Group 1 - The biotech industry is characterized by lengthy processes where companies incur significant costs while awaiting results from drug candidates, which often leads to binary outcomes [1] - There is a strong inclination towards investing in high-growth companies within sectors that are expected to experience exponential growth [1] - The focus is on understanding and investing in disruptive technologies and innovative enterprises, combining fundamental analysis with future trend predictions [1] Group 2 - The belief in the potential of innovation to generate substantial returns is emphasized, with a commitment to providing insightful analysis on relevant companies [1]

Clinical Trials and Efficacy - NGN-401 for Rett syndrome demonstrated promising interim clinical data, with the first participant dosed in Q4 2025 and enrollment expected to complete in 3-6 months[8]. - The Embolden™ registrational trial for NGN-401 is designed as a single-arm, open-label trial with a sample size of 20 females, requiring a 35% response rate for success[28]. - The primary endpoint of the Embolden trial is a responder-based composite endpoint, with key secondary endpoints focusing on developmental milestones[28]. - The trial's primary analysis will occur at 12 months, assessing the CGI-I score and developmental milestones gained[30]. - 12 of 13 clinical trial sites for the Embolden trial have been initiated, with enrollment expected to complete in 3-6 months[44]. - 5 out of 20 participants (25%) achieved the minimum threshold for success in the Embolden trial, with a CGI-I score of < 3 at 12 months[51]. - Participants dosed in the first half of 2025 show early efficacy, with 3 of 3 demonstrating functional gains at 6 months[54]. - The primary endpoint of the Embolden trial is focused on the gain of any one developmental milestone/skill at 12 months[54]. - NGN-401 demonstrated efficacy and safety in Mecp2 mouse models, with survival rates showing significant improvement[94]. - The company plans to announce additional Phase 1/2 clinical data in 2H 2025 and in 2026[90]. Manufacturing and Operational Capacity - Neurogene's internal manufacturing capabilities are designed to support commercial-grade products, avoiding potential future comparability challenges[14]. - Neurogene's facility in Houston spans 42,000 sq ft, including 6,000 sq ft of cleanrooms, enhancing its manufacturing capabilities[13]. - Cash runway is expected to fund operations through Q1 2028, providing strategic flexibility for ongoing and future projects[8]. - Cash runway is projected to fund operations through Q1 2028[90]. Patient Impact and Caregiver Insights - The U.S. prevalence of Rett syndrome is estimated to be between 6,000 and 9,000 patients, with a worldwide incidence of 1 in 10,000 females, indicating a significant unmet need for new treatment options[21]. - Significant improvements in communication and motor skills have been reported by caregivers, enhancing quality of life[85]. - Caregivers indicated that any skill gain or symptom improvement would provide significant respite and independence for their daughters with Rett syndrome[93]. - The majority of caregivers considered all queried skills in developmental milestones meaningful, highlighting the immense burden of care required[93]. Safety and Tolerability - NGN-401 remains generally well tolerated at the 1E15 vg dose level, with 9 treatment-emergent adverse events related to NGN-401 reported[86]. - All treatment emergent adverse events (TEAEs) related to NGN-401 have been Grade 1 (mild) or Grade 2 (moderate) in severity, with most participants experiencing mild liver enzyme elevations[87]. - Seizures have remained well controlled following the administration of NGN-401[87]. - No evidence of hemophagocytic lymphohistiocytosis (HLH) was found in any participant during the trials[87]. Future Directions - The company is evaluating opportunities for NGN-101 targeting CLN5 Batten Disease, expanding its clinical pipeline[9]. - The trial design for ages over 3 is expected to enable the most efficient path to market for NGN-401[44]. - The company aims to deliver durable, multidomain gains that grow over time with NGN-401[45]. - The Embolden registrational trial will expand the clinical trial footprint, more than doubling the presence in the U.S.[90].

