Phelan-McDermid syndrome

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.

A non-interventional study published in Frontiers in Psychiatry Psychometric profile characterization of 30 subjects with Phelan-McDermid Syndrome (PMS), defining three distinct subsets Study provides clinical scales and thresholds for patient selection in future clinical trials, based on aggressiveness, cognition, and behavioral traits Conducted in collaboration with the Medical and Molecular Genetics Institute (INGEMM) and the Research Institute La Paz Hospital (IdiPaz) in Madrid MADRID, SPAIN and CAMBRIDGE, MA, UNITED STATES, March 5th, 2025 - Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, announced today that the final results of an observational clinical study aimed at psychometrically characterizing individuals with Phelan-McDermid syndrome (PMS) carrying deletions or pathogenic variants in SHANK3 have been published online in the journal Frontiers in Psychiatry. The purpose of this study was to gather data that could serve as a foundation for a future precision psychiatry clinical trial involving vafidemstat for this patient population. Agitation and aggression are key components of PMS, and vafidemstat has demonstrated efficacy in reducing agitation and aggression in a basket trial involving patients with Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD), and Borderline Personality Disorder (BPD). This characterization paves the way for addressing these symptoms in a subset of PMS patients, further expanding the potential application of vafidemstat in reducing aggression in this specific patient population. Dr. Jordi Xaus, Oryzon’s CSO, stated, “The publication of these results in this prestigious clinical psychiatry journal marks a critical first step toward establishing vafidemstat as a novel personalized medicine therapy for relevant psychiatric indications. In recent years, a range of monogenic rare neurodevelopmental disorders linked to alterations in the epigenetic machinery and other key neuronal genes have been identified as potential targets for precision medicine. The use of LSD1 inhibitors has been shown to partially or fully rescue the complex phenotypes caused by these genetic mutations. Vafidemstat is currently the only LSD1 inhibitor in clinical development in CNS and represents a promising opportunity for these patients.” Dr. Julian Nevado, first author of the study and Head of Structural and Functional Genomics at INGEMM said “There is currently no treatment approved specifically for Phelan-McDermid syndrome. This study is a proof of concept that highlights the importance of patient stratification in PMS. Selecting PMS patients for a clinical trial based on their distinctive clinical and genetic characteristics will be essential in the era of personalized precision medicine.” In this pilot study, we clinically characterized the profile of 30 subjects, all diagnosed of molecularly confirmed PMS, by applying different psychometric scales, including Repetitive Behavior Questionnaire (RBQ), Vineland Adaptive Behavior Scales, ADOS-2, the Battelle developmental inventory screening test and the Behavior Problems Inventory (BPI). As reported in the publication, unsupervised hierarchical clustering of the collected psychometric data identified three groups of patients, with different cognitive, aggression and behavioral profile scores. Statistically significant differences in deletion sizes were detected comparing the three clusters (corrected by gender), and the size of the deletion appears to be correlated with some of the assayed scores. A link to access the online publication can be found here. Oryzon is developing vafidemstat in prevalent multifactorial psychiatric indications like BPD, with a Phase III trial in preparation, or schizophrenia, with the ongoing EVOLUTION Phase IIb trial, but is also committed to exploring the potential of vafidemstat in rare monogenic psychiatric and neurodevelopmental disorders such as PMS or Kabuki Syndrome. In the Phase IIb PORTICO trial in BPD, vafidemstat demonstrated nominal statistical significance in reducing agitation and aggression, also a relevant feature of some PMS patients and a significant caregiver burden that often results in sedation or institutionalization of these PMS patients. This published study provides relevant data for patient inclusion in a future clinical study exploring vafidemstat actionability for SHANK3-associated psychiatric disorders, including PMS, constituting a good example of how precision medicine may open new avenues to understand and treat Central Nervous System (CNS) disorders, pioneering individual management in PMS.

