Pitt-Hopkins Syndrome

When Siren Biotechnology CEO Nicole Paulk learned last month that top FDA official Peter Marks had resigned , she began looking outside the US for a place to host a planned clinical trial. The US has traditionally attracted drug studies with its robust infrastructure, diverse patient population and a smoother regulatory path to the world’s largest pharmaceutical market. But growing uncertainty over the FDA’s timelines and approval processes appears to be accelerating an existing paradigm: US drugmakers testing their drugs abroad. That follows the Trump administration’s cuts to the FDA and the departure of high-profile officials like Marks, who cited vaccine misinformation promoted by HHS Secretary Robert F. Kennedy Jr. in his resignation letter. Although best known for regulating vaccines, Marks also oversaw the review of cell and gene therapies. San Francisco-based Siren, which developed a gene therapy targeting aggressive brain cancers, has been pursuing FDA approval to start human testing in the US. But after Marks’ departure, the company is considering Canada for what could be a more predictable regulatory environment. “If I knew the FDA’s position definitively on certain regulatory pathways, that would be very different. But you can’t put all your eggs in one basket,” Paulk said. In a statement forwarded by a spokesperson, the FDA said “companies can remain confident in the strength, stability, and reliability of the FDA’s regulatory processes,” and that the agency is “not seeing any interruption in core program functions.” Likewise, some companies say that the FDA’s engagement has not fallen by the wayside, including vaccine maker GSK . FDA Commissioner Marty Makary meanwhile has vowed to accelerate approvals for rare disease therapies , reduce animal testing requirements and streamline development timelines. For companies, his words are promising but only aspirational at this point. “Since we are in the ultra-rare disease space, Makary’s words on creating paths for rare [diseases] creates hope, and we are looking forward to learning more about his plans,” Mahzi Therapeutics CEO Yael Weiss said. Mahzi, which is working on treatments for rare neurodevelopmental disorders, plans to seek regulatory approval to launch a clinical trial for a therapy targeting Pitt-Hopkins syndrome that causes developmental delays. The San Francisco company is exploring options abroad, in hopes of starting the study faster and due to “regulatory review timeline uncertainties,” Weiss said. Fears over regulatory delays grew even more real on Tuesday, when Stealth Therapeutics said the FDA would not meet its deadline for approving or rejecting the company’s rare disease drug. A person familiar with the situation said the company hadn’t been asked to run more trials or provide more data, that the FDA hadn’t identified any safety concerns, and that the agency hadn’t raised manufacturing issues — typical reasons for why it might reject a drug, Endpoints News reported. Camille Samuels, who sits on various biotech boards, said that several companies she advises were already looking at the UK and Australia for early-stage studies, and that “the disaster that is the FDA only heightens the desire to explore that option.” While an inviting concept now, experts urge companies not to make hasty decisions in case regulatory headwinds dissipate. “My personal counsel, if someone did call me with that request, would be to just sit down, chill out and make a coffee,” said Anthony Davies, CEO of Dark Horse Consulting, which advises cell and gene therapy companies. There are signs that the portion of clinical trials in the US is declining. According to data from the World Health Organization, about 20% of trials were conducted at least in part in the US in 2015. That percentage has declined over the last decade, to about 15%, as countries such as China and India have taken more share. With confidence in the FDA wavering, countries across the world are stepping up campaigns to attract clinical trials that bring in billions in research funding, create jobs and support biotech hubs. “While much public attention has focused on efforts to lure disillusioned US scientists, you could say similar initiatives exist to attract clinical trial activities,” said Aman Khera, a consultant and president of The Organisation for Professionals in Regulatory Affairs. Even before the Trump administration, some US companies said that FDA bureaucracy and regulatory hurdles have enticed companies to go abroad for clinical trials. It can be less expensive and quicker to start testing drugs elsewhere. Much of the recent interest in foreign clinical trial sites is coming from small to mid-sized biotech companies that face budget pressures due to an industry downturn. But even large pharma companies — which have long run multinational studies to obtain regulatory clearance in multiple regions — are looking to increase their international capacity, according to consultants. Many companies are “showing interest in or have already taken steps to move clinical trials overseas” in response to the FDA reorganization, Khera said. QurAlis, a Cambridge, MA-based company developing drugs for neurodegenerative diseases, was looking to run a Phase 2 clinical trial for an undisclosed program only in the US. But after FDA layoffs were announced, the company is now pursuing a multinational approach. “There is a reorganization ongoing, and that has an impact,” QurAlis CEO Kasper Roet said. “And the impact at the very least builds in uncertainty.” To some extent, international trials are more feasible because agencies in Europe, Canada, Australia and the UK have worked in recent years to harmonize guidelines with the FDA, whose decisions carry outsized weight globally . Still, overseas trials have limitations. Data from foreign trials may not always satisfy a common FDA requirement that study data reflect the US population. Genetic or environmental differences among patient populations can complicate results, and so “running local studies ensures that data reflects the target population’s safety and efficacy outcomes,” Khera said. For that reason, companies have incentive to run at least a portion of the studies for a drug in the US.