Core Insights - Neurogene reported positive interim data from the NGN-401 Phase 1/2 gene therapy trial for Rett syndrome, showing multidomain, durable gains with 35 developmental milestones acquired across eight participants [1][5] - The first participant has been dosed in the Embolden registrational trial of NGN-401, with complete enrollment expected in three to six months [1][2] - The company maintains a strong cash position, with $265.4 million in cash and equivalents, providing a runway through the first quarter of 2028 [11] Clinical Development Highlights - The NGN-401 gene therapy program for Rett syndrome has advanced significantly, with 12 of 13 trial sites initiated [2][5] - Interim clinical data from the pediatric cohort (ages 4-10) demonstrated functional improvements across all participants, with gains in hand function, language, and ambulation [5] - The therapy has been well-tolerated in both pediatric and adolescent/adult cohorts, with no significant adverse effects reported [5] Financial Results - For the third quarter of 2025, R&D expenses were $17.2 million, up from $16.3 million in the same period in 2024, primarily due to increased clinical trial costs [11] - General and administrative expenses rose to $6.6 million from $5.9 million year-over-year, driven by higher employee-related costs [11] - The net loss for the quarter was $21.0 million, compared to $20.2 million in the prior year [11] Regulatory Designations - NGN-401 has received multiple designations from the FDA, including Regenerative Medicine Advanced Therapy (RMAT) and orphan drug designation, indicating its potential as a significant treatment for Rett syndrome [8]

Financial Performance - The company reported a net loss of $65.6 million for the nine months ended September 30, 2025, compared to a net loss of $55.6 million for the same period in 2024, indicating an increase in losses year-over-year [129]. - As of September 30, 2025, the company had an accumulated deficit of $327.9 million and cash, cash equivalents, and short-term investments totaling $265.4 million [129]. - The net loss for Q3 2025 was $20.953 million, compared to a net loss of $20.217 million in Q3 2024, indicating a 3.6% increase in losses [148]. - For the nine months ended September 30, 2025, the company used $59.7 million in cash for operating activities, reflecting a net loss of $65.6 million [174]. - For the nine months ended September 30, 2024, the company used $53.1 million in cash for operating activities, reflecting a net loss of $55.6 million [175]. - Interest income for Q3 2025 was $2.739 million, an increase of 48.7% from $1.842 million in Q3 2024 [148]. - Other income increased by $1.1 million for the nine months ended September 30, 2025, mainly from state tax refunds [163]. - The company reported net cash provided by financing activities of $9.8 million for the nine months ended September 30, 2025, primarily from open market sales of common stock [178]. Research and Development - The company is developing NGN-401 for the treatment of Rett syndrome, with a registrational trial named Embolden currently evaluating a 1E15 vg dose in 20 female participants [107]. - The primary endpoint for the Embolden trial is a responder-based composite endpoint, with a minimum success threshold of 35% response rate (7 out of 20 patients) to reject the null hypothesis [109]. - Updated interim data from the Phase 1/2 trial showed that all pediatric participants experienced functional gains, with a total of 35 developmental milestones/skills gained across core clinical domains [111]. - The company completed enrollment in a Phase 1/2 clinical trial for NGN-101 in patients with CLN5 Batten disease but decided not to move forward with the program due to the denial of its RMAT application [125]. - The company is in the early discovery stage for additional potential programs utilizing its EXACT platform for complex neurological diseases [124]. - The company expects significant increases in research and development expenses over the next several years due to expanded clinical trials and personnel costs [139]. - Research and development expenses for Q3 2025 were $17.241 million, an increase of 5.9% from $16.285 million in Q3 2024 [148]. - For the nine months ended September 30, 2025, research and development expenses totaled $54.4 million, up 19.3% from $45.6 million in the same period of 2024 [153]. - The increase in Rett syndrome program expenses included a $2.1 million rise in preclinical costs and a $4.0 million increase in clinical trial costs for NGN-401 [154]. - The company anticipates continued increases in research and development and general and administrative expenses as it advances clinical development [156][159]. Operating Expenses - General and administrative expenses for Q3 2025 were $6.557 million, up 11.2% from $5.895 million in Q3 2024 [148]. - For the nine months ended September 30, 2025, general and administrative expenses reached $21.4 million, up 30.2% from $16.4 million in the same period of 2024 [158]. - Total operating expenses