SHANK3

Initial study will focus on adults with disease; company plans to initiate Phase I clinical trials in the U.S. in 2H2024 Preclinical studies in rodents and NHPs demonstrated improvement in neurobehavioral, cognitive and motor functional abnormalities: JAG201 delivers a functional SHANK3 gene directly into the CNS via the AAV9 vector to treat the root cause of the disease There are currently no treatments for the ~30,000 individuals in the U.S. with autism or Phelan-McDermid syndrome, where a SHANK3 mutation or deletion is present LAKE FOREST, Ill.--(BUSINESS WIRE)-- Jaguar Gene Therapy a biotechnology company accelerating breakthroughs in gene therapy for patients suffering from severe genetic diseases, including those that affect sizeable patient populations, today announced the U.S. Food and Drug Administration (FDA) has cleared the company’s Investigational New Drug (IND) Application for JAG201, a gene therapy for a genetic form of autism spectrum disorder (ASD) and Phelan-McDermid syndrome (PMS). There are currently no treatments for the ~30,000 individuals in the U.S. with ASD or PMS where a SHANK3 mutation or deletion is present. JAG201 aims to deliver functional SHANK3 via the AAV9 vector to treat the root cause of the disease. Preclinical studies in rodents and non-human primates (NHP) demonstrated that functional SHANK3 delivery leads to improvements in neurobehavioral, cognitive and motor function abnormalities. The company plans to initiate a Phase I trial in adults with ASD or PMS where a SHANK3 mutation or deletion is present in the United States in the second half of the year. “We are pleased to receive FDA clearance to bring our investigational SHANK3 gene therapy to the clinic. The pre-clinical data indicate that JAG201 may have the potential to be transformative for those suffering with the disorder,” said Joe Nolan, chief executive officer of Jaguar Gene Therapy. “This is a significant milestone for our company but more importantly for the approximately 30,000 individuals living with a genetic form of autism or Phelan-McDermid syndrome who can suffer from a range of clinical manifestations, including global developmental delay, impaired speech and communication, and worsening cognitive, social and motor function disability that ultimately requires 24-hour care and supervision. Currently, there are no treatment options to address the root cause – we hope to change that.” “As a clinician working directly with individuals living with SHANK3 haploinsufficiency and their families, I recognize deeply the profound challenges faced every single day,” said Alexander Kolevzon, M.D., professor of Psychiatry and Pediatrics at the Icahn School of Medicine at Mount Sinai. “The interventions we offer can certainly help but, frankly, they’re inadequate. My patients and all those with SHANK3 haploinsufficiency deserve a treatment option that addresses the underlying biology.” 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. 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, and based on the groundbreaking work of Guoping Feng, Ph.D. “My lab has focused on studying the molecular mechanisms regulating the development and function of synapses in the brain, including the role of SHANK3, because we believe the potential to address synaptic dysfunction could positively transform the lives of so many with neurodevelopmental disorders,” said Dr. Feng, Institute member of the Broad Institute and a senior scientist and director of model systems and neurobiology in the Broad's Stanley Center for Psychiatric Research, the Poitras Professor of Brain and Cognitive Sciences at MIT, associate director of the McGovern Institute, and a member of the Yang Tan Collective at MIT. “Having directly generated promising preclinical data in rodent and non-human primate models of SHANK3 insufficiency, thereby reducing the risk of the translational potential of JAG201, I am very excited to now follow Jaguar as they progress into the clinic with JAG201.” SHANK3 haploinsufficiency causes PMS (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 1% of patients with ASD, equating to around 30,000 patients in the U.S., although this estimate is 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 In the subset of ASD patients that also have moderate to profound intellectual disability (ID), the prevalence of SHANK3 mutations increases from approximately 1% to 2.12%.3,5 An Externally Led Patient Focused Drug Development (EL-PFDD) Meeting on PMS was held with the FDA in November 2022, hosted by CureSHANK and co-planned with the Phelan-McDermid Syndrome Foundation (PMSF). Key insights from the meeting include: PMS has severe quality of life impacts on those living with the disease, as well as on parents and siblings; PMS has an overwhelming unmet medical need; and existing therapies and medical treatments are not very effective.6 “As an organization dedicated to expediting life-changing therapies for Phelan-McDermid syndrome, we are thrilled for JAG201 to be cleared for clinical trials,” said Geraldine Bliss, founder and president of CureSHANK. “I understand first-hand as the parent of a young adult with Phelan-McDermid syndrome the dearth of available therapies and the incredible potential of a treatment that addresses the root cause of this severe and pervasive disease.” “Families deserve and are desperately waiting for treatments to address Phelan-McDermid syndrome, and we are very excited the FDA has cleared JAG201 for clinical trials,” said Ronni Blumenthal, CEO of the Phelan-McDermid Syndrome Foundation. “Members of our community are eager to have treatment options that could potentially lessen or eliminate even just one or two of the devastating symptoms of the disease, if not more, to positively improve the lives of our loved ones.” 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 IND-cleared program targets severe neurodevelopmental disorders caused by mutations or deletions in SHANK3 including a genetic form of autism spectrum disorder and Phelan-McDermid syndrome. The second pipeline program targets Type 1 galactosemia and the third targets Type 1 diabetes. Jaguar partners with Advanced Medicine Partners, soon to be spun out from Jaguar, to manufacture its therapeutics. 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. Leblond CS et al. PLoS Genet 2014; 10 (9): e1004580. 6. Phelan-McDermid Voice of the Patient Report. Available at: . Accessed January 2024. Disclosure Dr. Alexander Kolevzon has served as a paid consultant for Jaguar Gene Therapy.

