Jaguar Gene Therapy LLC

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.

Panelists from left to right: MeiraGTx CEO Alexandra Forbes, Jaguar Gene Therapy CEO Joe Nolan, and Lexeo Therapeutics CEO Nolan Townsend. Credit: Justine Ra/GlobalData With gene therapy programs, it is challenging to maintain the balancing act between the benefit and risk of a given indication, explained Nolan Townsend, CEO of Lexeo Therapeutics. Townsend was speaking at the two-day 2024 BIO CEO & Investor Conference in New York conference. On 6 February, scalability and development were the stars of discussions, with experts outlining the various factors involved in developing gene therapies. There has been a progression in development from small, orphan monogenic diseases into areas of higher risk and unmet need that can encompass disease states that are harder to treat, said Joe Nolan, CEO of the US-based biotech Jaguar Gene Therapy The gene therapy field has experienced more clinical holds than both biologics and small molecules because there were many unanswered questions on the ideal chemistry, manufacturing, and controls (CMC), dosage, immune suppression regimen, and routes of administration, said Townsend. But as the field has begun answering these questions, the risk profile of gene therapies will substantially decrease over time, he added. Aside from the balance of benefit and risk, another important consideration when developing gene therapies is determining how optimised the technology is to address a particular indication and how minimal a dose a patient can receive, said Alexandra Forbes, CEO of MeiraGTx . She provided an example of how MeiraGTx Parkinson’s program takes into account the smallest possible dosage and in turn, is associated with a lower cost of goods. See Also: Biotech execs say IRA is causing unintended effects for cancer drug development AbbVie licenses OSE’s chronic inflammation therapy for $48m upfront Providing a product at a price that the market can afford is essential, Forbes said. In addition, there needs to be a heavy emphasis on the budget impact of a given disease to move toward developing a cost-saving gene therapy, added Townsend. Manufacturing is critical for therapy development “Manufacturing your gene therapy is essential to your entire clinical development,” explained Forbes. MeiraGTx built its own facility as a startup because the processes required for the company’s biologics license application (BLA) study were not broadly available across CMOs at the time of study. The benefit of having manufacturing capacity/capability is the facilitation of commercialisation and scalability, with the bonus of established regulatory interactions and positive impact on cost of goods, she added. However, it is difficult to find people who understand the level of detail required when manufacturing commercially viable gene therapy product, Nolan said. The future of the gene therapy field lies in commercial-scale processes that are used in products like biologics, especially as technology catches up to the commercial demands of gene therapy indications, said Townsend.

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.