Acadia, Neuren Headed To Phase III With Trofinetide In Rett Syndrome
Executive Summary
Positive Phase II data in the unmet medical need could mean patients will have a therapy specific to their disease, rather than burdensome symptom-by-symptom treatment.
Partners Acadia Pharmaceuticals Inc. and Neuren Pharmaceuticals Ltd. have unveiled positive Phase II data for pediatric Rett syndrome patients that puts their molecule, trofinetide, on track for launch of a Phase III study later this year.
No drugs are approved to treat Rett, meaning patients are treated with more general therapies specific to one of the symptoms of their disease. However, data from an 82-patient Phase II study in female Rett syndrome patients ages 5-15 that are being published in the April 16 edition of Neurology – and were posted online on March 27 – show efficacy across three syndrome-specific measures for trofinetide.
A 27-patient cohort treated with a 200 mg/kg twice-daily dose of the drug – a novel synthetic analog of the amino terminal tripeptide of IGF-1 – met statistical significance compared to placebo on three out of five measures. Overall, while the 200 mg/kg dose did not hit the other two. The companies did give results for the 50 mg/kg and 100 mg/kg doses but they will not be taken forward in Rett syndrome.
The largest dose met statistical significance on the caregiver assessment Rett Syndrome Behavior Questionnaire (RSBQ; p=0.042) and on two clinician assessments – the Clinical Global Impression Scale-Improvement (CGI-I; p=0.029) and the RTT-Clinician Domain Specific Concerns Visual Analog Scale (RTT-DSC; p=0.025).
RSBQ and CGI-I will be used as the co-primary endpoints in a planned 180-patient Phase III study of Rett syndrome patients aged 5-20 scheduled to launch in the second half of 2019, after the sponsors complete manufacturing scale-up activities.
Australian firm Neuren previously showed efficacy with the candidate in adult Rett syndrome patients. It licensed North American development and commercial rights to trofinetide to San Diego-based Acadia in August, getting $10m up front and up to $455m in milestone payments. (Also see "Deal Watch, Licensing Focus: Roche, Sanofi Exit Ongoing Anticalin Development Efforts With Pieris" - Scrip, 16 Aug, 2018.)
Trofinetide is thought to address Rett syndrome by reducing neuroinflammation and supporting synaptic function. In the current study, all three doses were generally safe and well tolerated, the companies said.
Study author Daniel Glaze, director of the Blue Bird Circle Rett Center at Texas Children’s Hospital, said Rett patients and their families currently face a significant therapeutic burden both in terms of cost and the potential side effects of multiple therapies to treat the individual symptoms of the syndrome. These can include motor function deficits, cognitive issues and gastrointestinal (GI) problems. A therapy specifically addressing the core symptoms of Rett syndrome should provide significant benefit to patients and their families, he told Scrip.
“These are individuals who lose the ability to utilize spoken language to communicate in an effective way, so if we can improve their communication abilities, if we can improve their attention, it will be helpful to them,” Glaze said. “In addition, it probably will have an effect on behavior as well as improving attention and cognitive function and motor function.”
When Rett patients have seizures, generally they are given anti-epileptic medications, he noted, and special diets are used to address the disease's GI manifestations. “The standard of care is specific to the symptom,” Glaze explained. “For example, many of the children and adult patients have a variety of GI problems, so we can address that, whether it be constipation, gastroesophageal reflux, nutritional problems, failure to gain weight. There are standards for treating those problems in general, but not Rett-specific standards.”
He added that the study’s significance is increased because efficacy was demonstrated on both clinician and caregiver assessments. That is why one of each was chosen for the Phase III program. “Having three different measures completed by two different groups of individuals with different experiences and backgrounds indicates that this is strong evidence that this will be an effective medication for Rett syndrome,” Glaze said.
Biomedtracker lists four candidates in clinical development for Rett syndrome, although one – BioElectron Technology Corp.’s EPI-743 – has not reported data since 2014. Besides trofinetide, the others are Newron Pharmaceuticals SPA’s Phase I/II sarizotan, a serotonin 1A agonist, and Biohaven Pharmaceutical Holding Co. Ltd.’s Phase I BHV-5000, an NMDA receptor antagonist.
Glaze said trofinetide is the first Rett candidate to demonstrate both safety and efficacy in the clinic.
Neuren retains rights to the drug outside North America; Acadia had an option to bid on those rights, but Neuren decided late in 2018 to hold onto them. The Australian firm also has completed a Phase II study with trofinetide in Fragile X syndrome.