Rett girl has severe immune reaction to high dose of NGN-401
Trial continues with low-dose regimen following FDA review of safety data
A girl with Rett syndrome participating in a clinical trial testing gene therapy NGN-401 experienced a serious, treatment-related immune reaction.
The patient, who received a high dose of NGN-401 in an ongoing Phase 1/2 trial (NCT05898620), experienced signs of systemic (body-wide) hyperinflammatory syndrome, a rare and life-threatening immune response associated with exposure to high doses of the adeno-associated virus (AAV), the gene therapy’s delivery vehicle. She was in critical condition, as the case continued to evolve.
Developer Neurogene said it “proactively engaged” with the U.S. Food and Drug Administration (FDA) under the START program, which provides enhanced communications with the agency, after it was notified of the event.
After reviewing safety data, the FDA allowed the trial to proceed with the low-dose regimen. Further high-dose treatments have been discontinued, and the company said it no longer expects to complete enrollment in the low-dose group by the end of this year.
“We are deeply saddened for the family,” Rachel McMinn, PhD, founder and CEO of Neurogene, said in a company press release. “While no words could possibly provide comfort to her family, we ask the Rett syndrome community to join us in sending heartfelt thoughts to her family, friends and the dedicated clinicians who are caring for her. The safety of the participants in our clinical trial is and remains our foremost priority as we work to find solutions for this devastating disease.”
Gene therapy infused into brain
In most Rett cases, mutations in the MECP2 gene disrupt the function of MeCP2, a protein that controls the activity of other genes. As a result, the growth and connectivity of nerve cells is impaired, giving rise to disease symptoms.
NGN-401 is a one-time treatment that provides a full-length version of the MECP2 gene. It’s infused directly into the brain’s fluid-filled cavities carried by an AAV engineered to be safe, aiming to restore the production of a healthy MeCP2 protein and ease symptoms.
The Phase 1/2 trial was designed to enroll up to 16 girls with Rett, ages 4-10, at five sites in the U.S., two in the U.K., and one in Australia.
So far, none of the five girls who received a low dose of NGN-401 (1x1E 15 vector genomes) or the two other girls who received the high dose (3x1E 15 vector genomes) has experienced a serious treatment-related adverse event. All adverse events in the low-dose group have been mild, according to Neurogene.
Most treatment-related adverse events are known risks of AAV exposure and have responded to steroids. There have been no signs of toxicity related to too much MeCP2 or the administration procedure.
Efficacy data reported earlier this month showed that a low dose of NGN-401 led to new developmental milestones and meaningful gains in skills in the first four girls dosed. Clinicians and caregivers have confirmed these improvements, and each of the girls experienced fewer problems related to swallowing, constipation, and sleep.
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