DURHAM, N.C.--( BUSINESS WIRE )--Advanced Medicine Partners, an organization that delivers process development, manufacturing, analytical development and testing for advanced therapy products, today announced its launch from Jaguar Gene Therapy with funding led by Deerfield Management Company, with additional investors including ARCH Venture Partners, Nolan Capital and others. The newly independent company is helmed by a team of experts who were directly responsible for the CMC efforts for numerous commercially available therapeutics including three globally approved gene therapies. The organization will continue to lead CMC efforts for Jaguar Gene Therapy’s pipeline programs, will support CMC work for Deerfield academic projects and private portfolio companies, and has initiated work for several biotech and pharmaceutical clients. “Advanced Medicine Partners is a science- and mission-driven organization made up of one of the most experienced genetic medicines teams in the industry, and we are driven to deliver products and services that aim to set a new standard in the manufacturing and testing of innovative therapies,” said Andrew Knudten, CEO of Advanced Medicine Partners. “With so many biotechnology companies being slowed or halted due to manufacturing challenges including product quality and scalability, we have the experienced people and technology to deliver what’s acutely needed right now – therapeutic product with purity and potency levels that exceed expectations of partnering companies and regulators, and that will potentially bring positive benefit to patients.” Advanced Medicine Partners has a proprietary and proven development platform and has established a robust and reproducible adeno-associated virus (AAV) manufacturing process, which is among the most productive in the industry and consistently generates industry-leading functional full capsid ratios. Advanced Medicine Partners’ process has been used with multiple genes of interest as well as multiple wild-type AAV serotypes and engineered capsids. This manufacturing process prioritizes patient safety while reducing cost of goods and will strive to set the standard for what regulatory agencies expect and patients deserve. The company has also developed a suite of platform analytical methods that can be licensed and offers assay development services. Advanced Medicine Partners brings extensive operational experience from Jaguar Gene Therapy and other biotechnology companies, including AveXis, Novartis and Amgen. The Advanced Medicine Partners team has manufactured upwards of 350 total non-GMP batches and supplied over 20 preclinical studies, including IND-enabling efficacy and good laboratory practice (GLP) toxicology studies, as part of Jaguar. In addition to Advanced Medicine Partners’ manufacturing and analytical testing capabilities, the company offers GMP tech transfer capabilities and virtual CMC support. Advanced Medicine Partners currently operates with more than 33,000 square feet of lab, office and warehouse space in Cary and Durham, North Carolina. The company is in the process of building out a 174,000-square-foot GMP manufacturing facility in Durham. Advanced Medicine Partners has the ability to build dedicated capacity for partnered companies in this new facility. “We are very pleased to partner with the highly experienced team at Advanced Medicine Partners,” said Jonathan Leff, Partner at Deerfield Management Company. “With the demonstrated track record of the leadership team, the company brings much needed expertise and capability to the development and manufacturing of advanced products such as gene and cell therapies.” ABOUT ADVANCED MEDICINE PARTNERS Advanced Medicine Partners, LLC is driven to accelerate the development of innovative advanced medicines to enable partnering companies to make a positive difference for the patients they serve. With one of the most experienced genetic medicines teams – at all levels, from bench to boardroom – in the industry, the company uses its expertise to produce best-in-class advanced therapy products and analytics. Advanced Medicine Partners’ exclusive manufacturing platform consistently produces yields that are among the highest in the industry and purity profiles that continue to push the boundaries of what’s possible. For more information, please visit www.ampgtx.com and follow Advanced Medicine Partners on LinkedIn . ABOUT JAGUAR GENE THERAPY Jaguar Gene Therapy, LLC is 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, with a pending IND, targets severe neurodevelopmental disorders caused by mutations or deletions in SHANK3 including a genetic form of autism spectrum disorder and Phelan-McDermid syndrome. The second pipeline program targets Type 1 galactosemia and the third targets Type 1 diabetes. Jaguar partners with Advanced Medicine Partners , soon to be spun out from Jaguar, to produce its therapeutics. For more information, please visit www.jaguargenetherapy.com and follow Jaguar Gene Therapy on LinkedIn .

