Aquinox(NLTX) - 2024 Q4 - Annual Results

Company Overview Neurogene is a clinical-stage company focused on neurological diseases, leveraging its EXACT™ technology, a promising pipeline, and internal manufacturing capabilities Investment Highlights Neurogene positions itself as a differentiated clinical-stage company focused on complex neurological diseases, leveraging its proprietary EXACT™ technology, an attractive pipeline including a Rett syndrome candidate, internal manufacturing capabilities, and a cash runway into the second half of 2027 - Utilizes novel EXACT™ technology designed to overcome key limitations of conventional gene therapy[8] - The pipeline addresses attractive market opportunities, with a lead candidate for Rett syndrome[8] - Possesses internal manufacturing capabilities, providing financial and strategic flexibility[8] - Maintains a cash runway into the second half of 2027, enabling operations beyond key clinical inflection points[8] Clinical Pipeline The company's clinical-stage pipeline is led by NGN-401 for Rett Syndrome, currently in Phase 1/2, and includes NGN-101 for CLN5 Batten Disease in the IND-enabling stage Neurogene Clinical Pipeline Status | Product Candidate | Indication | Phase I/2 | | :--- | :--- | :--- | | NGN-401 | Rett Syndrome | In Progress | | NGN-101 | CLN5 Batten Disease | IND Enabling | In-House Manufacturing Capabilities Neurogene operates a wholly-owned 42,000 sq ft GMP manufacturing facility in Houston, providing strategic flexibility, cost advantages, and control over product quality and development timelines for its AAV-based therapies - Operates a 42,000 sq ft facility in Houston with 6,000 sq ft of cleanrooms for GMP manufacturing[13] - In-house manufacturing provides flexibility, cost advantages, and direct control over product quality and development timelines[13] - Process development expertise supports both HEK293 and Sf9/rBV manufacturing platforms[13] NGN-401 for Rett Syndrome Program The NGN-401 program for Rett Syndrome is detailed, covering its mechanism, clinical trial results, patient vignettes, and regulatory strategy Rett Syndrome and NGN-401 Mechanism of Action Rett Syndrome's unmet need, NGN-401's EXACT™ technology for MeCP2 regulation, and ICV administration rationale are detailed Disease Overview: Rett Syndrome Rett Syndrome is a severe X-linked neurological disorder caused by mutations in the MECP2 gene, with a U.S. prevalence of 6,000-9,000 patients and no approved disease-modifying treatments, representing a high unmet medical need - Rett Syndrome is an X-Linked disorder caused by mutations in the MECP2 gene[17] Rett Syndrome Market Opportunity | Metric | Value | | :--- | :--- | | U.S. Prevalence | ~6,000-9,000 patients | | Worldwide Incidence | 1:10,000 females | - There are no approved treatments that address the underlying genetic cause of the disease, indicating a significant unmet need[17] EXACT™ Technology and Therapeutic Approach NGN-401 utilizes EXACT™ technology to regulate MeCP2 transgene expression, aiming to deliver therapeutic protein levels to deficient cells while preventing toxic overexpression in healthy cells. This "genetic thermostat" mechanism is designed to widen the therapeutic window, a critical factor for treating Rett Syndrome where both too little and too much MeCP2 protein are harmful - Effective treatment for Rett Syndrome requires tight transgene regulation, as both insufficient and excessive MeCP2 gene expression are toxic[19] - EXACT™ technology functions as a "genetic thermostat," using embedded miRNA sequences to destroy excess transcripts and control transgene levels within a targeted therapeutic range[23] - NGN-401 is specifically designed to widen the therapeutic window by dampening overexpression and maintaining MeCP2 levels within a tolerable range[25][26] Rationale for ICV Administration Preclinical data in non-human primates (NHPs) demonstrated that intracerebroventricular (ICV) administration of the gene therapy resulted in significantly better distribution to key areas of the nervous system implicated in Rett Syndrome, such as the motor cortex and brainstem, compared to intrathecal-lumbar (IT-L) administration - In non-human primate studies, Intracerebroventricular (ICV) administration resulted in significantly better vector genome distribution to key brain areas underlying Rett Syndrome compared to Intrathecal-lumbar (IT-L) administration[27][28] Phase 1/2 Clinical Trial Results Interim data from the Phase 1/2 trial of NGN-401 shows compelling and durable improvements across multiple core domains of Rett Syndrome, including hand function, motor skills, communication, and autonomic function. All participants achieved a clinically meaningful two-point improvement on the CGI-I scale, with the 1E15 vg dose being generally well-tolerated Trial Design and Interim Data Summary The ongoing Phase 1/2 trial is evaluating NGN-401 in female Rett Syndrome patients (ages 4-10). The current protocol uses a 1E15 vg dose. Interim data