for the nine months ended September 30, 2025, were $75.799 million, compared to $62.018 million for the same period in 2024, reflecting a 22.2% increase [148]. Capital and Funding - The company has raised aggregate net proceeds of approximately $552.3 million since its inception, primarily through the sale of preferred and common stock [129]. - The company expects to require substantial additional capital to support ongoing operations and product development [168]. - The company has federal and state net operating loss carryforwards of $319.8 million and $39.6 million, respectively, which may offset future taxable income [146]. Regulatory and Compliance - The company received FDA clearance for its Investigational New Drug (IND) application for NGN-401 in January 2023 [108]. - The collaboration agreement with the University of Edinburgh was amended and extended through December 2026 to support pipeline development [132]. - The company has no products approved for sale and may never achieve regulatory and marketing approval for its product candidates [130]. - The company has no off-balance sheet arrangements as defined by SEC rules [195]. - The company’s financial statements are prepared in accordance with U.S. GAAP, with no material changes to significant accounting policies during the nine months ended September 30, 2025 [196]. Facilities and Lease Obligations - The company established a fully operational cGMP facility in Houston, Texas, to manufacture products for research and clinical studies, enhancing control over product quality and development timelines [126]. - The company has a lease obligation for its New York headquarters expiring in January 2028, covering approximately 6,000 square feet [181]. - The company has a lease for a manufacturing facility in Houston, Texas, expiring in August 2029, with an option to renew for two additional five-year terms [182]. - The company entered into a License Agreement with the University of Edinburgh, which includes obligations of up to $5.3 million in regulatory-related milestones and up to $25 million in sales-related milestones [191]. Contingent Liabilities - The total contingent value rights (CVR) liability as of September 30, 2025, was $1.1 million, compared to $1.8 million as of December 31, 2024 [188].

Core Insights - Neurogene has presented new interim clinical data for NGN-401, a gene therapy aimed at treating Rett syndrome, indicating strong potential for being both best-in-class and first-in-class [2][3] - The company emphasizes the necessity for gene therapy to achieve multiple developmental milestones and skill gains over time, rather than focusing on a single skill improvement [3] Clinical Data - The updated data from the Phase I/II trial of NGN-401 shows promising results, reinforcing the belief that it sets a new standard for gene therapy in Rett syndrome [3] - Key areas of improvement highlighted include hand function, gross motor function, and communication, with an emphasis on the durability of these skills over time [3]

Summary of Neurogene Conference Call Company Overview - **Company**: Neurogene (NasdaqGM:NGNE) - **Focus**: Development of gene therapies for rare neurological diseases, specifically targeting Rett syndrome with the product NGN-401 Key Points and Arguments Clinical Data and Efficacy - **New Interim Clinical Data**: Presentation of new interim clinical data from the phase 1-2 trial of NGN-401 for Rett syndrome treatment [2][3] - **Potential Best-in-Class Therapy**: NGN-401 is believed to be both best in class and first in class for Rett syndrome gene therapy, setting a new standard [2] - **Skill Gains**: Patients have gained a total of 35 skills across multiple domains, with all gains being durable and no skills lost [3][4] - **Patient Cohort**: Data covers eight pediatric patients aged four to eight, with follow-up ranging from six to 24 months [4] - **Functional Gains**: All five patients with at least 12 months of follow-up showed functional gains in core clinical domains, with four meeting the CGI-I responder definition [5][6] - **Skill Acquisition Over Time**: Skill gains increased over time, with 14 skills gained at six months post-treatment and gains more than doubling beyond 12 months [5][6] Administration and Technology - **ICV Administration**: The decision to use intracerebroventricular (ICV) administration is highlighted as a strength, essential for efficacy [3][4] - **Full-Length Gene Delivery**: NGN-401 delivers the full-length MECP2 gene, which is crucial for maximizing functional benefits [4] - **EXACT Technology**: This technology controls transgene levels to avoid overexpression toxicity [4] Safety Profile - **Well Tolerated**: NGN-401 remains well tolerated at the 1E15 dose, with all related events being mild or moderate [10][11] - **Liver Events**: Most liver events were mild and consistent with previous data, with no evidence of hyperinflammatory syndrome [10][11] - **Nerve Conduction Findings**: One patient had abnormal nerve conduction findings, which returned to normal, and were not