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FDA Greenlights Neurogene’s ‘Best-Case Scenario’ Pivotal Trial Design for Rett Syndrome Gene Therapy

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FDA Greenlights Neurogene’s ‘Best-Case Scenario’ Pivotal Trial Design for Rett Syndrome Gene Therapy

SHERIDAN, WYOMING – July 1, 2025 – Neurogene has reached alignment with the FDA regarding the design of a registrational study for the investigational gene therapy NGN-401 for Rett Syndrome, enabling the company to convert its current Phase I/II study into a pivotal trial—a milestone that analysts describe as the “best-case scenario.”

The FDA has allowed Neurogene to run “a single-arm and baseline-controlled study with female patients aged three years and up,” according to the company’s announcement. NGN-401 will be administered at a single dose, with the trial assessing treatment responders as measured by the Clinical Global Impression-Improvement (CGI-I) scale and the achievement of developmental milestones or skills.

Analysts Call Agreement the ‘Best-Case Scenario’

In a note to investors on Monday, analysts at William Blair noted that reaching agreement with the FDA is the “best-case scenario” for Neurogene, “as it allows for fast conversion of clinical trial sites.” The agreed-upon trial design also involves “a favorable/feasible control strategy, rigorous primary endpoint, and broad age range,” according to the analysts.

The endpoint, in particular, poses a stringent definition of what a treatment responder is, they added: “We believe the demonstration of clinical benefit as measured through CGI-I will be helpful during future labeling and payer discussions, if approved.”

Key Differences Highlighted with Competitor’s Trial

Stifel analysts agree, writing in a note that Neurogene’s pivotal study protocol is both “favorable” and “doable.” The use of a small sample and a single study arm, in particular, “aligns with the bull case,” they added.

Both Stifel and William Blair compared Neurogene’s study design on Monday with that of Taysha Gene Therapies, which last month also reached alignment with the FDA on a pivotal protocol for its own Rett syndrome gene therapy TSHA-102. The two studies look similar, according to both analyst firms, except for some key differences.

“We see Neurogene’s trial as differentiated by the lower age bound . . . and the definition of responder,” William Blair explained. Stifel analysts likewise flagged the differences in what constitutes a responder, noting that Taysha’s trial employs a lower hurdle for establishing efficacy. Neurogene however intentionally chose a more rigorous endpoint “for the broadest label . . . which could offer a meaningful commercial advantage,” Stifel explained, citing conversations with the biotech.

Safety Developments and Regulatory Shifts

Monday’s news follows months after Neurogene revealed that a patient died in its Phase I/II Rett syndrome study after being treated with a 3E15-vg dose of NGN-401. The FDA at the time allowed Neurogene to push through with the trial, but only using a lower dose—the same dose to be used in the pivotal study.

The alignment with the FDA is also in line with statements from the agency’s new leadership signaling support for regulatory flexibility for gene therapies and rare diseases.

In April, for instance, Commissioner Marty Makary said that he is open to considering a new pathway for approving rare disease therapies based on a candidate’s “plausible mechanism.” If drugs have a mechanism of action that is “scientifically plausible,” then they could be approved on a conditional basis.

Vinay Prasad, director of the Center for Biologics Evaluation and Research, also said last month that his office will “rapidly make available” treatments for rare diseases by being flexible with regulatory requirements, such as allowing the use of regulatory endpoints. “We will take action at the first sign of promise for rare diseases,” he said at the time. “We’re not going to wait.”

Strategic Path Forward

With the FDA’s endorsement of Neurogene’s pivotal trial design, the company is positioned to advance NGN-401 with a study protocol that balances scientific rigor with operational feasibility. Analysts believe the rigorous endpoint and control strategy could enable the broadest possible labeling if the therapy gains approval, potentially reshaping treatment options for Rett syndrome patients.

Learn more at www.neurogene.com.