as of October 2024 shows consistent, durable, and clinically meaningful gains of function across core clinical domains, with a generally well-tolerated safety profile - The Phase 1/2 trial is evaluating a 1E15 vg dose of NGN-401 in females aged 4-10 years with a clinical and genetic diagnosis of Classic Rett syndrome[33] - Interim data shows durable improvements, including a two-point improvement in the Clinical Global Impression-Improvement (CGI-I) scale for all participants[35] Baseline Characteristics of Dosed Participants (1E15 vg) | | Participant 1 | Participant 2 | Participant 3 | Participant 4 | | :--- | :--- | :--- | :--- | :--- | | Age at Dosing (Years) | 7 | 4 | 6 | 7 | | MECP2 Mutation Severity | Mild | Severe | Severe | Severe | | Baseline CGI-S Score | 4 (moderately ill) | 5 (markedly ill) | 5 (markedly ill) | 5 (markedly ill) | Efficacy Across Key Clinical Scales (CGI-I, RSBQ) All participants achieved a CGI-I score of "Much Improved" (a 2-point improvement), indicating clinically meaningful benefit that was observed early and sustained over time. Additionally, all participants showed improvements (reductions) in their Rett Syndrome Behavior Questionnaire (RSBQ) total scores, ranging from 28% to 52% - All participants achieved a CGI-I rating of "Much Improved" (a 2-point improvement from baseline), which is considered clinically meaningful and was observed early after treatment[38][41][42] Improvement on Rett Syndrome Behavior Questionnaire (RSBQ) | Participant | Time Post-Tx | RSBQ Point Change | RSBQ % Change | | :--- | :--- | :--- | :--- | | Pt:1 | 15 mos. | -10 pts. | -28% | | Pt:2 | 12 mos. | -32 pts. | -52% | | Pt:3 | 9 mos. | -5 pts. | -29% | | Pt:4 | 3 mos. | -8 pts. | -28% | Improvements in Autonomic Function Objective assessments showed improvements in autonomic functions. Patients with baseline sleep deficits experienced increased sleep efficiency. Those with constipation saw improvements in stool consistency. One patient with dysphagia (difficulty swallowing) regained the ability to drink from a cup and eat solid foods - Patients 1 and 2, who had sleep deficits at baseline, experienced improvements in sleep efficiency as measured by a wearable device[47] - Patients 1, 2, and 4, who had constipation at baseline, experienced improvements as measured by the caregiver-reported modified Bristol Stool Form Scale[47] - Patient 3, who had dysphagia at baseline, is now able to drink from a cup and chew and swallow food items[47] Participant Vignettes and Natural History Comparison This section provides detailed case studies for four trial participants, highlighting their multi-domain improvements in fine motor, gross motor, and communication skills post-treatment. These gains, including the acquisition of complex skills not typically seen at their age, are contrasted with the expected disease progression based on Rett Syndrome natural history data, suggesting a treatment effect beyond typical development Natural History of Rett Syndrome Rett Syndrome is characterized by a period of developmental regression in early childhood (around 1-4 years), where acquired skills like hand function and communication are lost. Natural history data shows that while simple skills may be acquired early, many are lost, and more complex skills are generally never acquired by children in the 4-10 year age range - Rett Syndrome progression involves an early developmental regression phase (approx. 1-4 years) characterized by the loss of acquired skills, including fine motor and communication[50] - According to the U.S. Natural History Study of Rett Syndrome (RNHS), complex skills like using a spoon/fork, running, or climbing stairs are generally not acquired by patients aged 4-10[52][54] Participant 1 Case Study At 15 months post-treatment, Patient 1 (7 years old at dosing) demonstrated significant improvements, developing a pincer grasp, self-feeding, and achieving a more fluid gait. She learned complex skills not expected from natural history, such as climbing stairs without help, and re-learned skills like waving hello - At 15 months post-treatment, Pt:1 developed a pincer grasp, could self-feed, and exhibited a more fluid, heel-to-toe walk[55] - Pt:1 newly learned complex skills not expected based on natural history data, including climbing up and down stairs without help[57] Participant 2 Case Study Patient 2 (4 years old, severe baseline) showed remarkable progress 12 months post-treatment, going from no functional hand use to holding a juice box and starting to self-feed. She also developed a steadier gait and began speaking words like "mama" and "dada" in context, skills that were either lost or never acquired - At 12 months post-treatment, Pt:2, who had no functional hand use at baseline, could hold a juice box, start to self-feed, and say "mama" and "dada" in context[58] - Pt:2 re-learned skills such as using words with meaning and newly learned to follow a command without a gesture, which is outside the expected progression