De-Risking Treatment Development: Paving the Way for Therapeutic Successes

The Foundation for Prader-Willi Research (FPWR) employs a "de-risking" funding strategy to accelerate the development of new treatments for Prader-Willi syndrome (PWS). We are here to take the risks, fund new ideas, and help build the resources that will advance treatments to the finish line.

As a rare disease, PWS lacks the substantial funding that more common conditions like cancer may receive. This means we must be strategic with our investments to make the most of our limited resources. One way we maximize our impact is by making small, seed investments in early-stage research, allowing projects to advance to a stage where they can attract essential partnerships that support their further development.

Drug development is inherently risky, with countless obstacles that can prevent a promising new treatment from reaching patients. FPWR takes on the early risks, funding and supporting the initial stages of promising research through both financial resources and collaborative guidance. This early support makes investments in drug development more appealing and less risky for pharmaceutical partners. The goal of FPWR’s de-risking approach is to advance early-stage research to a point where larger companies or federal agencies, with the resources needed to bring a treatment through the final stages, can take it forward and ultimately deliver it to individuals with PWS.

In this post, we highlight three examples of FPWR’s de-risking approach that are paving the way for groundbreaking advancements in Prader-Willi syndrome research.

DCCR: The First Potential Treatment for Hyperphagia in PWS

In 2014, a small biotech company aimed to conduct a Phase 2 clinical trial to evaluate the safety and efficacy of DCCR for treating hyperphagia in PWS. Recognizing the potential of this treatment, FPWR made a critical financial investment to ensure this study could move forward. Feedback from reviewers in the FPWR grant program helped refine the clinical trial protocol to more efficiently achieve its goals.

As DCCR progressed, FPWR’s contributions continued to play a pivotal role. Data from the PATH for PWS study—a natural history sub-study within the Global PWS Registry—was used to compare natural history data of hyperphagia in PWS against outcomes from the DESTINY-PWS Phase 3 clinical trial (Strong et al., 2024). Results showed statistically significant improvements in hyperphagia for individuals taking DCCR compared to the natural progression observed in the PATH for PWS study. This comparative data was instrumental in the biotech company’s discussions with the FDA, supporting the advancement of the DCCR program.

Today, thanks to these collaborative efforts, a New Drug Application (NDA) for DCCR has been submitted, and we await the FDA’s decision on next steps. FPWR's early and continued support has been essential in de-risking and propelling this promising treatment forward for the PWS community.

Vagus Nerve Stimulation: A Potential Treatment of Behavior Outbursts in PWS

Two small pilot studies, partially funded by FPWR, have shown that vagus nerve stimulation may offer significant benefits for individuals with PWS. However, due to limited commercial incentives for devices, there was no clear path forward for this promising technology. To address this challenge, FPWR has stepped in to advance vagus nerve stimulation (VNS) for managing behavioral outbursts.

FPWR is conducting a multi-center, phase 3 VNS trial across the U.S., known as the VNS4PWS trial. This study will evaluate the safety and efficacy of VNS for reducing temper outbursts in PWS. It will enroll around 100 participants, ages 10 to 40, with PWS and a history of behavioral challenges. With an estimated cost of $1.3 million, VNS4PWS represents FPWR’s largest single research initiative to date, with the ultimate goal of making this device available to all individuals with PWS who would benefit from it.

Targeting SMCHD2 To Accomplish Genetic Therapy for PWS: Addressing the Underlying Cause of PWS and SYS

Genetic therapies have the potential to provide transformative treatments in PWS and are attractive because they seek to directly correct the underlying issue in PWS—the lack of expression of several critical genes in the PWS region of chromosome 15. In theory, such an approach might simultaneously improve many aspects of PWS.

SMCHD1 is an important regulator of the PWS cluster of genes on chromosome 15. Inhibiting SMCHD1 could, therefore, be a potential new treatment for PWS and SYS by returning the function of the PWS genes at the cellular level. FPWR has supported Dr. Marnie Blewitt’s initial studies that demonstrated the feasibility of this gene therapy approach and paved the way for an additional $5M investment from “WEHI Ventures 66ten.” With the additional funds, Dr. Blewitt’s team will continue developing a new drug that inhibits SMCHD1 function and possibly transforms the lives of people with PWS.

Through strategic investments and innovative collaborations, FPWR is accelerating the development of potential therapies for PWS and SYS. We remain committed to continuing our pioneering role, de-risking initiatives that have the potential to transform the lives of people with Prader-Willi and Schaff-Yang syndromes. Together, we will one day have treatments so that our loved ones can live full and independent lives.