Genable Moves Closer to a Gene Therapy Clinical Trial for Dominant RP

October 10, 2014

After a recent meeting with the U.S. Food and Drug Administration (FDA), the Irish biopharmaceutical company Genable is on course to launch the first gene therapy clinical trial for people with an autosomal dominant retinal disease. The condition is retinitis pigmentosa caused by mutations in the gene rhodopsin (RHO), which affects about 30,000 people in the United States and Europe and thousands more around the world.

Jason Loveridge, Ph.D., Genable’s chief executive officer, says that the feedback the company received from a pre-IND meeting with the FDA puts the company in a good position to seek authorization of a clinical trial in the near future, so long as development of the therapy continues as planned. IND is an acronym for Investigational New Drug Application, which is submitted to the FDA by organizations seeking to launch human studies in the United States.

Applicants often request a pre-IND meeting to get feedback on their development plans and improve their chances that the FDA will authorize a clinical trial. The Foundation Fighting Blindness funded the development of Genable’s therapy early on, and continues to provide the company with consultation.

“To get our gene therapy, GT038, into a human study, we need to do more work in our large-animal model, the pig,” says Loveridge. “We need to ensure it’s safe for patients and determine the most effective dose.” When the treatment is a pill or eye drop, dosage can be easily changed for the patient. GT038, however, is injected underneath the retina, so dosage cannot be adjusted once it has been administered.

Before its gene therapy is used in a clinical trial, Genable will also have to meet good manufacturing practices, or GMP, to ensure that the treatment qualifies for use in humans. The company has partnered with Spark Therapeutics, which is currently conducting a Phase III clinical trial of a gene therapy for Leber congenital amaurosis (LCA) caused by RPE65 mutations. Genable will use Spark’s manufacturing system to produce an adeno-associated virus, or AAV, for gene delivery into the retinal cells. AAVs have performed safely and effectively over the last six years in a number of clinical trials for retinal-disease treatments.

“Spark is one of the best groups in the world for doing this,” says Loveridge. “Their gene therapy originally came from Jean Bennett at The Children’s Hospital of Philadelphia, and they have an excellent track record. They have a lot of experience developing ocular gene therapies, and we can benefit from their clinical expertise as well.”

However, developing a gene therapy for autosomal dominant retinitis pigmentosa (adRP) presents a technical hurdle that has yet to be cleared in the clinic. Most retinal gene therapies currently in human studies are for autosomal recessive conditions, in which a mutated gene results in an insufficient amount of protein. Simply replacing the gene corrects the problem. But in adRP caused by RHO mutations, the mutated gene leads to the production of a toxic protein. Treatment will likely require a two-step process: Shutting down the mutated RHO and replacing it.

Development of GT038 began 10 years ago and was performed by Jane Farrar, Ph.D., Paul Kenna, Ph.D., and their colleagues at Trinity College Dublin. “To date, Genable has shown that its novel and proprietary approach of using suppression and replacement works in mouse models of the disease,” Loveridge explains. “And, now, we have formulated the final drug candidate, GT038, which will go into humans.”

The Foundation Fighting Blindness funded early GT038 research, and, today, its chief researcher officer, Stephen Rose, Ph.D., serves Genable in a consultative capacity. Patricia Zilliox, Ph.D., the chief drug development officer at the Foundation’s Clinical Research Institute, also provides the company with insights into the clinical development of GT038. “Now that we are moving toward the clinic, we have been speaking a lot with Patricia and Steve,” Loveridge says. “They’ve been very helpful to us, providing extensive expertise and advice. Patricia has been involved in clinical ophthalmology for a long time. It is invaluable to have access to her experience and knowledge.”