Neurogene(NGNE) - 2025 Q2 - Quarterly Results

Company Overview Neurogene's overview covers disclaimers, its focus on genetic medicines, clinical pipeline, and in-house AAV manufacturing capabilities Disclaimer This section outlines the forward-looking nature of statements within the presentation, emphasizing that actual results may differ due to various risks and uncertainties - The communication contains forward-looking statements regarding Neurogene's therapeutic programs (NGN-401, NGN-101), clinical trial designs, expected results, market potential, safety, manufacturing capabilities, and financial runway, based on current beliefs and assumptions and involving risks and uncertainties detailed in SEC filings[3][4] - Industry and market data are based on third-party sources and internal estimates, with Neurogene not independently verifying all information[5] - The presentation may contain trademarks, service marks, trade names, and copyrights belonging to their respective owners[6] Neurogene at a Glance Neurogene is focused on developing genetic medicines for rare neurological diseases, with its lead program NGN-401 for Rett syndrome showing promising interim clinical data - Neurogene's lead program, NGN-401 for Rett syndrome, has demonstrated promising interim clinical data, with registrational trial activities underway[8] - NGN-401 utilizes EXACT™, a proprietary transgene regulation technology addressing a key limitation in gene therapy[8] - The company has extended its cash runway into early 2028[8] Clinical Stage Pipeline Neurogene's clinical pipeline includes NGN-401 for Rett Syndrome, which is currently undergoing registrational trial activities with additional interim data expected in 2H:25 Neurogene Clinical Stage Pipeline | Product Candidate | Indication | Near-Term Expected Milestones | | :---------------- | :----------------- | :---------------------------------------------- | | NGN-401 | Rett Syndrome | Registrational Trial Activities Underway, Additional Interim Data 2H:25 | | NGN-101 | CLN5 Batten Disease | Evaluating Opportunities for Program | Manufacturing Capabilities Neurogene operates a wholly-owned, fully integrated in-house AAV manufacturing facility in Houston, spanning 42,000 sq ft with 6,000 sq ft of cleanrooms - Neurogene operates a 42,000 sq ft facility in Houston, including 6,000 sq ft of cleanrooms, for wholly-owned and fully integrated in-house AAV manufacturing[13] - Current research and clinical-grade manufacturing capabilities are designed for commercial-grade product to prevent future comparability issues[14] - In-house manufacturing provides flexibility, low-cost production, control over product quality and timelines, and expertise in HEK293 and Sf9/rBV platforms[16] NGN-401 for Rett Syndrome This section details NGN-401, Neurogene's lead gene therapy for Rett Syndrome, covering its mechanism, clinical trial design, and interim Phase 1/2 data Introduction to NGN-401 NGN-401 is Neurogene's lead gene therapy program for Rett Syndrome, leveraging its proprietary EXACT™ transgene regulation technology to address the underlying genetic cause of the disease - NGN-401 is a gene therapy for Rett Syndrome utilizing the EXACT™ transgene regulation technology[17] Rett Syndrome: Disease Overview and Unmet Need Rett syndrome is a devastating, progressive X-linked neurological disorder caused by MECP2 gene mutations, primarily affecting females with a U.S. prevalence of ~6,000-9,000 patients - Rett syndrome is an X-linked disorder caused by MeCP2 gene mutations, with a U.S. prevalence of approximately 6,000-9,000 patients and a worldwide incidence of 1:10,000 females[21] - The disease is characterized by early onset developmental regression, loss of purposeful hand use, impaired motor skills, communication difficulties, and autonomic dysfunction, with no approved treatments addressing the root cause[22][23] NGN-401: Mechanism of Action and Delivery NGN-401 is designed as a potential best-in-class gene therapy for Rett Syndrome, utilizing EXACT™ technology to ensure consistent and tightly controlled MeCP2 protein expression - NGN-401 employs EXACT™ transgene regulation technology to deliver consistent and tightly controlled MeCP2 protein expression on a cell-by-cell basis[25] - The therapy utilizes the full-length human MECP2 gene, translating a fully functioning MeCP2 protein[25] - Intracerebroventricular (ICV) delivery provides broad targeting of brain and nervous system regions relevant to Rett syndrome pathophysiology, as shown in preclinical models[25] Embolden™ Registrational Trial Design Neurogene has obtained FDA agreement on the design of the Embolden™ registrational trial for NGN-401, which is an open-label, single-arm, baseline-controlled study - FDA has provided written agreement on key elements of the Embolden™ Registrational Trial design for NGN-401[27] Embolden™ Registrational Trial Design | Design | Open-label, single arm, baseline control (patient acting as own control) | | :---------------- | :----------------------------------------------------------------------- | | Patient Population | Females ages ≥ 3 years with Rett syndrome | | Dose | 1E15 vg | | Primary Endpoint | Responder-based composite endpoint at 12 months: Gain of any one developmental milestone and CGI-I of < 3 skill captured through video recordings | - The Phase 1/2 trial is converting to a registrational trial, with a proposed N=20 for the open-label, baseline-controlled arm, targeting females with Classic Rett syndrome in the post-regression stage, aged >3 years, with pathogenic MECP2 mutation and CGI-S score of 4-6[28] Trial Design and Endpoints The Embolden™ registrational trial is an open-label, single-arm study with patients serving as their own controls, focusing on females aged ≥3 years with Rett syndrome - The trial will evaluate 28 developmental skills/milestones across fine motor/hand function, gross motor/ambulation, and communication, selected for their meaningfulness to caregivers and