Laruparetigene zosaparvovec

Beacon Therapeutics has found the light in a rare vision loss disease that has left larger companies in the dark. The biotech’s gene therapy for X-linked retinitis pigmentosa (XLRP) successfully improved visual acuity in a pivotal trial, setting up the startup to seek regulatory approval. The phase 2/3 Vista study tested two dose levels of laruparetigene zovaparvovec (laru-zova) in 85 men and boys who are primarily affected by XLRP. Twelve months after treatment, none of the patients in the control group showed improvements in visual acuity that met the trial’s definition for a responder, which was the ability to read 15 more letters on an eye chart under low light. In contrast, 24.1% of patients in the low-dose group and 31% of patients in the high-dose group were responders, meeting the trial’s primary endpoint. “We've now demonstrated, in a pivotal study, the kinds of treatment effects that a medicine like this could have on a debilitating, blinding disease that affects hundreds of thousands of patients around the world,” Beacon CEO Lance Baldo, M.D., told Fierce in an interview. “This is going to be an amazing journey for us over the next couple of years.” Beacon is wasting no time putting its data before regulators, with plans to start a rolling biologics license application to the FDA before the year’s end, Baldo said. The company also plans to pursue approval in the European Union and the U.K., he added, although bringing laru-zova to its full potential may require finding partners. “For a small biotech, 80-plus people, do we plan to go this alone, or might we consider partners who might have infrastructure and expertise in some of those markets?” the CEO said. “We're keeping all of our options open at this time.” To succeed in XLRP, Beacon stood on the shoulders of giants, Baldo said, specifically the much larger biopharma operations of Biogen and Johnson & Johnson. Biogen’s XLRP gene therapy trial missed its primary endpoint in a phase 2/3 trial back in 2021, while J&J suffered a phase 3 setback last year. J&J’s partner, MeiraGTx, has since bought back the gene therapy and plans to push for approval this year despite the unsuccessful trial. Baldo sees two key reasons why Beacon’s Vista trial prevailed where others have stumbled. The first has to do with the trial design. Biogen’s study used a measure of retina sensitivity as its primary endpoint, while J&J’s assessed patients’ ability to navigate a virtual maze. These endpoints, Baldo explained, were primarily inspired by trials run for other diseases, which made sense at the time, given how much was unknown about XLRP. “Sometimes it pays to be second or third when you go after this stuff because you can learn from your predecessors,” Baldo said. “We're thankful to not just the companies that came before, but all the patients and the clinicians that donated all their time, so that we can learn and we can get better.” Another key ingredient in the trial’s recipe for success is laru-zova itself. The therapy packages a full-length copy of the retinitis pigmentosa GTPase regulator (RPGR) gene inside a viral capsid and is injected directly into the back of the eye. “The gene in the native form is very unstable,” Baldo said of RPGR. In order to make sure the full gene could last long enough inside the body to produce functional protein, Beacon tweaked the genetic code itself. DNA comprises of three-letter sequences called codons that each correspond to a different amino acid, the fundamental building blocks of proteins. Because multiple different codons code for the same amino acid, the scientists could swap unstable codons for more stable ones without interfering with the protein’s ultimate structure. “The secret sauce that we've got is that codon optimization to create a really stable full-length gene that then transcribes the full-length protein,” Baldo explained. That protein then “localizes to those photoreceptors and allows the machinery to start working again.” Mutations in RPGR are one of the most common causes of XLRP, though other genes can be implicated in the disease too. Whatever the cause, the disease leads to a gradual loss of rod and cone cells in the retina that erodes vision, with symptoms sometimes starting as early as the teenage years. Baldo recalled to Fierce that when he first became CEO at Beacon in 2024, a retina specialist friend told him he didn’t think he would be able to take the job if he was in Baldo’s position. “He goes, ‘I hate that disease. There's nothing you can do for those patients',” Baldo remembered. “We've demonstrated not just that we can arrest the development of disease; we can actually return letters and lines of vision to them.”