Ceroid Lipofuscinosis, Neuronal 5

Neurogene licensed a CLN5 gene therapy program from the University of North Carolina at Chapel Hill.\n Neurogene followed up a premarket setback to its Rett syndrome program Monday with a postmarket confirmation that development of another gene therapy has hit a wall.The postmarket update covered NGN-101, a gene therapy Neurogene was developing as a treatment for CLN5 Batten disease, and repeated what the biotech disclosed last week. Three months ago, the biotech said it planned to meet with the FDA and try to align with the agency on clinical requirements to support a streamlined registration pathway. Neurogene framed alignment on a streamlined pathway as critical for continued investment in the program.Talks with the FDA haven’t gone according to plan. Seeking a streamlined pathway, Neurogene submitted a Regenerative Medicine Advanced Therapy (RMAT) application to the FDA. The biotech said the filing met the standard of preliminary clinical evidence required to obtain an RMAT designation.However, the FDA denied the application. Neurogene responded by dropping plans to advance NGN-101. The decision reflects the rarity of CLN5 Batten disease, which led the biotech to conclude it would need to align with the FDA on a streamlined registrational pathway to support further investment in the asset. Neurogene said in a release that it is now evaluating options for the program. The biotech licensed the CLN5 gene therapy program from the University of North Carolina at Chapel Hill (UNC) back in 2019. The deal was small, with Neurogene agreeing to pay UNC up to $1.7 million in sales-related milestones and making five-figure payments tied to the progress of the program. UNC received $15,000 when the candidate secured orphan drug designation and $30,000 when phase 1 dosing began.The UNC deal led to Neurogene becoming the first company to test a gene therapy in people with CLN5 Batten disease. The biotech recently completed enrolling the six subjects in its phase 1/2 dose-escalation trial. Other organizations are working on treatments for CLN2 and CLN3 disease, but NGN-101 is the only CLN5 therapy listed on ClinicalTrials.gov.Neurogene’s stock plummeted after it disclosed the setback to the Rett gene therapy, closing down more than 40% at below $20.Editor’s Note: This article was updated at 11 am ET on Nov. 19 to say Neurogene previously disclosed the CLN5 update. 

Businessman jumps carefully on cracked or broken graph. Concept of under pressure. iStock, Afry Harvy After failing to receive the RMAT designation from the FDA for its early-stage Batten disease gene therapy, Neurogene tells investors that it’s evaluating options for the program. In addition to a Monday morning announcement of a complication for its Rett syndrome gene therapy, Neurogene has dropped another doozy on investors in stopping its gene therapy program for Batten disease. In its third quarter earnings release and a prior press release on Nov. 11, Neurogene stated that while it had completed enrollment for the NGN-101 Phase I/II trial, it does not expect to move forward at this time. Due to the rarity of CLN5 Batten disease—estimated to occur in 2 to 4 of every 100,000 births in the U.S.—the biotech was counting on the FDA’s Regenerative Medicine Advance Therapy designation to support the program. However, the RMAT application was denied, and the company is now “evaluating options for the program.” This blow follows on the heels of a hit to another of its lead rare disease programs, NGN-401 for Rett syndrome. Neurogene shared news of a serious adverse event last Monday, sending shares tumbling 35%. This Monday, the company revealed further details including that the patient remains in critical condition, sending the stock down another 36% upon the opening bell—though William Blair analyst Sami Corwin said in a note to investors Tuesday that this negative stock reaction was “overblown.” Indeed, the adverse event reported was not fatal to the Rett program. Neurogene stated that the patient suffering from systemic hyperinflammatory syndrome, a dangerous immune response associated with high doses of adeno-associated virus gene therapies, was in the high-dose arm of the trial, which will now be paused, and no further patients will be enrolled in the cohort. The low-dose arm will continue, however. No other serious adverse events have been reported in the trial. The first four patients treated at the lower dose showed consistent improvements across key Rett syndrome scales, and all five achieved a clinically meaningful rating of “much improved” on the clinical global impression-improvement scale, the company said. Treatment-related adverse events in this dosage group were grade 1, with the treatment well-tolerated. NGN-401 is part of the FDA’s START program for supporting and accelerating clinical development for rare diseases. Within this program, Neurogene was able to quickly get an FDA review of the safety data for NGN-401 and be allowed to proceed with the Phase I/II trial at the lower dose. Corwin credits the START program with likely preventing a clinical hold. She continues to see the efficacy data as “impressive” and reiterated the investment firm’s view that NGN-401 is a “potentially first-in-class and best-in-class gene therapy for Rett syndrome.” In its third quarter release, Neurogene said it will share its registrational trial design for NGN-401 in the first half of 2025. Thanks to a private placement of $200 million earlier this month, the company’s cash runway currently extends into 2027. Neurogene expects to advance another product candidate into the clinic next year. Correction (Nov. 19): This story was updated to clarify that Neurogene first announced the Batten disease discontinuation on Nov. 11 prior to releasing details on the adverse event in a study of Rett syndrome, not after. BioSpace regrets the error.

Neurogene’s stock $NGNE fell 35% in post-market trading on Monday after a Rett syndrome patient who received a high dose of the company’s gene therapy experienced a serious adverse event, overshadowing other promising data from an early-stage clinical trial. The rare disease, which mostly affects girls, causes a loss in motor functions and the ability to communicate. Four patients who got a low dose of Neurogene’s therapy gained motor skills and improved on other measures, the company reported. But among three patients who got a higher dose, one of them  recently experienced a serious adverse event that’s consistent with what the company called “known risks of AAV gene therapy.” Neurogene did not provide additional details. In a conference call following the results, company representatives said the issue emerged just before the trial results were presented. “We literally just learned within the last several hours, so the data is very much emerging,” said Julie Jordan, the company’s chief medical officer. “As I mentioned, we are still collecting information.” Jordan said the issue won’t impact the low-dose version of the therapy, which has shown a favorable safety profile. The company is planning to test the low-dose therapy in a clinical trial that could support FDA approval. Neurogene’s stock dropped to $46 a share in after-hours trading, down from $71 at market close. Taysha Gene Therapies, which is also developing a therapy for Rett syndrome, saw its stock $TSHA jump 27% to $2.02 in post-market results. The four patients who received a low dose of Neurogene’s therapy registered major improvements, or a score of 2, on what’s known as a Clinical Global Impression Scale of Improvement. They also saw gains ranging from 28% to 52% on a questionnaire administered by caregivers.  These improvements included the ability to use objects like a fork, walk more smoothly and better communicate. It’s rare to see Rett syndrome patients learn or relearn such abilities, Neurogene representatives said during the call. Neurogene also reported that the company doesn’t expect to move forward with its therapy targeting the rare condition CLN5 Batten disease. The FDA denied the company’s application for streamlined approval, which would have lessened development costs. Neurogene said it’s evaluating options for the therapy. Endpoints News previously reported that Neurogene stopped work on its therapy aimed at a different rare disease called aspartylglucosaminuria, or AGU. The potential medicine was among dozens of therapies for rare conditions that were paused because of a downturn in the biotech industry.