Natural History of Rett Syndrome and Managing Adverse Events with Newly FDA-Approved Trofinetide

Robin Ryther, MD, PhD

Trofinetide (Daybue; Acadia Pharmaceuticals) is a novel synthetic analog of the amino‐terminal tripeptide of IGF-1 aimed to potentially reduce neuroinflammation and supporting synaptic function. Recently, the FDA approved the agent for the treatment of Rett syndrome in adult and pediatric patients 2 years of age and older in late-March 2023, making it the first approved therapy for the condition. The approval was supported by findings from the phase 3 LAVENDER study (NCT04181723).¹

The study included 187 female patients with Rett syndrome between the ages of 5 and 20 years who were evaluated over a 12-week period. Results showed statistically significant improvement compared with placebo on both coprimary 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. Diarrhea was among the most common adverse events, reported by 80.6% of patients in the treatment group versus 19.1% in the placebo. Also, vomiting was reported, affecting 26.9% of patients in the treatment group versus 9.6% in the placebo.

Robin Ryther, MD, PhD, director of the Rett Spectrum Clinic at Washington University in St. Louis School of Medicine, sat down in an interview with NeurologyLive® to share her response to the recent approval. In addition, she talked about previous research conducted in the field and how the therapy could change the landscape of care for patients with Rett syndrome. Ryther also spoke about the possible positive downstream effects the approval could have on other treatment developments, as well as provided some recommendations for what clinicians should be aware of when prescribing the treatment to their patients.

NeurologyLive®: What was your immediate reaction to the approval of trofinetide?

Robin Ryther, MD, PhD: Over the moon excitement! For most physicians, we don't get an opportunity to experience a moment like this in our career, where we have a new treatment, a new option to help families that never had an option before. It’s absolutely exciting to find out what's going to happen next.

What happens next and how do you anticipate the introduction of this therapy to change the landscape of care?

One of the reasons that we got to the place that we're at is the Natural History Study [NCT02738281] that was initially under the direction of Alan Percy, MD. This was a 20-year plus study that helped us to learn about the full breadth and detail of what can happen to patients with Rett syndrome. That laid the groundwork for us to then understand if an intervention would change that background. From that perspective, we get to start that work over again, because now we have to find out what the natural history of Rett syndrome is when you're exposed to trofinetide. We hope certainly, in most cases, as soon as possible and as young as possible.

Do you foresee any added positive downstream effects on care, or drug development?

As a group, rare diseases are incredibly common but individually, they're very rare. One of the battles we've always fought is education. Whether it's education to families themselves, education to other physicians, education to the community at large. As part of this moment, we also get more press. There's more exposure to Rett syndrome itself, which helps more and more people learn about it, and hopefully understand it.

The second layer to that discussion is for all rare diseases, it helps prove it's possible. We've been very privileged to work with incredibly dedicated, highly organized, very passionate families. It is their work, and their willingness for 20 years to drive multiple states away to participate in things like the Natural History Study. It prepared them to be part of this study and it prepared them to be part of the creation of a treatment. Without that background, we're not where we are today. It might have taken us another 15 years. For all rare diseases, this brings hope, not just for Rett syndrome, but for all groups that can say “yes, we can do this, we can get companies interested in something that doesn't have the same numbers as Down syndrome or as more in common diseases like epilepsy.” At the same time, it can be a successful drug trial and bringing a treatment to market that is going to be helpful and beneficial.

Are there any considerations that physicians should take when using this therapy when prescribing it to patients?

One of my biggest concerns is that it does have a pretty substantial side effect in terms of vomiting and diarrhea. The numbers for weight loss are also fairly large. My initial assumptions entering the trial, about how to manage those were wrong. My concern for patients and families and their physicians who may be less familiar with drugs, is that they'll give up too easily. As we start this treatment, if they get one of those roadblocks, and it's particularly a difficult roadblock to solve, if they give up and move on, then they won't have this opportunity to be treated. From that perspective, I think that's going to be one of our biggest challenges nationally, to make sure that we're educating not just the families, but the physicians who will also be taking care of them.

How do we manage a world where we flip our entire discussion of constipation to now diarrhea, and who's going to be most at risk? How do we manage it? The level of aggressive, immediate treatment that requires that, I would have been terrified at the start of the study to do. Now I know, “nope, stop everything, stop doing this from dose one.” There are just some quirks to it. Without that familiarity, you may not be as successful in treating it. If you're not as successful in treating it, and you stop the drug, well, then you can't benefit from the drug either.

Transcript edited for clarity.

REFERENCES
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 April 4, 2023. https://acadia.com/media/news-releases/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/