related to NGN-401 [11][35] Regulatory and Market Position - **Trial Design**: The Embolden trial is a single-arm study with a primary endpoint at 12 months, expected to complete enrollment in the next three to six months [15][29] - **Comparison with Competitors**: Neurogene's data shows more skills gained in fewer patients compared to Taysha's data, with a focus on durability and complexity of skills [12][13][14] - **Regulatory Engagement**: Neurogene has had extensive engagement with the FDA, ensuring alignment on trial protocols and statistical analysis [19][21] Future Outlook - **Additional Data**: More data is expected to be released in 2026, with sufficient cash to fund operations through the first quarter of 2028 [11] - **Market Opportunity**: There is a significant market opportunity for NGN-401, addressing a huge unmet need in Rett syndrome treatment [30] Other Important Content - **Caregiver Testimonials**: Improvements in daily living activities and health-related quality of life were noted, although not detailed in the presentation [10] - **Cognitive Improvement**: Improvements in communication and executive function were observed, suggesting potential long-term cognitive benefits [26][28] - **Patient Variability**: The study included patients with variable baseline impairments, showing benefits across different levels of disease severity [31][33] This summary encapsulates the critical insights from the Neurogene conference call, highlighting the company's advancements in gene therapy for Rett syndrome and its strategic positioning in the market.

Summary of Neurogene Conference Call - October 14, 2025 Company Overview - **Company**: Neurogene Inc. (NasdaqGM:NGNE) - **Industry**: Genetic Medicines, specifically focusing on gene therapy for neurological disorders such as Rett syndrome Key Points and Arguments Recent Developments - Neurogene has completed discussions with the FDA and plans to begin dosing participants in its registrational study this quarter [4][10] - Results from a non-human primate study were presented, demonstrating that Intracerebroventricular (ICV) administration is significantly more effective than Intrathecal (IT) lumbar administration for CNS disorders, with a 10 to 100-fold increase in drug delivery to the brain [4][5] - The company has expanded its U.S. clinical trial sites to 13, which will facilitate future commercialization [4][10] Administration Route and Efficacy - ICV administration is preferred for CNS disorders as it delivers more drug directly to the brain, which is crucial for conditions like Rett syndrome [5][6] - Caregivers are reportedly more encouraged by ICV due to its perceived effectiveness in delivering drugs to the brain [7][10] - Neurogene emphasizes that the focus should be on delivering the best treatment rather than being the first to market, as caregivers prioritize meaningful and durable results [8][9] Clinical Trial Design and Patient Enrollment - Neurogene is enrolling patients as young as three years old, which is seen as advantageous since earlier treatment may prevent irreversible neurological deficits [26][28] - The company believes that having efficacy data in younger patients will be valuable from a regulatory perspective [29] Comparison with Competitors - Neurogene's approach to measuring efficacy includes a composite endpoint that combines multiple skills gained, which is argued to provide a more comprehensive view of patient improvement compared to competitors [20][21] - The company believes that the overlap in milestones between its study and Taysha's study is minimal, and the depth of response in treated patients will be crucial for product differentiation [19][34] Regulatory Considerations - There is confusion regarding the FDA's stance on six-month data as a meaningful endpoint. Neurogene maintains that a 12-month endpoint is more appropriate for demonstrating clinical significance [22][23] - The company has a monitoring protocol in place to address safety concerns, which is viewed as an advantage over competitors [31][32] Market Perception and Valuation - Despite recent positive momentum in Neurogene's stock, there remains a significant valuation gap compared to competitors, attributed to past safety concerns [31][32] - The company believes that as it distances itself from previous safety issues, the market will recognize the advantages of its ICV delivery method and overall efficacy [32][33] Additional Important Points - Neurogene is focused on providing a broad label with efficacy data that addresses the needs of caregivers and clinicians, particularly in the early stages of Rett syndrome [34] - The company is not using certain structured efficacy scales that competitors have emphasized, believing that their own assessments will provide more clinically meaningful data [30] This summary encapsulates the key discussions and insights from the Neurogene conference call, highlighting the company's strategic focus, competitive positioning, and regulatory considerations in the context of gene therapy for Rett syndrome.