Highlights: Significant improvement was assessed by both clinicians and caregivers across multiple efficacy measures Improvements were consistently seen across clinically important aspects of Phelan-McDermid syndrome, including communication, behaviour, cognition/learning and socialisation Clinician and caregiver global efficacy measures showed a level of improvement typically considered clinically meaningful: - Clinical Global Impression of Improvement (CGI-I) - mean score of 2.4, with 16 out of 18 children showing improvement assessed by clinicians - Caregiver Overall Impression of Change (CIC) – mean score of 2.7, with 15 out of 18 children showing improvement assessed by caregivers For 10 out of 14 efficacy endpoints, improvement from baseline on overall/total scores was statistically significant (Wilcoxon signed rank test p<0.05) NNZ-2591 was safe and well tolerated, with no clinically significant changes in laboratory values or other safety parameters during treatment MELBOURNE, Australia, Dec. 18, 2023 /PRNewswire/ -- Neuren Pharmaceuticals (ASX: NEU) today announced top-line results from its Phase 2 clinical trial of NNZ-2591 in children with Phelan-McDermid syndrome (PMS). Significant improvement was observed by both clinicians and caregivers from treatment, across multiple efficacy measures. Improvements were consistently seen across many of the core PMS characteristics. PMS has severe quality of life impacts for those living with the syndrome, as well as parents and siblings. There are no approved treatments for PMS despite its severely debilitating impact. Neuren CEO Jon Pilcher commented "The strength and consistency of these results has exceeded our expectations and gives us high confidence as we strive to accelerate the development of a potential first therapy to address the overwhelming unmet medical need of PMS. We are very grateful to all the people at the trial sites in the United States and in the PMS community who enabled this groundbreaking trial to be completed successfully." Elizabeth Berry-Kravis, MD, PhD, Professor Department of Pediatrics at Rush University Medical Center in Chicago and an Investigator in the study, commented: "Although the Phase 2 trial was an open label study, I am very encouraged that both clinicians and caregivers observed pervasive improvements across multiple, clinically important features of PMS including communication, cognition, learning, socialisation and behaviour. Improvements typically considered clinically meaningful were achieved in the clinician rated CGI-I as well as the caregiver rated CIC. I look forward to seeing this program advance to the next stage of development for the PMS community". Study design The open label Phase 2 trial in up to 20 children aged 3 to 12 years at four hospitals in the United States examined safety, tolerability, pharmacokinetics and efficacy over 13 weeks of treatment with NNZ2591. NNZ-2591 was administered to all subjects as an oral liquid dose twice daily, with escalation in two stages up to the target dose of 12 mg/kg during the first 6 weeks of treatment, subject to independent review of safety and tolerability data. The study commenced with at least 4 weeks of screening and observation to thoroughly examine baseline characteristics prior to treatment, followed by the treatment period of 13 weeks. A follow-up assessment was made 2 weeks after the end of treatment. 23 children were screened, 5 failed screening and 18 entered the study. The mean age was 8.6 years. The primary endpoints of this first trial in children were safety, tolerability and pharmacokinetics. Secondary endpoints included 14 efficacy measures assessed by clinicians and by caregivers. Efficacy measures included global measures assessing overall change, measures assessing specific symptom areas and measures assessing quality of life. Safety and tolerability NNZ-2591 was well tolerated and demonstrated a good safety profile. Most Treatment Emergent Adverse Events (TEAEs) were mild to moderate. There was only one Serious TEAE (gastroenteritis), which was not related to study drug and occurred during the safety follow-up period after end of treatment. Three subjects discontinued due to TEAEs, two testing positive for COVID-19 and one due to seizures that were not related to study drug. No clinically significant changes in laboratory values, electrocardiogram (ECG) or other safety parameters were observed during treatment. Efficacy Improvement from baseline on overall/total scores was statistically significant (Wilcoxon signed rank test p<0.05) for 10 out of 14 efficacy endpoints. The results for the global measures rated by both clinicians and caregivers showed a level of improvement typically considered clinically meaningful. 