Submissions follow Ethics Committee Approvals for Both Studies Received Earlier This Month and Have Been Accepted for INVIMA Priority Review Under Fast Track Program for Rare Disease BOSTON, April 29, 2025 /PRNewswire/ -- Unravel Biosciences, Inc., ("Unravel"), an AI-enabled therapeutics company established to advance drugs for complex diseases, today announced the submission of clinical study applications for Unravel's RVL-001 proof of concept clinical trials for Rett syndrome ("RTT") and Pitt Hopkins syndrome ("PTHS") in Colombia. Both applications have been submitted under a pilot program by the Colombian Health Regulatory Agency ("INVIMA"), allowing for priority review and fast track approval for orphan and high unmet need diseases. Unravel anticipates study initiation in the early summer for both programs at the Universidad de Antioquia's Center for Technological Development ("PECET"), a clinical study center of excellence and designated INVIMA clinical trial site in Medellin, Colombia. Both RVL-001 proof of concept studies are designed as placebo-controlled, "n-of-1" trials with a target enrollment of 15 patients with RTT and 5 patients with PTHS. "Today's announcement represents an important milestone towards Unravel's evolution into a clinical-stage company," said Richard Novak, Ph.D., Unravel Co-Founder and CEO. "We look forward to INVIMA's expedited review of our study applications and are prepared to start patient dosing soon after we receive INVIMA approval." RTT and PTHS are both rare neurogenetic disorders starting in early childhood that lead to debilitating cognitive, motor and autonomic disability. Despite one approved treatment for RTT, there remains a significant unmet need for novel treatments having meaningful efficacy and acceptable safety and tolerability. There are no known treatments for PTHS. Unravel's proprietary BioNAV™ drug discovery platform identified RVL-001 as a potentially promising therapeutic drug for Rett Syndrome and PTHS. In addition to Unravel's RVL-001 program for RTT and PTHS, the company has also initiated development work on RVL-002, a first-in-class novel molecule for Rett syndrome. "The Rett and Pitt Hopkins Syndrome communities, including families, caregivers and treating physicians, have been eagerly awaiting the opportunity to participate in meaningful clinical research to find potentially beneficial therapeutics for their loved ones." said Dr. Carolina Lesmes, Pediatric Neurologist and Principal Investigator of the RVL-001 studies. "We are ready to initiate these two important studies to assess the safety and potential efficacy of RVL-001." About Unravel Biosciences Unravel Biosciences is a therapeutics company founded on the principle that biological networks inform clinical outcomes. By using primary patient data with AI systems biology computation, rapid in vivo screening, and clinical validation of discovered targets, Unravel enables drug development with unprecedented efficiency. Unravel leverages its proprietary BioNAV™ platform combining target and drug prediction with patient stratification by efficacy and toxicity response to find treatments for complex diseases. Unravel's platform has led to two clinical trials starting in 2025. Unravel's platform developed RVL002, a first-in-class new small molecule targeting mitochondrial metabolism, and RVL027 and RVL068, molecules targeting two novel mechanisms to treat dystonias. The rareSHIFT™ program provides platform access to foundation and biotech partners to accelerate and clinically derisk therapeutics. and SOURCE Unravel Biosciences, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

