Neuren AGM 30th May, page-27

i think this summary provides a clear precis of the FDA decision to approve Trofinetide
https://www.fda.gov/media/168491/download

Benefit-Risk Integrated Assessment (extract from pg 15-16)
The evidence of effectiveness has some limitations, including concerns with the quality of the primary outcome measure, the
RSBQ, and disproportionate adverse events, drug discontinuations, and concomitant medication use in the trofinetide group.
However, application of regulatory flexibility allows for the determination of substantial evidence of effectiveness based on one
adequate and well-controlled study with confirmatory evidence given the unmet need in this rare, severe, and life-threatening
disorder.
The safety profile of trofinetide is acceptable to support approval. The two most common adverse reactions, diarrhea and
vomiting were very frequent and led to withdrawal of 40% of subjects in long term studies. Though generally rated as mild to
moderate in severity, labeling will ensure that prescribers, caregivers, and patients are aware of these adverse reactions. For
immobile patients, chronic diarrhea has the potential to lead to multiple serious complications if not anticipated, prepared for,
and treated. The potential for weight loss, or inadequate weight gain during development, along with a potential for worsening
baseline seizures may also be safety concerns for trofinetide but are monitorable conditions. The high rate of concomitant use of
antidiarrheals should also be monitored given that they may carry their own risks. However, these safety concerns are
monitorable and addressable.
In conclusion, the Applicant has met the evidentiary standard of substantial evidence of effectiveness. Safety risks are
monitorable and treatable. In the Voice of the Patient report of the externally-led patient focused drug development meeting of
March 11, 2022, patients and caregivers expressed a dire unmet therapeutic need for treatments that directly address Rettsyndrome, to improve communication and hand use, and their willingness to try anything to lessen the suffering of patients.
Given that Rett syndrome is a rare, severe, and life-threatening condition, it is appropriate to apply regulatory flexibility in
accepting one well controlled and adequate study along with confirmatory evidence to establish the effectiveness of trofinetide
for the treatment of Rett syndrome. Therefore, this reviewer recommends approval of trofinetide. Trofinetide will be the first FDA
approved treatment for adults and pediatric patients 2 years of age and older with Rett syndrome