16 out of 18 children showed improvement measured by the Clinical Global Impression of Improvement (CGI-I), an assessment by the clinician of the child's overall status compared with baseline. The mean CGI-I score was 2.4. 10 children received a score of either 1 ("very much improved") or 2 ("much improved"). 15 out of 18 children showed improvement measured by the Caregiver Overall Impression of Change (CIC), an assessment by the caregiver of the child's overall status compared with baseline. The mean CIC score was 2.7. Seven children received a score of either 1 ("very much improved") or 2 ("much improved"). Other ongoing Phase 2 trials of NNZ-2591 Neuren is also conducting Phase 2 clinical trials of NNZ-2591 in children with three other neurodevelopmental disorders – Pitt Hopkins syndrome, Angelman syndrome and Prader-Willi syndrome. Top-line results from the Pitt Hopkins syndrome trial are expected in Q2 2024. All four programs have been granted Orphan Drug designation by the US Food and Drug Administration (FDA) and are being developed under Investigational New Drug (IND) applications. Each syndrome is a seriously debilitating neurological disorder that emerges in early childhood and has no or limited approved treatment options. Detailed results are available in the full announcement: About Phelan-McDermid syndrome Phelan-McDermid syndrome is caused by a deletion or other change in the 22q13 region of chromosome 22, which includes the SHANK3 gene, or a mutation of the gene. PMS is also known as 22q13 deletion syndrome. The SHANK3 gene codes for the shank3 protein, which supports the structure of synapses between nerve cells in the brain. It is estimated that between 1 in 8,000 and 1 in 15,000 people have PMS. There are no medications, drugs, or therapies specifically for PMS, which has an overwhelming unmet medical need. PMS has severe quality of life impacts on those living with it, as well as on parents and siblings. The most common characteristics are moderate to severe developmental and intellectual impairment and developmental delay, delayed or absent speech, symptoms of autism, low muscle tone, motor delays, mild to severe epilepsy, difficulties with toilet training and problems with eating. Further information about PMS is available at: About Neuren Neuren is developing new drug therapies to treat multiple serious neurological disorders that emerge in early childhood and have no or limited approved treatment options. Recognising the urgent unmet need, all programs have been granted "orphan drug" designation in the United States. Orphan drug designation provides incentives to encourage development of therapies for rare and serious diseases. DAYBUE™ (trofinetide) is approved by the US Food and Drug Administration (FDA) for the treatment of Rett syndrome in adult and pediatric patients two years of age and older. Neuren has granted an exclusive worldwide licence to Acadia Pharmaceuticals Inc. for the development and commercialisation of trofinetide. Neuren's second drug candidate, NNZ-2591 is in Phase 2 development for each of Phelan-McDermid syndrome, Angelman syndrome, Pitt Hopkins syndrome and Prader-Willi syndrome. ASX Listing Rules information This announcement was authorized to be given to the ASX by the board of directors of Neuren Pharmaceuticals Limited, Suite 201, 697 Burke Road, Camberwell, VIC 3124 Forward-looking Statements This announcement contains forward-looking statements that are subject to risks and uncertainties. Such statements involve known and unknown risks and important factors that may cause the actual results, performance or achievements of Neuren to be materially different from the statements in this announcement. SOURCE Neuren Pharmaceuticals Ltd