NGN-401

Neurogene disclosed in a filing with the US Securities and Exchange Commission that a patient who suffered a serious adverse event (AE) in an ongoing Phase I/II study of its gene therapy for Rett syndrome has now died. The company first said last week that a participant given the higher 3E15 vg dose of NGN-401 had experienced a treatment-related serious AE described as "consistent with known risks of AAV gene therapy." The issue clouded promising efficacy seen in the low-dose group (for related analysis, see Spotlight On: SAE could swing balance of power in Rett gene therapy battle).More recently, Neurogene indicated that the participant — who was dosed on November 5 — was in a "critical condition" having experienced signs of a systemic hyperinflammatory syndrome, which are associated with aberrant cytokine release and include haemophagocytic lymphohistiocytosis and multisystem inflammatory syndrome. NGN-401 is an AAV9 gene therapy candidate that works by delivering a full-length human MeCP2 gene using Neurogene's EXACT transgene regulation technology. The biotech continues to investigate the lower 1E15 vg dose of NGN-401 in the trial in both the paediatric and adolescent/adult cohorts.

iStock, Olena Koliesnik Despite the death, the FDA has allowed Neurogene to forge ahead with the Phase I/II Rett syndrome trial, but using only the lower 1E15 vg dose of its investigational gene therapy NGN-401. Neurogene revealed in an SEC filing on Thursday that a patient has died in its Phase I/II Rett syndrome clinical trial after being dosed with its investigational gene therapy. The patient had been treated with the higher, 3E15-vg dose of NGN-401 when they experienced what was initially described only as a treatment-related serious adverse event (SAE). In a follow-up announcement on Monday, Neurogene disclosed that the patient had developed systemic hyperinflammatory syndrome—a known but severe side effect of adeno-associated virus gene therapies—and was in critical condition. In an investor note, BMO Capital Markets analysts Keith Tapper and Evan Seigerman called the death “tragic,” noting that while hyperinflammatory syndrome is a “rare outcome,” it has nevertheless been documented in other systemically dosed AAV gene therapies, especially “above the 1E14vg/kg dose, which appears to be a cutoff for toxicity.” “The entire Neurogene team is sending our deepest condolences to her family and loved ones,” a company spokesperson said in a statement to BioSpace . “Neurogene is motivated by the improvements observed in multiple aspects of Rett syndrome in those who received the 1E15 vg dose, and we look forward to advancing NGN-401.” In its SEC filing on Thursday, Neurogene revealed that the FDA has allowed it to continue the Phase I/II study, but only using the lower 1E15 vg dose, which the regulator has cleared for administration in pediatric, adolescent and adult patients. Depending on the results of this study, the biotech intends to advance the gene therapy into registrational studies using its 1E15 vg dose. “Importantly, this outcome was concerned by FDA when deciding that the low-dose cohort could continue,” the BMO analysts wrote in their note, referring to the patient death. “This suggests that the FDA is aware of the nature of the SAE and likely agrees that it is related to AAV overexposure.” Rett syndrome is a rare genetic disorder that afflicts one in every 10,000 female births worldwide, and even fewer males. Babies with the disease suffer from the progressive deterioration of motor skills and impaired language and development. Rett syndrome also manifests as breathing problems, scoliosis and seizures. In its data drop last week, Neurogene revealed that even at the lower 1E15 vg dose, NGN-401 can elicit clinically meaningful benefits, with the first four treated patients achieving a “much improved” rating on the clinician-rated Clinical Global Impression Scale of Improvement. Patients also hit key developmental milestones or gained skills in at least one core Rett syndrome domain, such as language, communication, hand function, ambulation and gross and fine motor skills. According to Tapper and Seigerman, Neurogene is expected to provide more details regarding its registrational trial plans for NGN-401 in the first half of 2025, while more data from the Phase I/II study will come later next year. Beyond its troubles in Rett Syndrome, Neurogene on Tuesday also announced that it has suspended its Batten disease program after failing to win the FDA’s Regenerative Medicine Advance Therapy designation.