Rare disease drug development in the news: What does this mean for the Phelan-McDermid syndrome community?

Measuring Change that Matters

One important consideration in any clinical trial is how researchers measure whether a treatment is helping. In order for the FDA to consider a treatment for approval, these measures, called endpoints, need to capture changes compared to baseline and compared to a placebo (if part of the clinical trial). But perhaps more importantly, these measures must capture changes that matter in daily life.

What does this mean for Phelan-McDermid syndrome?

This is why PMSF is so focused on projects developing and validating new outcome measures, especially those that are tailored for individuals with developmental delay, intellectual disabilities, or limited or no verbal speech. PMSF has partnered with projects like Inchstone and ORCA, which attempt to measure meaningful change in populations like Phelan-McDermid syndrome. We also have invested in projects like ROSCO and PIP-2 through our PMSF Grant Program to design and validate new measures of communication and severe neuropsychiatric illness, both of which are meaningful symptoms identified by our community. 

The Angelman trial used the Bayley-4 cognitive assessment as its primary endpoint. Measuring changes in cognition can be challenging for individuals with significant developmental delays. A person may gain meaningful skills that an assessment does not fully capture. However, we do not yet know whether limitations in measurement contributed to this trial’s outcome.

For Phelan-McDermid syndrome, this highlights the importance of developing and validating tools that can capture meaningful changes across different abilities and ways of communicating. PMSF supports this work through projects focused on communication and neuropsychiatric symptoms, helping researchers prepare to evaluate potential treatments.

Dosing and Treatment Effects

Unlike AAV-based gene therapies, which are generally designed to be administered once, ASO therapies typically require repeated doses because their effect can decrease over time. For ASOs delivered into the cerebrospinal fluid (CSF), researchers must understand how well the therapy reaches its target, how much it changes the intended protein, and how long those effects last. These factors help determine the appropriate dose, dosing schedule, and timing of clinical assessments.

What does this mean for Phelan-McDermid syndrome?

Preclinical studies in rodents and non-human primates can provide important information about how well a potential ASO therapy reaches the central nervous system (including the brain), how much it increases SHANK3 protein, and how long those effects last. As programs like PYC’s move toward human trials, these findings will help inform dosing strategies and clinical study design. Including caregivers’ observations of when potential benefits emerge and how they change over time will also be important.

Clinical Trial Design

Strong clinical trial design is essential for determining whether a treatment is effective. Phase 1/2 trials (like JAG201) are often open-label, meaning everyone knows who is receiving treatment. These studies provide critical initial data on potential efficacy, but they can be influenced by “expectancy effects”. When families, clinicians, or researchers know someone is receiving a promising treatment, their expectations can unintentionally influence how changes are observed, reported, or assessed, even on standardized assessments. Expectancy effects are well-documented in the literature across medical conditions and different treatment types. 

This is why randomized, double-blind, placebo-controlled trials (see our glossary) are important for determining whether improvements are due to treatment rather than other factors. 

What does this mean for Phelan-McDermid syndrome?

As more treatments move into clinical trials for Phelan-McDermid syndrome, rigorous study design will be essential for understanding their effectiveness. Families also play an important role in protecting trial integrity by being mindful of how sharing treatment experiences could unintentionally influence other study participants or study evaluators. This is why we have provided guidance on sharing experiences during clinical trials. 

Progress, Patience, and Persistence
Developing new treatments for rare diseases takes time, and success is never guaranteed. From first dosing to FDA approval, the gene therapy for Sanfilippo syndrome type A took approximately 10 years, while the ASO therapy for Alexander disease took approximately 5 years. Although each treatment follows a unique development and regulatory pathway, these examples remind us that even promising therapies typically require several years of research and clinical trials before reaching approval.

For Phelan-McDermid syndrome, JAG201 is still in the early stages of clinical development, with the first child receiving treatment in 2025. The ongoing Phase 1/2 trial is evaluating its safety and looking for early signs of benefit. JAG201 has received FDA Fast Track and Rare Pediatric Disease designations, which recognize important unmet needs and provide opportunities to facilitate development and regulatory review. While these are encouraging milestones, they do not guarantee approval or establish a timeline for when a treatment may become available. 

Another encouraging development is FDA’s recently announced Rare Disease Framework Initiative, which aims to provide a more flexible approach to evaluating treatments for rare diseases, recognizing challenges such as small patient populations and the difficulty of conducting traditional clinical trials. For Phelan-McDermid syndrome, this reinforces the importance of PMSF’s investments in natural history research, meaningful outcome measures, and incorporating family perspectives into research. While still being developed, this initiative represents a promising step toward addressing the unique challenges of rare disease drug development. As PMSF’s Chief Science Officer, I will be submitting a response to the FDA to help ensure that the needs and perspectives of the Phelan-McDermid syndrome community are considered as this framework develops.

Because drug development also comes with setbacks, and many promising therapies never reach FDA approval, this is why it is so important to pursue multiple therapeutic approaches for Phelan-McDermid syndrome, including gene therapy, ASOs, and small molecules. Different treatments may target different aspects of the condition, and not every approach will work equally well for every individual. 

PMSF continues to support basic and translational research through our grant program to help identify new therapeutic avenues and opportunities to repurpose existing drugs. Ultimately, our goal is to build a diverse pipeline of potential treatments rather than rely on the success of any single program.