Core Insights - Neurogene (NASDAQ:NGNE) is actively participating in the H.C. Wainwright Genetic Medicines Virtual Conference, demonstrating its commitment to innovation in genetic medicine [1][2] - The stock rating for NGNE was upgraded to "Buy" by H.C. Wainwright on October 2, 2025, at a price of $20.97, which has led to a subsequent increase in stock price to $26.26, reflecting an approximate 11.89% rise [1][2] - NGNE's stock has shown significant volatility, with trading prices ranging from a low of $23.10 to a high of $27.56 today, indicating active trading and interest in the company [2] Market Performance - Over the past year, NGNE's stock has experienced a high of $74.49 and a low of $6.88, which has influenced investor decisions and market perception [2] - The company's current market capitalization is approximately $374.78 million, with a trading volume of 221,727 shares, suggesting strong investor interest in the genetic medicine sector on the NASDAQ exchange [2]

Core Points - Neurogene Inc. is a clinical-stage company focused on developing genetic medicines for rare neurological diseases [1] - The company's Compensation Committee approved the grant of non-qualified stock options for a total of 9,390 shares to four new employees [1] - The grant date for these stock options is set for October 1, 2025 [1]

[Company Overview](index=1&type=section&id=Company%20Overview) Neurogene's overview covers disclaimers, its focus on genetic medicines, clinical pipeline, and in-house AAV manufacturing capabilities [Disclaimer](index=2&type=section&id=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](index=3&type=chunk)[4](index=4&type=chunk) - Industry and market data are based on third-party sources and internal estimates, with Neurogene not independently verifying all information[5](index=5&type=chunk) - The presentation may contain trademarks, service marks, trade names, and copyrights belonging to their respective owners[6](index=6&type=chunk) [Neurogene at a Glance](index=3&type=section&id=Neurogene%3A%20Developing%20Life-Changing%20Genetic%20Medicines%20For%20Rare%20Neurological%20Diseases) 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](index=8&type=chunk) - NGN-401 utilizes **EXACT™**, a proprietary transgene regulation technology addressing a key limitation in gene therapy[8](index=8&type=chunk) - The company has extended its **cash runway into early 2028**[8](index=8&type=chunk) [Clinical Stage Pipeline](index=4&type=section&id=Neurogene%20Clinical%20Stage%20Pipeline) 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](index=5&type=section&id=Wholly%20Owned%20and%20Fully%20Integrated%20In-House%20AAV%20Manufacturing) 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](index=13&type=chunk) - Current research and clinical-grade manufacturing capabilities are designed for commercial-grade product to prevent future comparability issues[14](index=14&type=chunk) - In-house manufacturing provides **flexibility, low-cost production, control over product quality and timelines**, and expertise in HEK293 and Sf9/rBV platforms[16](index=16&type=chunk) [NGN-401 for Rett Syndrome](index=6&type=section&id=NGN-401%20for%20Rett%20Syndrome) 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](index=6&type=section&id=NGN-401%20for%20Rett%20Syndrome) 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](index=17&type=chunk) [Rett Syndrome: Disease Overview and Unmet Need](index=7&type=section&id=Rett%20Syndrome%20-%20Devastating%20Disorder%20with%20High%20Unmet%20Need) 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](index=21&type=chunk) - 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](index=22&type=chunk)[23](index=23&type=chunk) [NGN-401: Mechanism of Action and Delivery](index=9&type=section&id=NGN-401%3A%20Potential%20to%20be%20Best-in-Class%20Gene%20Therapy%20for%20Rett%20Syndrome) 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](index=25&type=chunk) - The therapy utilizes the **full-length human MECP2 