprietary formulation containing allantoin which overcomes the low solubility of allantoin at neutral pH and its intrinsic instability. This formulation allows the emulsification and stability of allantoin at concentrations up to 9%, whereas allantoin is usually pharmaceutically unstable at concentrations above 0.5%. In addition, a suitable formulation was developed that allows allantoin to be delivered across various skin barriers in a dose related manner, without systemic absorption. Allantoin in SD-101 has demonstrated stability for over three years at room temperature, whereas in the absence of this stabilization, a viable shelf-life of less than a few months is achievable. Allantoin has been designated as an orphan product (designation 01-1510). SD-101 has also received breakthrough therapy (BT) designation by the FDA for the treatment of patients with inherited EB, which may enable expedited development and approval of SD-101 for EB patients. In addition, the Dermatology division of FDA has agreed to waive the majority of the long-term toxicology studies, including carcinogenicity and reproductive studies. Agreement with the division was also reached regarding the study design for the pivotal program, including the definition of the primary endpoint. Lastly, the size of the safety database needed to support registration has also been agreed with the Division. This grant will be used to assist in the completion of the pivotal clinicl program necessary for registration and approval of SD-101 for the treatment of skin effects across the various types of EB.

Public Health Relevance

The human skin consists of two primary layers: an outermost layer called the epidermis which is thin, tough and waterproof and works as a shield to repel damaging bacteria and viruses. The layer underneath called the dermis cushions the body from stress and strain. In individuals with healthy skin, there are protein anchors between these two layers that prevent them from moving independently from one another (shearing). In people born with Epidermolysis Bullosa (EB), a rare genetic connective tissue disorder, the two skin layers lack the protein anchors that hold them together, resulting in extremely fragile skin. Because the skin is so fragile, even a minor injury (like rubbing or pressure) will separate the layers of the skin and form blisters and painful sores. Infection and non-healing wounds are serious problems for EB. EB commonly causes blister and lesion formation on the skin but it can also affect the mouth, esophagus, lungs, muscles, eyes, nails and teeth. There are three main types of inherited EB (Simplex, Dystrophic, and Junctional) and, based on the type, the symptoms can range from mild to disabling or life threatening. People diagnosed with the mild form of the disease lead a painful life with blisters mainly on the hands and feet, but their disease is not typically disfiguring or lethal. In more severe forms, there is generalized blistering of the skin, and the skin appears to be peeled off. The fingers may fuse and hands contract, reducing movement. Chronic damage from the condition often leads to development of skin cancer, which typically develops with patients in their 20's or 30's and can be lethal. There is currently no cure or effective treatment for EB. Treatment is largely prophylactic, and involves protecting the skin from damage, relieving itching that occurs with healing of the wounds, applying protective bandaging with use of barrier creams like Vaseline or Aquaphor to prevent adhering of the bandages to the skin and preventing infection, controlling pain with medications, and using antibiotics to control infections. Management of the disease is extremely difficult for both patients and their families and involves a lifelong commitment by the family members.Scioderm, INC. is developing SD-101 dermal cream (formulation containing allantoin) for the treatment of EB. In this grant Scioderm is proposing a clinical program for the use of SD-101 to demonstrate healing of chronic wounds and lesional skin associated with patients with EB. Secondarily, SD-101 will also be used for reduction of skin blistering and erosions associated with EB, by facilitating healing of skin lesions and reducing the incidence and/ or severity of new lesions. We expect SD-101 will be safe and effective as p reliminary clinical investigations have shown fast and complete healing of wounds in EB patients. In addition, SD-101 was found safe to date in clinical trials performed in both healthy volunteers and EB patients. EB is acknowledged as a rare disease by the U.S. Food and Drug Administration (FDA) and to further develop the product and to make the cream available to EB has also received breakthrough therapy (BT) designation by the FDA for the treatment of patients with inherited EB, which may enable expedited development and approval of SD-101 for EB patients. In addition, the Dermatology division of FDA has agreed to waive the majority of the long-term toxicology studies, including carcinogenicity and reproductive studies. Agreement with the division was also reached regarding the study design for the pivotal program, including the definition of the primary endpoint for the clinical studies. patients, Allantoin has been designated as an orphan product (designation 01-1510). SD-101 This grant will be used to assist in the completion of the pivotal clinical program necessary for approval of SD-101 for the treatment of skin effects across the various types of EB.

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Research Project (R01)
Project #
1R01FD005093-01
Application #
8798909
Study Section
Special Emphasis Panel (ZFD1-OPD-N (S1))
Project Start
2015-09-01
Project End
2016-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Scioderm, Inc.
Department
Type
DUNS #
010219380
City
Durham
State
NC
Country
United States
Zip Code
27703