For children with epidermolysis bullosa, the debate about whether to pull off Band-Aids quickly or peel them back slowly does not apply. From head to toe, special bandages cover skin so fragile that anything but the most slow and careful removal can rip open a wound worse than the one the dressing was protecting. Brett Kopelan, executive director of the Dystrophic Epidermolysis Bullosa Research Association of America (DebRA), and the parent of a 7-year-old girl who has the disease, says he has seen children rip their own skin scratching itchy wounds.
There are no approved drugs that treat epidermolysis bullosa or heal its chronic wounds. But Durham, NC company Scioderm is on the cusp of late-stage clinical studies for an experimental skin cream that, if proven effective in improving wound healing, could become the first Food and Drug Administration-approved treatment for the disease.
“If they’re right, it would be a huge quality of life impact,” Kopelan says of Scioderm’s efforts. “Just the idea of being able to wear shoes more regularly, or (use) less bandages that are constricting, from a pain point of view or an itch point of view it would be almost a game change.”
Epidermolysis bullosa, or EB, is a group of connective tissue disorders caused by gene mutations in any one of 18 genes that may block or disrupt the formation of collagen, a structural protein that attaches the skin’s layers. Without collagen to connect the epidermis to the underlying dermis, even a slight chafing can blister or wound the skin. EB patients are sometimes called “butterfly children” because their skin is delicate, like a butterfly’s wings. DebRA counts 30,000 EB cases in the United States and 500,000 worldwide.
There are four types genetically-inherited EB; the disease can range from mild to devastatingly severe. Babies with the most severe forms usually die in their first year—mostly from infections in open wounds. Those who live into the teenage years and older face the additional risk of developing an aggressive form of skin cancer. Rarely does anyone with the more severe forms of the disorder live past the age of 30.
Scioderm’s experimental treatment is a topical cream (named Zorblisa) containing the active ingredient allantoin. Allantoin is a natural substance found in some plants and the urine of many mammals, and that has found use in dermatological products. It is known to soften keratin, the fibrous proteins in skin, enabling skin to hold more moisture. It’s already FDA approved as a cosmetic ingredient used in over-the-counter items like toothpaste, shampoo, and even some skin care products. But allantoin is unstable and has a short half life, Kopelan says. Scioderm’s cream keeps allantoin stable and delivers it in a higher concentration than commercially available skin products.
The cream did not originate with Scioderm. It was first tested in a 2009 clinical trial by the now defunct Minnesota skin products firm, Alwyn Company, Inc. Robert Ryan, Scioderm’s CEO and co-founder, says families of EB patients had asked Alwyn for a Vaseline-like barrier cream to prevent bandages from sticking to skin. Alwyn developed a topical cream that contained allantoin. Even through the cream had a low concentration of the ingredient, patients reported that their wounds healed faster with the treatment. Based on that feedback, Ryan says Alwyn decided to develop a formulation for a Phase 1 study in eight patients.
Ryan learned of the allantoin cream while working in regulatory affairs for Wilmington, NC contract research organization PPD, which was working with Alwyn. After completing the Phase 1 study in 2010, Alwyn decided to pursue a different drug program, Ryan says. In 2012, Ryan reached a deal to acquire the allantoin cream and Alwyn’s patents. The cream became the lead drug candidate for the newly-formed Scioderm.
While Alwyn’s formulation showed efficacy, Ryan suspected that more of the active ingredient would yield better results so Scioderm’s topical cream, Zorblisa, has a higher concentration of allantoin than the Alwyn cream. Ryan says the higher concentrations have demonstrated better healing results. In 2012, Scioderm completed a Phase 2 study of eight patients evaluating the drug. It was an open label study, in which both patients and doctors were aware that the patients were being treated with the experimental drug.
EB patients can have wounds that persist for months, even years, Ryan says. But in Scioderm’s Phase 2 study, the cream resulted in complete closure of 88 percent of chronic lesions within one month. Body surface area coverage of lesions and erosions were reduced by 57 percent after three months of daily treatment.
A randomized and placebo-controlled Phase 2b trial completed earlier this year studied 48 patients, with similar results. “We had them healing in a month, in some cases even earlier than that,” Ryan says. “Wounds that would not heal are healing and are healing at a much faster rate.”