rarity of acquisition after age 3 in natural history[29][30][31][32] Caregiver Feedback on Meaningfulness Research with Rett syndrome caregivers confirmed that all queried developmental skills across fine motor, gross motor, and communication domains are considered highly meaningful - Caregiver research (Nov-Dec 2024, Jan 2025) with 30-27 caregivers of daughters aged 3-22 years confirmed that all queried developmental milestones/skills in fine motor, gross motor, and communication domains were considered meaningful[33][34] - Caregivers emphasized that skill gains would provide respite, increased independence, reduced physical strain, enhanced safety, and improved dignity for patients and their families[34][41] Phase 1/2 Clinical Data Interim Phase 1/2 data for NGN-401 at the 1E15 vg dose level demonstrated durable and consistent improvements across multiple clinical scales and core domains - Phase 1/2 data demonstrated durable improvements across multiple scales, including a two-point improvement in CGI-I in all participants, with consistent gains in hand function, gross motor, and communication[42][43] - Clinically meaningful gains of skills and developmental milestones were observed beyond natural history expectations, alongside objective improvements in autonomic domains such as sleep and constipation[43] - The 1E15 vg NGN-401 dose was generally well-tolerated, with no evidence of Hemophagocytic lymphohistiocytosis (HLH) observed[43] Efficacy and Patient Characteristics The initial four participants in the Phase 1/2 trial, ranging from moderate to severe disease, all achieved a CGI-I rating of 'Much Improved' (score ≤ 3) by 3-9 months post-treatment Baseline Characteristics of Dosed Participants (1E15 vg) | | Participant 1 (Pt:1) | Participant 2 (Pt:2) | Participant 3 (Pt:3) | Participant 4 (Pt:4) | Participant 5 (Pt:5) | | :----------------------- | :------------------- | :------------------- | :------------------- | :------------------- | :------------------- | | Age at Dosing in Years | 7 | 4 | ୧ | 7 | 6 | | MECP2 Mutation Severity | Mild | Severe | Severe | Severe | Severe | | Baseline Disease Severity (CGI-S) | 4 (moderately ill) | 5 (markedly ill) | 5 (markedly ill) | 5 (markedly ill) | 5 (markedly ill) | | Time Post Treatment (Months) | ~15 | ~12 | ~9 | < R | s | CGI-I Scores Post Treatment with NGN-401 (First Four Participants) | | 3 mos. | 6 mos. | 9 mos. | 12 mos. | 15 mos. | | :--- | :----------------- | :----------------- | :----------------- | :----------------- | :----------------- | | Pt:1 | 3 - Minimally Improved | 2 - Much Improved | 2 - Much Improved | 2 - Much Improved | 2 - Much Improved | | Pt:2 | 2 - Much Improved | 2 - Much Improved | 2 - Much Improved | 2 - Much Improved | | | Pt:3 | 3 - Minimally Improved | 3 - Minimally Improved | 2 - Much Improved | | | | Pt:4 | 2 - Much Improved | | | | | - Across the first four participants, an aggregate of 23 skills were acquired, with consistent improvements observed across key Rett Syndrome scales (CGI-I, CGI-S, RSBQ) and functional improvements in core clinical domains (hand function, gross motor, communication, autonomic, attentiveness)[49] Safety Profile (HLH) Neurogene has implemented comprehensive HLH risk mitigation protocols for the Phase 1/2 and registrational trials, including dose level restrictions and daily monitoring - HLH risk mitigation protocols include dose level restrictions (not at/above 1E14 vg/kg), daily monitoring of ferritin, fever, and falling blood counts in the first week post-dosing, and requiring sites to have anakinra available[68] - No participants at the 1E15 vg dose level have presented with clinical symptoms of HLH/hyperinflammatory syndrome[71] - Transient ferritin elevations were observed in 4 of 5 recently dosed subjects, peaking at Study Day 5-6 and recovering to Baseline by Day 10-12 without intervention[71] Key Anticipated Milestones This section outlines Neurogene's upcoming regulatory and clinical milestones for NGN-401 and NGN-101, along with its projected cash runway Key Upcoming Anticipated Milestones and Pipeline Developments Neurogene anticipates providing a regulatory update and initiating registrational trial activities for NGN-401 in 1H:25, with additional Phase 1/2 clinical data expected in 2H:25 - For Rett Syndrome (NGN-401), Neurogene plans a regulatory update and initiation of registrational trial activities in 1H:25, with additional Phase 1/2 clinical data expected in 2H:25[73][74] - For CLN5 Batten Disease (NGN-101), the company is evaluating program opportunities[74] - Cash runway is projected to fund operations into early 2028[75] Appendix The appendix provides supplementary detailed data on autonomic function improvements and preclinical efficacy and safety of NGN-401 in mouse models Detailed Autonomic Function Data The appendix provides detailed objective data on autonomic function improvements observed in Phase 1/2 participants - Pt:1 and Pt:2, with baseline sleep deficits, experienced improvements in sleep parameters (e.g., sleep efficiency increased from 83% to 90% for Pt:1, and 90% to >95% for Pt:2) and constipation, measured by wearable devices and caregiver-reported Bristol Stool Form Scale[66][77][79][80][82] - Pt:3, with severe dysphagia at baseline, gained the ability to swallow liquids and chew/swallow soft foods by 3 months post-NGN-401, and could self-feed by 9 months[67][83] - Pt:4 experienced improvements in constipation by Month 4 post-treatment[66][85][86] Preclinical Data (Mouse Models) Preclinical studies in Mecp2 mouse models demonstrated NGN-401's efficacy and safety, showing that ICV delivery achieved targeted MeCP2 levels and improved survival - ICV delivery of NGN-401 in Mecp2 mouse models achieved targeted MeCP2 levels and improved survival in both male knockout and female heterozygous mice[90][91] - EXACT™ technology ensures consistent and narrow expression of MeCP2 on a cell-by-cell basis, preventing potential issues from unregulated gene expression[93][94]