gene**, translating a fully functioning MeCP2 protein[25](index=25&type=chunk) - **Intracerebroventricular (ICV) delivery** provides broad targeting of brain and nervous system regions relevant to Rett syndrome pathophysiology, as shown in preclinical models[25](index=25&type=chunk) [Embolden™ Registrational Trial Design](index=10&type=section&id=NGN-401%20Embolden%E2%84%A2%20Registrational%20Trial) 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](index=27&type=chunk) 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](index=28&type=chunk) [Trial Design and Endpoints](index=11&type=section&id=Trial%20Design%20and%20Endpoints) 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](index=29&type=chunk)[30](index=30&type=chunk)[31](index=31&type=chunk)[32](index=32&type=chunk) [Caregiver Feedback on Meaningfulness](index=14&type=section&id=Rett%20Syndrome%20Caregiver%20Research%20Demonstrated%20Clinical%20Meaningfulness%20of%20Developmental%20Milestone%2FSkill%20Acquisition) 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](index=33&type=chunk)[34](index=34&type=chunk) - Caregivers emphasized that skill gains would provide **respite, increased independence, reduced physical strain, enhanced safety, and improved dignity** for patients and their families[34](index=34&type=chunk)[41](index=41&type=chunk) [Phase 1/2 Clinical Data](index=16&type=section&id=Phase%201%2F2%20Data%20Support%20Registrational%20Trial%20Design) 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](index=42&type=chunk)[43](index=43&type=chunk) - **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](index=43&type=chunk) - The **1E15 vg NGN-401 dose** was generally well-tolerated, with **no evidence of Hemophagocytic lymphohistiocytosis (HLH)** observed[43](index=43&type=chunk) [Efficacy and Patient Characteristics](index=16&type=section&id=Efficacy%20and%20Patient%20Characteristics) 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](index=49&type=chunk) [Safety Profile (HLH)](index=25&type=section&id=No%20Evidence%20of%20HLH%2FHyperinflammatory%20Syndrome%20at%20the%201E15%20vg%20Dose%20Level) 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](index=68&type=chunk) - **No participants at the 1E15 vg dose level** have presented with clinical symptoms of HLH/hyperinflammatory syndrome[71](index=71&type=chunk) - **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](index=71&type=chunk) [Key Anticipated Milestones](index=27&type=section&id=Key%20Anticipated%20Milestone%20Events) 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](index=28&type=section&id=Key%20Upcoming%20Anticipated%20Milestones%20and%20Pipeline%20Developments) 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](index=73&type=chunk)[74](index=74&type=chunk) - For CLN5 Batten Disease (NGN-101), the company is evaluating program opportunities[74](index=74&type=chunk) - Cash runway is projected to fund operations into **early 2028**[75](index=75&type=chunk) [Appendix](index=29&type=section&id=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](index=30&type=section&id=Detailed%20Autonomic%20Function%20Data) 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](index=66&type=chunk)[77](index=77&type=chunk)[79](index=79&type=chunk)[80](index=80&type=chunk)[82](index=82&type=chunk) - 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](index=67&type=chunk)[83](index=83&type=chunk) - Pt:4 experienced improvements in constipation by **Month 4 post-treatment**[66](index=66&type=chunk)[85](index=85&type=chunk)[86](index=86&type=chunk) [Preclinical Data (Mouse Models)](index=34&type=section&id=NGN-401%20Demonstrated%20Efficacy%20and%20Safety%20in%20Mecp2%20Mouse%20Models) 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](index=90&type=chunk)[91](index=91&type=chunk) - **EXACT™ technology** ensures consistent and narrow expression of MeCP2 on a cell-by-cell basis, preventing potential issues from unregulated gene expression[93](index=93&type=chunk)[94](index=94&type=chunk)