Based on an early evaluation of the results and the fact that there are no current treatments for EB, the FDA last year designated Scioderm’s topical cream a “breakthrough therapy.” That provides the company more active communication with regulators during clinical trials. It also means that the FDA could approve Scioderm’s cream without a Phase 3 trial, based on the results from the Phase 2 studies. If that happens, Scioderm would need to conduct a trial after the drug reaches the market in order to confirm the results. But European regulators will require a Phase 3 trial for approval so Ryan says Scioderm plans on late-stage studies, regardless of what the FDA decides. Scioderm has not yet met with the agency to discuss its latest clinical trial results. Scioderm’s next steps will depend on the outcome of those discussions.
But the FDA has also designated the Scioderm cream an “orphan drug,” reserved for drugs that treat rare diseases affecting fewer than 200,000 people. Orphan drug status waives regulatory filing fees and, if the FDA approves the drug, grants marketing exclusivity and tax breaks. Kopelan says those incentives make rare disease drug development attractive to companies that would otherwise be wary of developing and selling a product for a tiny patient population.
Scioderm was able to raise $16 million in a Series A round led last year by Morgenthaler Ventures, with participation from Technology Partners. The funding is enough to carry Scioderm through Phase 3 testing, so it won’t need the deeper pockets of a large pharmaceutical company to finance late-stage studies. But Ryan says he has already spoken with large pharmaceutical companies interested in the orphan drug. Ryan says Scioderm could license the allantoin cream to pharmaceutical partners, who would sell the drug in specific geographic regions around the world. Or Scioderm could become part of a larger company in an acquisition.
Ryan says Scioderm could also opt to commercialize the drug alone, financing the endeavor with an initial public stock offering. Because EB is a rare disease addressing a small patient group, Scioderm would not need a large sales force, so it’s feasible for the small company to go to market alone. Based on his discussions with insurance companies, Ryan believes payers will reimburse for the treatment because EB patients currently have no approved treatment options.
Scioderm, however, isn’t the only company working on EB treatments. There’s growing interest in the pharmaceutical industry, and among academic researchers, because of the orphan drug status for EB treatments and because of the major unmet medical need, says Kopelan.
In 2007, the University of Minnesota used bone marrow transplants to implant cells that produce the collagen that EB patients lack. In that study, funded in part by the National Institutes of Health, researchers observed more collagen in the patients’ skin. They also did not detect antibodies to the donor cells, according to study results published in the New England Journal of Medicine.
In a different approach, Fibrocell Science (NASDAQ: FCSC) is working with patients’ own cells. The idea is to genetically modify patients’ collagen-producing cells, inserting the gene that produces collagen with the goal of producing healthy skin. Fibrocell has partnered with synthetic biology company Intrexon (NYSE: XON) to develop the treatment, which is being prepared for clinical trials.
Another tack, taken by Shire (NASDAQ: SHPG), is trying to grow skin over the wounds of EB patients using a diabetic foot ulcer treatment called Dermagraft. Shire acquired Dermagraft in 2011 from San Diego firm Advanced Biohealing for $750 million. Placed over a wound, Dermagraft is a mesh material that contains skin cells that produce connective tissue. As the body absorbs the mesh, the cells in Dermagraft help new skin to form. Shire took Dermagraft as far as Phase 3 clinical trials in EB but terminated the study last year, then sold Dermagraft to Organogenesis as part of a companywide reorganization that halted Shire’s regenerative medicine ambitions. Organogenesis markets Dermagraft as a diabetic foot ulcer treatment, but has said nothing about developing it for EB. Meanwhile, Shire’s EB efforts are now focused on a protein replacement therapy. Shire acquired the pre-clinical technology, which involves a genetically-engineered form of collagen, from Lotus Tissue Repair.
The business case for developing all of these EB treatments, says Kopelan, is further bolstered by opportunities to apply successful treatments to other skin disorders. Ryan, for instance, acknowledges potential broader applications of Scioderm’s allantoin cream, but says that right now, the company is focused on EB.
In addition, there will probably be markets for several EB treatments, Kopelan believes. He envisions that EB will be treated with a combination of products, perhaps a gene or cell therapy and skin grafts, along with topical agents to address persistent wounds. New treatments, including Scioderm’s allantoin cream, could make EB a chronic condition managed by modern medicine, he says.
“You’re not curing the disease, but you’re addressing some of the most prominent symptoms out there and that’s incredibly important,” he says.