Some diseases were long considered incurable, even untreatable. Epidermolysis bullosa (EB) is one of them.
But as technology advances, so does therapeutic possibilities. With the advent of gene therapy, EB patients may finally have an effective treatment to look forward to.
Abeona Therapeutics is running the most advanced effort to develop a gene therapy, called EB-101, for patients with recessive dystrophic EB (RDEB) — a development that the U.S. Food and Drug Administration (FDA) recently encouraged to speed up.
“We brought a patient with us to the FDA when we had one of our recent interactions with them — where they allowed us to move forward out of the Phase 1/2 and directly into a pivotal Phase 3 trial,” said Timothy Miller, Abeona’s president and CEO, when Epidermolysis Bullosa News spoke to him this week about the therapy’s development.
“Part of that was because the patient was able to take off her sleeve and say: Look, this is the difference between a treated arm and a non-treated arm,” Miller added.
Bringing a patient to a FDA meeting may sound like an unusual strategy in drug development. But Abeona is no stranger to patient interactions. In fact, Miller sees it as crucial that members of his team, including scientists and regulatory staff, understand what patients and their families are going through.
Every couple of months, the company has an EB lunch and learn, allowing patients and employees to interact. There, pictures of a room full of bandage boxes, or stories of how kids are afraid of waking up for fear that their clothes are stuck to their body, help Abeona employees to understand the urgency of the problem they are trying to solve.
“I think it’s an important step in making sure that people understand that what they’re working on in the lab is going to go into a human to try and save their life,” Miller said.
Replacing a faulty gene
The different types of EB are a consequence of four different faulty genes. In RDEB, the COL7A1 gene is mutated, resulting in a faulty collagen type 7 protein.
This protein helps to anchor the outer layers of the skin to the deeper layers. Without it, even gentle trauma causes the skin to blister and fall off; patients, Miller noted, are barred from doing many things that people without the condition take for granted.
“Even right now, sitting here at my desk, I’m resting my forearm against the desk — something that an EB patient can’t really do.”
Abeona is developing what may be an effective and safe way to overcome this.
Researchers use harmless viruses to deliver a functional gene into a patient’s own skin cells, or keratinocytes. Using the gene therapy on cells in the lab, the treatment corrects the defective gene in up to 80 percent of cells.
These cells are first gathered and isolated from a tissue sample. After the gene has been introduced, the cells are grown into sheets about “the size of an iPhone 6,” Miller said. Then they are transplanted onto the blistered skin of a patient.
“The whole process really only takes about four weeks,” he said.
In 2010, Abeona started a Phase 1/2 clinical trial (NCT01263379), aiming to use these genetically altered skin transplants to treat children with RDEB.
In the trial, patients receive six such sheets each time — allowing researchers to standardize processes to make outcome measurements more reliable.
But as these patients lack skin on between 30% and 70% of their body surface, they can get several six-patch treatments. Evidence points to significantly improved skin quality in treated patients.
“The skin is much stronger to the touch, and it’s much more robust. And now we know, based on the early phase clinical trial data, that these grafts are able to last up to three or four years,” said Miller.
Abeona measures the effectiveness of the transplants in terms of wound closure. A graft is considered still attached and working if wound closure is at least 50 percent. Recently released results show that closure has ranged between 83 and 100 percent over the months and years since the trial started.
“So we can tell you that over three or four years, over 90 percent of them are still greater than 50 percent closed, which is not what you’d expect from the natural history studies. At that point, a 100 percent of those wounds are basically 0 percent closed,” Miller said.
In addition, researchers have confirmed that functional collagen 7, as well as the anchoring fibrils, are present up to two years after the treatment.
In rare disease treatment development, natural history studies allow scientists to perform clinical trials without the use of a placebo group as a control comparison. Before EB-101 was ready for human testing, Abeona performed a natural history study that included 128 RDEB patients. Data on how the disease develops without treatment is now an invaluable asset in ongoing and future trials.
At this point, the trial has seven patients enrolled in the Phase 1/2 trial. The patient with the longest follow-up has been in the study for four years, and all seven have reached one year of follow-up. But while the study initially aimed to recruit 10 participants, no new patients will enter the trial.
Instead, the FDA recommended that Abeona start recruiting into a Phase 3 trial. While study design details are still being worked out with the FDA, this trial will have a setup similar to the earlier study and launch in 2018, Miller said.
Long-term outcomes, of course, won’t be known for years. But Abeona plans to make initial data, showing how patients are progressing, available by the end of 2018 or early 2019, Miller said.
As preparations for the Phase 3 trial are ongoing, Abeona is also working towards longer term goals. In October, the company announced the launch of the Elisa Linton Center for Rare Disease Therapies in Cleveland, Ohio.
The center will be a commercial manufacturing facility for gene and cell therapies for several rare diseases, providing scientists with the material needed throughout research and development, as well as clinical use, of such treatments.
Since Miller believes that the technology used in EB-101 can be readily adapted to other forms of EB, or even other skin diseases, the center will make the move into other areas easier.
Abeona is also working on another gene therapy for RDEB.
Collagen type 7 is not only present in skin. Mucous membranes, such as in the esophagus, are also affected by abrasion. The company’s second gene therapy, EB-201, has so far only been tested in animals. But it has one advantage. It can be delivered straight to patient tissues, without the need for transplants.
The key to this — to all gene therapy, really — is delivery, Miller said.
“You need to get the target gene to the right place, in the right amount, and have it stay there for a long time. This is really how the EB-201 program has taken off. Because we know that with our current vectors [viral carriers], we can do that.”
Early studies suggest that it may be used to treat more sensitive areas — such as the esophagus or the skin between the fingers — by being locally delivered to these tissues. If successful, the therapy can be used in combination with EB-101, used to treat larger skin areas.
Roughly a month ago, a German-Italian research team made headlines when publishing the outcomes of gene therapy approach, similar to Abeona’s, used in a boy dying from junctional EB. While the company is not now working on other forms of EB, Miller thought the team’s efforta proof-of-concept that large transplants are possible.
RDEB is, however, not only the most common form of EB, but also its most severe form, Miller pointed out.
“These [patients], they lost their digits, they lost their eyesight … And then, you start talking about the fact that most of them die from squamous cell carcinomas, and don’t reach the age 18,” he said.
Abeona is the Roman goddess of safe passage, the protectress of children as they leave home, Miller said. His company took that name because “with rare diseases, 70 percent of these kids they don’t reach the age of 18, and they end up never leaving home.
“So, I think that in the future, for us, our goal is to try to be able to manufacture enough of these as fast as we can to make sure that we can meet all the patient demands,” he concluded.