for her severe baseline[61] Participant 3 Case Study Patient 3 (6 years old, non-ambulatory at baseline) showed improvements 9 months post-treatment, including the ability to sit independently and self-feed solid foods, overcoming a baseline dysphagia that required pureed food. These re-learned skills are significant given her severe starting point - At 9 months post-treatment, Pt:3, who could not sit independently at baseline, was able to sit independently and self-feed solid foods, overcoming previous swallowing difficulties[63] - Pt:3 re-learned key skills post-treatment, including using a pincer grasp, self-feeding, and sitting independently[64] Participant 4 Case Study At 3 months post-treatment, Patient 4 (7 years old, non-ambulatory) showed early improvements in hand function, becoming able to use regular utensils to self-feed. She also showed improved emotional expression, laughing appropriately at context - At 3 months post-treatment, Pt:4 was able to use regular utensils to self-feed, an improvement from adaptive utensils at baseline, and showed more appropriate emotional responses[66] - Pt:4 newly learned the complex skill of using utensils to self-feed without assistance, an achievement well outside the expectations from natural history data[67] Regulatory Strategy Neurogene is actively engaging with the FDA to accelerate the NGN-401 program towards registration. The company is leveraging its participation in the FDA's START Program and its RMAT designation, which provides eligibility for Accelerated Approval, to streamline communication and registrational planning - Leveraging participation in the FDA's START Program to accelerate communication and registrational planning[68] - The program has Regenerative Medicine Advanced Therapy (RMAT) designation, providing eligibility for an Accelerated Approval pathway, rolling BLA submission, and potential for Priority Review[68] - The company has achieved FDA alignment on its potency assay strategy to support future registration and manufacturing scale-up[68] Outlook and Milestones Neurogene outlines its strategic outlook and key upcoming milestones for the NGN-401 program and financial runway Key Anticipated Milestones Neurogene has outlined key upcoming milestones, focusing on the NGN-401 program for Rett syndrome. The company plans to provide a regulatory update on the pivotal trial in the first half of 2025 and announce additional Phase 1/2 clinical data in the second half of 2025. The company's cash runway is expected to fund these activities into the second half of 2027 Upcoming Anticipated Milestones | Program | Milestone | Timing | | :--- | :--- | :--- | | NGN-401 (Rett) | Provide regulatory update regarding pivotal trial | 1H:25 | | NGN-401 (Rett) | Announce additional Phase 1/2 clinical data | 2H:25 | | NGN-101 (CLN5 Batten) | Evaluate opportunities for the program | Ongoing | | Corporate | Cash runway expected to fund operations | into 2H:27 | Appendix The appendix provides supplementary information on clinical scales, patient improvements, and preclinical data Detailed Clinical Scale Information and Functional Improvements This section offers a deeper dive into the clinical assessment tools and patient-level data. It explains the domains of the CGI-S scale and presents detailed, time-course data for each of the four participants across hand function, gross motor skills, communication, and objective measures of autonomic function like sleep and constipation - Provides a detailed breakdown of the Clinical Global Impression-Severity (CGI-S) scale, noting it is not designed to be sensitive to change and that substantial gains are required to improve the score by one point[75][76] - Presents detailed, longitudinal data for each participant, showing gains in hand function (e.g., developing pincer grasp), gross motor function (e.g., improved gait, ability to sit/stand), and communication (e.g., making choices, vocalizations)[78][80][82] - Includes objective data on autonomic function, such as charts showing improved sleep efficiency and decreased sleep position changes for Pt:1 and Pt:2, and improved stool consistency for patients with baseline constipation[89][93][96] Preclinical Data Preclinical data in mouse models of Rett Syndrome demonstrated that NGN-401 provided a survival benefit in both male knockout and female heterozygous mice. Furthermore, the EXACT technology was shown to deliver consistent, narrow levels of MECP2 expression on a cell-by-cell basis, supporting its mechanism of regulating transgene expression to avoid toxicity - In preclinical mouse models, ICV delivery of NGN-401 demonstrated a significant survival benefit in both male knockout and female heterozygous mice, which mirror the genetics of human females with Rett syndrome[98] - Cellular-level analysis showed that the EXACT technology achieves a narrow and consistent expression of MECP2, in contrast to the wide and potentially toxic variability seen with conventional gene therapy constructs[99][100]