iStock, z_wei Ionis and Ultragenyx are competing to develop oligonucleotide treatments for Angelman syndrome, but will Neuren’s peptide catch up? Several companies are working on new investigational treatments for Angelman syndrome , a rare genetic disorder that affects the nervous system and causes developmental delays, intellectual disability, seizures and speech impairment. Ionis and Ultragenyx are competing to bring investigational antisense oligonucleotide treatments to the market, while Neuren is betting on a synthetic peptide that can be delivered orally. It’s a tight race in a disease space with a high unmet need. Affecting 500,000 to 1 million patients worldwide, Angelman syndrome has no approved disease-modifying treatments. Although antiseizure medication is available, these drugs do not address the root cause, a genetic mutation in the UBE3A gene on chromosome 15. In Angelman syndrome, only the copy of the UBE3A gene inherited from the mother is functional, while the father’s allele is mutated. Both Ionis and Ultragenyx are currently in Phase III trials with their oligonucleotides, called ION582 and GTX-102, respectively. Meanwhile, Neuren is conducting a mid-stage trial on NNZ-2591 , a twice-daily oral solution consisting of a synthetic peptide that modulates acetylcholine neurotransmission. Ionis’ ION582 is an investigational intrathecal injection that targets a long noncoding RNA to increase expression of the UBE3A protein in neurons. In November 2024, Ionis announced positive Phase II results from its Phase I/IIa HALOS trial. According to Ionis , 97% of participants given the medium or high dose saw an improvement on the Angelman Syndrome Clinical Global Improvement Change (SAS-CGI-C) scale. The HALOS trial had three parts. The first consisted of five multiple ascending dose cohorts, while the second and third part each used two groups to assess the long-term effects of ION582. Ionis has said it plans to start Phase III trials for ION582 in the first half of 2025. Ultragenyx’s GTX-102 is an intrathecally administered antisense oligonucleotide that inhibits expression of UBE3A by using a human-mouse hybrid protein to reactivate expression of the deficient protein. In November 2024, Ultragenyx announced positive data from its Phase I/II trial of the investigational drug. According to Ultragenyx , 22 of 28 patients achieved clinically meaningful improvement in at least one domain within the Multi-domain Responder Index, a tool for assessing clinical benefit in rare diseases such as Angelman. As of December 2024, Ultragenyx had dosed the first patient in its Phase III ASPIRE trial for Angelman syndrome. For its part, Neuren is focusing on a different mechanism. Excessive acetylcholine has been found to lead to neural hyperexcitability and seizures in Angelman syndrome patients. In August 2024, the company released positive Phase II results from an open-label trial of NNZ-2591. According to Neuren , participants showed statistically significant and clinically meaningful improvement from baseline. (In addition to Angelman syndrome, NNZ-2591 is undergoing clinical trials for other diseases , including Phelan-McDermid Syndrome, Pitt Hopkins Syndrome and Prader-Willi Syndrome.) Overall, while Ionis and Ultragenyx are currently ahead in the Angelman syndrome race for approval, Neuren’s NNZ-2591 has potential in multiple indications that could allow for flexibility in the market. All three investigational products so far appear to be safe and efficacious, and the ultimate deciding factor in their success may boil down to whichever reaches the market first. But there are other factors to consider. Ionis and Ultragenyx are still determining optimal dosing strategies, testing injection frequencies ranging from approximately once per month to once every three months, while Neuren’s oral administration route is the least invasive of the three products. The race may seem to be too close to call, but given that both Ionis and Ultragenyx are relying on improvement in the Bayley Scales for Infant and Toddler Development-4 as a primary endpoint for their Phase III trials, relatively direct comparisons can be made between the two intrathecal products when the final clinical trial results are released. Keep an eye on the Angelman syndrome race as more data come out in the next 2–3 years.