JNJ-74765340

For Lewis Winton, the world looks different from one eye. In the first few months after getting a gene therapy in his right eye, Winton kept covering his other eye with his hand. Winton, a 31-year-old who works for the Royal National Institute of Blind People, a UK charity for blind people, is a recipient of an experimental gene therapy developed by Johnson & Johnson and MeiraGTx for a rare and progressive eye disease called X-linked retinitis pigmentosa (XLRP). Winton received the therapy in only one eye while enrolled in an early-stage study. Seeing through his treated eye, the world looked more vibrant. Observing his wife’s face, her eyebrows appeared bolder and darker, Winton recalled. He read license plate numbers, watched the sunset turn to dusk, and noticed how the Netflix logo looked redder and sharper. Looking only through his untreated eye, “it was like watching a TV screen from the 1950s,” Winton said. However, it’s unclear if the therapy has a future since J&J disclosed in early May that a late-stage study had failed. The company said in a statement it is still digesting the data and determining next steps, but patients like Winton, researchers and advocates are imploring J&J to apply for approval of the gene therapy known as bota-vec. “Before Johnson & Johnson gives up on that, they should discuss with the FDA,” said José-Alain Sahel, chair of the ophthalmology department at the University of Pittsburgh. “They should put everything on the table.” As patients and physicians wait to see whether J&J will proceed with its gene therapy, the dilemma raises questions about how the challenges of designing rare disease clinical trials can hamper promising new treatments, and what that means for the field of gene therapy, which has been losing the interest of large pharma companies and investors. The four academic investigators who spoke with Endpoints News for this story say that the primary endpoint used in the trial was not ideal, and the other secondary measures showed that the therapy improved vision for patients who otherwise have no treatment options. In addition, 30 investigators, including Sahel, who participated in J&J’s LUMEOS Phase 3 study, signed a letter dated June 6 calling on the company to seek FDA approval. The letter was published by the prominent eye disease nonprofit Foundation Fighting Blindness. “This is a failed trial, not a failed treatment,” said Rachel Huckfeldt, a Harvard and Massachusetts Eye and Ear ophthalmologist who signed the letter. “There are so many people that stand to benefit from it that I sincerely hope the regulators get a chance to review it.” Johnson & Johnson’s decision whether to submit bota-vec to the FDA arrives at a crucial moment. Large drugmakers are stepping away from the rare disease gene therapy field and the industry is questioning whether investing in these treatments is profitable. If J&J does decide to apply for approval, it’s unknown how the FDA would approach the gene therapy. While uncommon, the regulator has approved therapies using data from failed trials. And the new FDA leaders in the Trump administration have repeatedly said they want to speed up development of rare disease treatments. “This would be an example of something that would really test the case of what the FDA says they want to do,” Foundation Fighting Blindness CEO Jason Menzo said. “This is like the perfect case study.” Foundation Fighting Blindness has received sponsorship funding from J&J. If the company chooses not to seek approval, it would serve as another signal of pharma’s waning interest in these gene therapies. Sahel worries that doing so could scare away investment in future treatments. “If the second biggest [pharmaceutical] company in the world is reticent about trying to get approvals, what on earth does that mean for rare disease?” said Michel Michaelides, head of clinical ophthalmology at MeiraGTx and a University College London ophthalmologist. He also serves as a consultant for J&J. He is one of the researchers who developed the therapy while it was at University College London. The rights were later acquired by MeiraGTx. In 2023, MeiraGTx sold the eye gene therapy to J&J. XLRP impacts around 20,000 people in the US and Europe. Menzo believes there’s a business case to be made for using gene therapies to treat the disease because, while it’s rare, it’s a larger indication compared to an eye disease called Leber congenital amaurosis, for which the first and only eye gene therapy was approved: Roche’s Luxturna. “We’re working to understand the totality of the data, inclusive of the clinical relevance of improvement shown on the majority of secondary endpoints,” a J&J spokesperson told Endpoints in an email. “We remain engaged with the advocacy and research community and greatly appreciate their continued support as we work to determine next steps.” X-linked retinitis pigmentosa is a genetic condition that results in progressive vision loss and potentially blindness in mostly boys and men. Most people are diagnosed in childhood or in adolescence, and there are no approved treatments. “It’s devastating,” said Leila Sierra, whose son Matthew was one of a handful of children to receive the gene therapy in the Phase 3 trial, “when the doctor looks at you and says, ‘There really isn’t anything you can do about it.’ You can sit and wait and get prepared for this change that is coming up. We were even told, ‘Maybe you can start planning Braille classes.’” The Sierra family lives in Miami, but sought out doctors at Mass Eye and Ear and then traveled to Boston for treatment. Matthew, now 12, received the treatment last year when he was 11. Click on the image to see the full-sized version XLRP is caused by a gene defect that leads retinal cells to die over time. A key symptom of the disease is loss of night vision. The experimental therapy delivers virus packages with functioning versions of that gene to the retina, in hopes of counteracting the loss of those retinal cells and preserving or even bringing back vision. In J&J’s Phase 3 LUMEOS study, 95 patients were split into two groups: One group received bota-vec, while the other had treatment deferred for one year. The primary endpoint was improvement in what’s called a “vision-guided mobility assessment.” In simpler terms, it’s how well patients navigate a maze in low light. It’s similar to the test used in Luxturna’s pivotal study. The maze used in J&J’s Phase 3 trial was made specifically for that study and has not been used to test any other therapy. It’s a common challenge for rare disease drugmakers to have to develop their own tests from scratch or validate new endpoints. In the study, the group that received the gene therapy experienced a 13.4% greater improvement on the test at one year compared to the control group. That result was not statistically significant, though J&J called it “directionally supportive.” But the study’s investigators described the data as “noisy,” saying that patients in the control group did better than expected on the maze. The therapy also substantially improved measures of vision on more straightforward tests, like low-luminance visual acuity, which is like reading an eye chart with sunglasses. On that endpoint, 45% of patients who received the gene therapy could read at least two more lines of letters on the eye chart compared to 7% of control group participants. “If they had picked almost any other outcome as the primary endpoint, it would have been a slam dunk for approval,” Jason Comander, another Harvard and Mass Eye and Ear ophthalmologist, wrote in an email. Comander was the surgeon at the Mass Eye and Ear trial site for J&J’s therapy, while Huckfeldt was the principal investigator. Huckfeldt and Comander don’t have a personal financial stake in bota-vec, but Mass Eye and Ear would receive royalties if it were approved. Huckfeldt also consults for J&J. The therapy also looked generally safe in the clinical trial, with most adverse events being mild or moderate. Seventy percent of participants experienced eye inflammation. Because the treatment is delivered directly into the eye, it doesn’t face the same safety concerns as other gene therapies that travel throughout the body. There is another gene therapy for XLRP in late-stage testing by a well-funded biotech startup called Beacon Therapeutics . That study’s primary endpoint measures sight using an eye chart at low light. Beacon’s study is nearly fully enrolled, and the company expects data before the end of next year. In an unusual move, J&J never published the Phase 3 data in a press release or shared it at a medical meeting. Its presentation in May in Salt Lake City at the Retinal Therapeutics Innovation Summit, which the Foundation Fighting Blindness co-hosted, is not publicly available, though the organization posted a summary of the results. Endpoints reported in May that the study failed, citing results posted on J&J’s website for healthcare providers, but the company has since taken down that information. Winton’s hope is that other people with XLRP will get the option to receive gene therapy, but he also hopes to get his second eye treated. He learned from Michaelides, his doctor, after his interview with Endpoints that J&J recently opened a study for treating the second eye of patients who participated in the early-stage trial. “This might apply for many people living with RP, but my dream is not to have perfect vision — that would be amazing in a utopian world,” Winton said. “My dream is just to have some vision — some usable, functional vision.”