Trofinetide Approval Brings Encouragement for Rett Disease, Rare Neurodevelopmental Disorders


Jeffery Neul, MD, PhD, director of the Vanderbilt Kennedy Center, and professor of pediatrics at Vanderbilt University Medical Center, shared his reactions and thoughts to the approval of trofinetide.

Jeffrey L. Neul, MD, PhD, Annette Schaffer Eskind Chair and director, Vanderbilt Kennedy Center; professor of pediatrics, Vanderbilt University Medical Center

Jeffrey L. Neul, MD, PhD

On March 10, 2023, the FDA approved trofinetide (Daybue; Acadia Pharmaceuticals) for the treatment of Rett syndrome in adult and pediatric patients 2 years of age and older, supported by data from the phase 3 LAVENDER study (NCT04181723). The treatment, a novel synthetic analog of the amino‐terminal tripeptide of IGF-1 designed to potentially reduce neuroinflammation and supporting synaptic function, is the first and only approved therapy for Rett syndrome.1

The phase 3 study included a total of 187 female patients with Rett syndrome between the ages of 5 and 20 years evaluated over a 12-week period. The data demonstrated statistically significant improvement compared with placebo on both co-primary efficacy end points, as measured by the change from baseline in Rett Syndrome Behavior Questionnaire (RSBQ) total score (P = .018) and the Clinical Global Impression-Improvement (CGI-I) scale score (P= .003) at week 12.

Following the approval, Jeffery Neul, MD, PhD, the director of the Vanderbilt Kennedy Center, and professor of pediatrics at Vanderbilt University Medical Center, sat down in an interview with NeurologyLive® to share his initial reaction to the FDA’s decision. In addition, he offered a brief overview of the data as well as how he sees the shift in the landscape of care with this new approved therapy for Rett syndrome. Neul also spoke of some considerations that clinicians should be aware of when prescribing this treatment.

NeurologyLive®: What was your immediate reaction to trofinetide's approval?

Jeffery Neul, MD, PhD: Well, I was pretty excited. We've been living in a world where we've only been able to treat people with Rett syndrome using symptomatic treatments that were not designed for the condition or never tested in Rett. Having an actual first approved drug for Rett Syndrome by the FDA is a very exciting event to see happen. It's a combination of multiple decades of research, going back even before the gene discovery. Since the gene discovery in 1999, and development of animal models to be able to evaluate possible therapies preclinically, we’ve moved into these phase two and 3 trials, successfully meeting endpoints. It's nice to see this combination of all that research.

In the field of neurodevelopmental disabilities and neurodevelopmental disorders, unfortunately, there have been a lack of approved therapies. It was the first FDA approval specifically for Rett syndrome and not a drug that was previously approved for another condition and repurposed for use in Rett syndrome. Not only is this the first drug approved for Rett syndrome it's also the first drug approved broadly for a neurodevelopmental disorder, rather than just for a specific symptom like seizures. I think that's very encouraging.

One of the things that I find most encouraging and exciting is that it can be done. You can do a successful clinical development through a phase 3 and get an FDA approval for a drug in neurodevelopmental disorders. This applies with a number of other instances and conditions, like in Fragile X and Angelman syndrome, where there have been enough failures that people are starting to get cold feet about doing this research. I hope that this helps encourage people to realize that, “Yes, we can do research in these disorders, and we can ultimately be successful to see drugs move to the point of getting FDA approval.”

How do you anticipate the introduction of this therapy will change the landscape of care? Do you foresee any added positive downstream effects on care or drug development?

Having an approved drug for Rett syndrome is going to change the landscape of how we take care of patients with Rett syndrome. But I think we're going to continue to see treatments and we're going to continue to see trials in Rett syndrome. This is even encouraging for that. Other than now, there's evidence that things can be done. I think this is just the beginning of other clinical trials assessing other approaches in Rett and probably some of them successfully achieving their goals. Yes, it also does encourage the concept of clinical trials in these other rare neurodevelopmental disorders.

Could you offer an overview of the data to this point on trofinetide?

The phase 3 trial had 2 coprimary endpoints. One was a caregiver rated scale called the Rett Syndrome Behavior Questionnaire and the other is a scale called the Clinical Global Impression Improvement. Both of them were chosen in favor of trofinetide and used during the double-blind lavender trial. The key declared secondary endpoint was a communication scale, caregiver rated communication scale. They've also presented some results about the open label extension that occurred. I can't quote them exactly, but it showed similar movement on both of those measures for the people who crossed over from placebo into the open label to those who had been on trofinetide continuously.

Are there any considerations that physicians should take when using this therapy and are there any adverse events of interest or monitoring?

Well, I think, the most common treatment and merchant adverse event was diarrhea and vomiting. Diarrhea is very unusual in Rett syndrome. Most people who had Rett syndrome are severely constipated. We have to give a lot of medications like laxatives and other things to try to address patient constipation. This is quite the opposite direction. I think that for clinicians when thinking about starting this, they're going to have to think about how to manage this potential side effect. During the course of the trial, the company started developing management plans. I think they're continuing to do that, and probably will grow out. The post approval phase will provide support for these clinicians in the management.

Is there anything else you think is important for the clinical community to know about this drug?

I have to admit, I've read the press release, but I haven't read the anything actual details about what they said. But what I did see is that they said it was [approved for] ages 2 and up. It doesn't seem like there's no upper limit of age, as far as I can tell, which I think is good because previously, the first double blind phase 2 trial was in adults with between 16 and 45 years old, and that showed signals of efficacy. Then there was a phase 2 trial that was in children aged 5 to 20 years old. It wasn't clear what was going to be the age range that would be approved, and what I understand it's just over 2 years old. That's just something to know that I think opens up a lot more people who could potentially be on this.

It's very exciting not only just for Rett syndrome, but really for neurodevelopmental disorders. I think it will help for other people who have other disorders and their families, but also hopefully keep interest in the people who are developing and testing drugs for these conditions.

Transcript edited for clarity.

1. Acadia Pharmaceuticals Announces U.S. FDA Approval of DAYBUE™ (trofinetide) for the Treatment of Rett Syndrome in Adult and Pediatric Patients Two Years of Age and Older News Release. Acadia Pharmaceuticals. March 10, 2023. Accessed March 13, 2023.
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