FDA signs off on pivotal trial design for NGN-401 gene therapy
Evidence from Embolden could support application for approval
Neurogene has received written agreement from the U.S. Food and Drug Administration (FDA) for a registrational trial of NGN-401, a gene therapy candidate for Rett syndrome. A registrational, or pivotal, trial is designed to provide the evidence needed to support an application for FDA approval.
“We appreciate the partnership with the FDA as we aligned on the key elements of our NGN-401 registrational trial design, which will allow for rapid conversion of the current Phase 1/2 study to a pivotal trial,” Rachel McMinn, PhD, founder and CEO of Neurogene, said in a company press release.
The company also announced its design for the study, called Embolden, including outcome metrics developed with input from Rett caregivers. Data from an ongoing Phase 1/2 trial (NCT05898620), which has completed enrollment, supported the trial design. Neurogene has begun steps to launch the registrational trial, according to the press release.
Non-disease-causing virus carries genetic material to brain cells
Rett is a neurodevelopmental disorder that primarily affects girls and is typically caused by mutations in the MECP2 gene. This gene contains instructions to manufacture a protein of the same name, which helps regulate the activity of other genes. Reduced activity of the MeCP2 protein can impact various aspects of brain development, leading to delays in motor and cognitive skills, as well as other symptoms.
With NGN-401, Neurogene aims to provide a functional copy of MEPC2 to brain cells, allowing them to manufacture their own MeCP2 protein. A virus, engineered so as not to cause disease, carries this packaged genetic material to brain cells. The therapy is injected into fluid-filled cavities in the brain via a one-time infusion.
While too little MECP2 activity can be harmful, so can overly high levels of the protein. To help achieve a safe balance, NGN-401 uses Neurogene’s EXACT gene therapy technology, which can regulate the gene’s activity in each cell individually.
In mouse models of Rett and healthy primates, EXACT machinery allowed animals to tolerate the therapy. Without this component, delivering a copy of MECP2 resulted in severe toxicity. NGN-401 improved survival in the mouse model.
Participants treated with NGN-401 have demonstrated increased independence, with both fine and gross motor function improvement, and gained the ability to better communicate wants, needs and choices.
These findings supported the Phase 1/2 trial, which has dosed five girls so far. Initial data showed mild adverse events with a low dose of the therapy (1x1E 15 vector genomes). After a severe immune reaction in one participant on a higher dose (3x1E 15 vector genomes), the trial proceeded with the low-dose regimen.
Results from the first four girls dosed with the low dose showed that NGN-401 led to new developmental milestones and seen meaningful gains in skills, with improvements in hand function and fine motor control, language and communication, and walking and gross motor function. Benefits were also noted on the Clinical Global Impression-Improvement (CGI-I) scale, which reflects the clinician perspective of improvement
“Participants treated with NGN-401 have demonstrated increased independence, with both fine and gross motor function improvement, and gained the ability to better communicate wants, needs, and choices,” Elizabeth M. Berry-Kravis, MD, PhD, principal investigator in the clinical trial, said in the press release. “I have been impressed with the improvements observed in participants after NGN-401 administration, which have included global improvement in signs and symptoms of Rett syndrome and gains of multi-domain developmental milestones that would not be expected to occur spontaneously in the post-regression stage of Rett syndrome.”
Study participants serve as their own control
Embolden will include participants ages 3 and older. This choice followed analysis of an International Rett Syndrome Foundation (IRSF)-sponsored natural history study, which showed that individuals with Rett in this age range don’t typically learn new skills or reach new developmental milestones. With no spontaneous improvement expected, researchers can likely attribute any functional gains in this population to the therapy.
”Evaluating treatment effect in participants ages 3 and above in the registrational study will provide important insights on the potential benefits of NGN-401 in younger patients early in the course of this progressive disease,” Berry-Kravis said.
Approximately 18 females will participate in Embolden, per Neurogene’s proposal. All participants will receive the gene therapy, with each individual acting as their own control. This means that researchers will measure developmental outcomes relative to each person’s starting point.
The study’s primary outcome is a combined metric of whether participants respond to the therapy. This includes CGI-I score changes and gains of one or more items from a list of 28 developmental milestones and skills. Data from a caregiver survey helped generate this list of functional gains that caregivers would consider clinically meaningful.
”We appreciate the thoughtful design of the trial that importantly incorporates the caregiver perspective on what meaningful improvement may look like,” said Monica Coenraads, founder and CEO of the Rett Syndrome Research Trust.
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