Here is the expert commentary. Very encouraging. Especially as we only need to repeat Ph2. As I posted a few days ago, after watching the interview with Dr Treagus, NEU are in discussions for Japan and Europe. ACAD are spending $65m on Ph3 trial, just for Retts, before they get s look at the results. And are committed to an even bigger spend on FX development.
I can’t see why NEU can’t demand at least $65m upfront for EU and another $35M upfront for Japan and that’s just for Rhett’s. This might be all wrapped up by the end of June. Of course ACAD could always come in over the top.
This article about the Retts trial should make shareholders feel a lot more comfortable.
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Expert Commentary
An editorial in the same issue of Neurology said the study “provides a remarkable glimpse into the future of targeted treatments for neurodevelopmental disorders.” Until now, the authors of the editorial noted, most of the targeted treatments that have shown promise in animal models have not translated to patients.
The positive findings in this trofinetide trial could have stemmed partly from evaluating younger children, including a placebo run-in, and utilizing measures designed specifically for Rett syndrome, the authors of the editorial said.
Embarking on a targeted treatment at a younger age may offer the most benefit to a child with Rett syndrome, said Randi J. Hagerman, MD, the editorial's corresponding author and medical director of the MIND Institute at the University of California, Davis, where she is distinguished professor and endowed chair in Fragile X research.
“The earlier you start treatment, the better the outcome in many of these neurodevelopmental disorders,” Dr. Hagerman told Neurology Today. “We see the same issues in Fragile X syndrome.”
In a young child, Dr. Hagerman suspects that controlling a protein's expression may have positive effects on the developing brain. As a result, “you build a better brain to handle the demands of developing normal cognition,” she said.
Targeting specific biochemical signaling systems in the brain marks the beginning of a new area in pharmaceutical trials for neurodevelopmental disorders, said Gregory N. Barnes, MD, PhD, associate professor in the department of neurology and director of the University of Louisville Autism Center in Louisville, Kentucky.
“There is still much more work to be done to determine whether this medicine will be safe and effective in Rett syndrome,” Dr. Barnes said. Nonetheless, “Rett syndrome is a paradigm for the heterogenous populations in neurodevelopmental disorders in which we test medicines.”
Investigators of future studies would want to “flesh out” the optimal dose, frequency, and mode of administration, as well as the time to a measurable effect. “Is 200 mg/kg BID really your top dose or not?” Dr. Barnes questioned. With the high cost of new medications, it would be ideal if a drug could work well at the lowest possible dose, he said.
The positive effects of trofinetide compared with placebo are encouraging, and participants' regression after stopping the medication at the trial's conclusion adds credibility to the results. However, Dr. Barnes said, trofinetide's performance over a longer period is important to ascertain.
“All drugs, and certainly anticonvulsant drugs, have their honeymoon effects, meaning that they can work for the first three to six months,” and then they may wear off, Dr. Barnes said. For other drugs, “the effect holds as long as the patient takes them.”
Sunil Mehta, MD, PhD, a psychiatrist at Mayo Clinic in Rochester, MN, commended the “very well-designed study” for providing “compelling evidence that trofinetide used to treat Rett syndrome should move into phase 3 clinical trials.” He added that the “data regarding safety was reassuring that a larger trial can be ethically conducted.”
As an exploratory study, the phase 2 trial “wasn't large enough or long enough to prove that this drug is safe for clinical use.” For instance, potentially rare events such as 1 death in 1,000 individuals would have evaded detection, Dr. Mehta said.
The fact that trofinetide is a derivative of insulin-like growth factor-1 raises concerns over the potential for long-term risks, such as cancer, weight gain, and hormonal imbalances. Determining these risks requires “months to years of monitoring patients on a medication before they are known,” he said.
Furthermore, the data raise a number of important questions for future researchers to ponder. For example, despite the overall separation from placebo on a number of symptom measures, a subset of patients taking the highest dose of trofinetide experienced significant improvements while others on this dose did not make any progress, Dr. Mehta said.
“Identifying the characteristics of these responders will be worthwhile moving forward,” he said. “In many neurodevelopmental disorders, clinicians have wondered if there are developmental windows or age ranges when a child is much more receptive to treatment. It would be fascinating to know if the patients who had the greatest response to trofinetide were also the youngest.”
As a phase 2 study, the trial convincingly encourages further investment into the drug, Dr. Mehta said. “If I were a parent of a child with Rett syndrome, this study would give me hope.”
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