A girl with Rett syndrome dosed with Neurogene’s gene therapy for the condition died last week, the company reported in a U.S. Securities and Exchange Commission filing on 20 November. Neurogene subsequently halted tests of the dose the girl had received but plans to continue testing a lower dose.
On 5 November, the girl received 3E15 vector genomes (vg) of the therapy, NGN-401, as part of the high-dose group in an ongoing open-label clinical trial in girls aged 4 to 10.
After the girl began experiencing signs of a systemic immune reaction, the U.S. Food and Drug Administration (FDA) reviewed safety data from girls in a low-dose group who had received 1E15 vg of NGN-401 and allowed Neurogene to proceed with the trial at that dose, but “the Company is updating the trial protocol to remove the 3E15 vg dose,” according to a statement a Neurogene spokesperson shared with The Transmitter. The company “does not plan to enroll any further participants” in the 3E15 vg dose group, a press release says.
“The high dose in this trial is being stopped, but the trial itself is not being stopped, which I think means that the FDA has enough data on the safety and the efficacy to weigh that risk-benefit ratio,” says Kyle Fink, associate professor of neurology at the University of California, Davis. On 11 November, Neurogene shared that the first four participants in the low-dose group demonstrated improvements in language and communication, hand function and gross motor skills and had experienced no serious adverse events.
“Time will tell, but I think it’s incredibly encouraging that patients are showing levels of improvement and that it seems to be safe in those patients,” Fink says. “The metrics that [Neurogene] is sharing in terms of how the patients are doing seems to be highly encouraging.”
The therapy contains a copy of the gene that encodes the MECP2 protein; the gene’s output is diminished in Rett syndrome, which causes the condition’s characteristic communication difficulties, intellectual disability and motor dysfunction. The gene is delivered through an adeno-associated virus serotype 9 (AAV9) vector. Two other girls in Neurogene’s trial have received the high dose, and five girls have received the lower dose.
NGN-401 is one of several Rett therapies under development, including another gene therapy—TSHA-102 from Taysha Gene Therapies—that is currently being tested in two ongoing clinical trials: one in girls aged 5 to 8 and another in girls and women aged 12 and up (Taysha declined to comment for this story). The FDA approved the first drug for Rett syndrome, trofinitide, in March 2023.
The participant’s death in the Neurogene trial is “devastating” but does not necessarily change the landscape of therapy development or the position of one company against another, Fink says, because “it’s still incredibly early.” The researchers involved in clinical trials are still trying to learn things such as how much of a therapy reaches the brain and how much MECP2 it produces, he adds. “You hope that when things like this happen, that the whole field learns from it and continues to improve and move forward.”
This adverse event is “an n of 1” but still provides knowledge about brain-directed gene therapy, says Eric Marsh, professor of neurology and pediatrics at the University of Pennsylvania. Marsh has spoken with Neurogene and Taysha about leading a clinical trial site for both therapies but has not joined either trial. “I think it starts to tell us about, potentially, ‘What is the upper limit of safe dosing for an AAV9?’” he says. But “it’s just one data point. A really bad, terrible data point, but one data point.”
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eurogene first announced during an investor briefing on 11 November that one of the three participants in the high-dose group had developed a serious adverse event, but the company did not provide any details. After sharing the preliminary results from the low-dose group, Neurogene announced that they planned to expand the high-dose arm into adolescents and adults aged 16 and older.Those plans have changed. On 18 November, Neurogene shared that the participant was in “critical condition” and had developed signs of “systemic hyperinflammatory syndrome, a rare and life-threatening immune response” linked to high AAV doses, according to a press release.
Although it is uncommon, participants have died from immune reactions to high doses of AAV vectors in clinical trials for spinal muscular atrophy and Duchenne muscular dystrophy gene therapies. Viral vectors can cause liver toxicity and trigger a systemic immune reaction, particularly when administered through an intravenous (IV) injection. Some researchers are working to develop non-viral vectors for gene therapies to circumvent this issue.
Delivery methods that target the central nervous system, however, typically cause a milder reaction. NGN-401 is delivered directly to cerebrospinal fluid in the ventricles of the brain, also known as intracerebroventricular (ICV) administration. In 2017, a 2-year-old boy with Canavan disease received gene therapy through simultaneous IV and ICV delivery and did not experience any adverse events. TSHA-102 is injected into cerebrospinal fluid in the spinal cord.
Because of these administration routes, the main safety concern for Rett syndrome gene therapies was not adverse reactions to the vector but potential toxicity caused by creating too much of the MECP2 protein, says Walter E. Kaufmann, adjunct professor of human genetics at Emory University School of Medicine and visiting scientist at Boston Children’s Hospital. Kaufmann is not involved in the Neurogene clinical trial but has worked as a consultant for Taysha Gene Therapies.
“Nonetheless, the reported event is an event of an immune reaction that certainly shows that an inflammatory response can be present even when you administer more directly into the CNS,” Kaufmann says.
Data from other trials suggest that “some of the AAV does leak into the periphery no matter what,” Fink says, even when it is delivered directly into cerebrospinal fluid compartments. “Some of it’s going to get out.”
This event doesn’t upend the knowledge that direct-to-brain administration produces a milder immune response than an IV, Marsh says. “The issue, though, is at what dose does enough get out that it starts to elicit the same systemic response that systemic administration does?” he adds. “That’s the unknown.”