The company recently conducted a Type C meeting with the U.S. Food and Drug Administration (FDA) and is cleared to proceed with dosing of pediatric patients (2+ years) with JAG201 with expansion into adults (18+ years) following the pediatric cohort The first gene therapy clinical trial to evaluate therapeutic impact in a genetic form of autism and Phelan-McDermid syndrome. Site initiation to begin immediately and patient enrollment anticipated in Q12025. There are currently no treatments for the ~46,000 individuals in the U.S. with autism due to SHANK3 haploinsufficiency and those diagnosed with Phelan-McDermid syndrome JAG201 has been granted Rare Pediatric Disease designation and Fast Track designation by the FDA LAKE FOREST, Ill.--(BUSINESS WIRE)-- Jaguar Gene Therapy, a clinical-stage biotechnology company accelerating breakthroughs in gene therapy for patients suffering from severe genetic diseases including those that impact sizeable patient populations, today announced the receipt of U.S. Food and Drug Administration (FDA) responses from a Type C meeting regarding the Phase I clinical trial for JAG201, a gene replacement therapy that targets a genetic form of autism spectrum disorder (ASD) where a SHANK3 mutation or deletion is present, and Phelan-McDermid syndrome. Specifically, the company received the FDA’s agreement to administer JAG201 to both pediatric and adult patients. Jaguar Gene Therapy plans to dose the first pediatric patient in Q1 of 2025 with expansion into adults following the pediatric cohort. “We are pleased to have reached agreement with the FDA to dose both pediatric and adult patients in our initial Phase I clinical trial of JAG201. Our preclinical data suggest that the administration of the gene therapy early in life provides a clear potential for benefits to be realized,” said Joe Nolan, CEO of Jaguar Gene Therapy. “Our hope is that potential early success in the pediatric population will open the door to evaluating JAG201 in broader patient populations. We look forward to continuing to work with the FDA, key opinion leaders and advocacy organizations in our efforts to bring forward a gene therapy treatment for autism spectrum disorder due to SHANK3 haploinsufficiency and genetically confirmed Phelan-McDermid syndrome.” “I think intervening earlier in a patient’s course of illness to address the underlying deficits caused by the SHANK3 deficiency while individuals are still actively undergoing development will provide a greater potential for benefit,” said Alexander Kolevzon, M.D., Professor of Psychiatry and Pediatrics at the Icahn School of Medicine at Mount Sinai. “There is an incredibly high unmet need among people living with Phelan-McDermid syndrome, and we expect there will be many eligible patients to participate in this important clinical trial.” JAG201 delivers a functional SHANK3 minigene via an adeno-associated virus serotype 9 (AAV9) vector to target neurons in the central nervous system. The therapy is administered via a one-time unilateral intracerebroventricular (ICV) injection, targeting the entire brain and spinal cord. JAG201 is designed to transduce haploinsufficient neurons to provide proper SHANK3 levels and to durably restore the synaptic function required for learning and memory, which underlie appropriate neurodevelopment and maintenance of cognitive, communicative, social and motor skills. The program is exclusively licensed from Broad Institute of MIT and Harvard. Recently, the FDA granted Rare Pediatric Disease designation for JAG201. The designation is granted for products that treat serious and life-threatening rare pediatric diseases. Under this program, companies are eligible to receive a priority review voucher for a subsequent marketing application for a different product following approval of a product with Rare Pediatric Disease designation. The FDA has also granted Fast Track designation for JAG201 based on the potential for the therapy to address a high unmet medical need for patients living with ASD where a SHANK3 mutation or deletion is present, and Phelan-McDermid syndrome. Currently, there are no therapeutic treatments approved for SHANK3 haploinsufficiency. Fast Track status allows for enhanced communication and collaboration between the FDA and drug developers, potentially accelerating the delivery of treatments to patients. About SHANK3 haploinsufficiency in ASD and Phelan-McDermid syndrome SHANK3 haploinsufficiency leads to synaptic dysfunction, disrupting communication between nerve cells. It causes a reduction of several key receptors and signaling proteins at excitatory synapses, resulting in impaired synaptic formation and function. Adequate synapse function is an essential prerequisite of all neuronal processing, including higher cognitive functions and learning. SHANK3 haploinsufficiency causes Phelan-McDermid syndrome (also known as 22q13.3 deletion syndrome), a rare genetic disorder with an estimated prevalence of 1 in 10,000.1,2 Genetic sequencing studies indicate that SHANK3 mutations may be present in approximately 0.5%-0.69% of patients with ASD, equating to around 46,000 patients in the U.S., including approximately 10,000 pediatric patients under the age of 18, although diagnosed cases are perceived as low by clinical experts given the barriers of access and low adoption of genetic testing in the diagnostic journey of ASD.3,4,5,6 In the subset of ASD patients who also have moderate to profound intellectual disability (ID), the prevalence of SHANK3 mutations increases from less than 1% to 2.12%.3,7 About Jaguar Gene Therapy Jaguar Gene Therapy, LLC is a clinical-stage biotechnology company dedicated to accelerating breakthroughs in gene therapy for patients suffering from severe genetic diseases including those that impact sizeable patient populations. The company is made up of a proven team of experts who have first-hand experience in bringing novel gene therapy treatments to patients and their families. Jaguar is rapidly advancing an initial pipeline of three programs. The company’s lead program targets severe neurodevelopmental disorders caused by SHANK3 haploinsufficiency, due to loss of function mutations or deletions in SHANK3 including a genetic form of autism spectrum disorder and Phelan-McDermid syndrome. A clinical trial in pediatric patients is planned to begin in Q1 of 2025. The second pipeline program targets Type 1 galactosemia and the third targets Type 1 diabetes. Jaguar’s key investors include Deerfield Management Company, ARCH Venture Partners and Eli Lilly and Company. For more information, please visit and follow Jaguar Gene Therapy on LinkedIn. References 1. Costales JL et al. Neurotherapeutics 2015; 12 (3): 620–630. 2. What is Phelan-McDermid syndrome? Available at: . Accessed January 2023. 3. Betancur C et al. Mol Autism 2013; 4 (1): 17. 4. Jaguar Gene Therapy market research, 2022; data on file. 5. 6. 7. Leblond CS et al. PLoS Genet 2014; 10 (9): e1004580. Disclosure Dr. Alexander Kolevzon has served as a paid consultant for Jaguar Gene Therapy.