Phase 3 Study on Gene Therapy for Inherited Retinal Disease Choroideremia Offers Important Insight

The clinical trial didn’t reach its endpoint but still expands researchers’ knowledge on the possibilities of gene therapy for choroideremia.

A newly published study in Nature Medicine that shows gene therapy failed to meet FDA requirements for treatment of the inherited and devastating retinal disease choroideremia might sound like a negative result, but it’s also an important lesson learned.

“Basically, this study didn’t reach its endpoint. On the other hand, I think the reason it’s in a high-impact journal is because it helps to tell us what can be gained with gene therapy,” said one of the study’s authors, Byron L. Lam, M.D., Mark J. Daily Professor at Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine. “It increases our body of knowledge of the effects of gene therapy, the safety of gene therapy, and what we can reasonably expect gene therapy to do in inherited retinal diseases.”

Gene Therapy for Retinal Disease That Can Cause Vision Loss

A genetically caused retinal disease, choroideremia results in progressive vision loss starting in early childhood. This rare, X-linked retinal degeneration affects males and can cause complete vision loss by the time a person reaches late adulthood.

A gene therapy called timrepigene emparvovec (Biogen), aimed at treating mutations in the CHM gene which cause choroideremia, is among the first gene therapies to have made it to phase 3 trials and possible FDA approval. Bascom Palmer researchers conducted the phase 2 choroideremia gene therapy trial on this treatment, and Dr. Lam and his colleagues Janet Davis, M.D., and Ninel Gregori, M.D., were the first to treat choroideremia patients with this gene therapy in the U.S.

In the phase 3, multicenter, international trial, Dr. Lam, who directs the Mark J. Daily Inherited Retinal Diseases Research Center at Bascom Palmer, and colleagues studied the safety and efficacy of different gene therapy doses in people with choroideremia over 12 months.

Clinical Trial Results Offer Optimism

They found that three of 65 participants in the high-dose group and one of 34 in the low-dose group reached the FDA’s required endpoint of a 15-or-more letter improvement on a standard vision chart. None of the people studied who did not receive the therapy (the control group) experienced the same level of improvement.

They also found that nine people in the high-dose group, six in the low-dose group and one among the controls achieved a 10-letter-or-more improvement from the study’s start.

While these results did not meet the FDA’s requirements for this study’s design, choroideremia remains a viable target for gene therapy. However, future trials might look at the goals of outcome success through a different lens, according to Dr. Lam.

“Inherited retinal diseases affect both eyes and have devastating impacts on people’s lives and livelihoods,” he said. “In almost all cases, there is nothing we can do to treat patients short of vision support.”

The FDA has approved one therapy to date for a different inherited retinal disease. In most cases, however, it’s a tall order to think that treating a malfunctioning gene can improve visual function.

“The approved therapy is for a kind of inherited retinal disease in which the retina structure is intact. In most inherited retinal diseases, the retinal structure isn’t intact,” Dr. Lam said. “So, instead of thinking that one can improve patients with inherited retinal disease, maybe a more viable goal of treatment would be to slow the progression and perhaps turn time back.”

Gene Therapy to Slow Vision Loss

The fact that this gene therapy did improve vision in some patients with choroideremia suggests that it could slow the progression, meaning the therapy could keep someone at the current level of vision for a longer period of time or even restore vision to where it was years earlier.

“Those results would mean the world to people gradually losing their vision,” he said.

Dr. Lam and Bascom Palmer colleagues are conducting many clinical trials in choroideremia and other inherited retinal diseases, including studies designed with novel outcome measures.

“Through the Mark J. Daily Inherited Retinal Diseases Research Center at Bascom Palmer, we are committed to conducting innovative research that has translational value leading to new treatments that can be tested in humans, so that people with these diseases can live better, more productive lives,” he said.

Tags: Bascom Palmer Eye Institute, Dr. Janet Davis, Dr. Ninel Gregori, gene therapy, ophthalmology