Slide 1: Interim Clinical Data from Phase 1/2 Trial Evaluating NGN-401 for Rett Syndrome
CONFIDENTIAL Interim Clinical Data from Phase 1/2 Trial Evaluating NGN-401 Gene Therapy for the Treatment of Rett Syndrome November 11, 2024
Slide 2: Disclaimer: Forward Looking Statements
Disclaimer 2 Forward Looking Statements This communication contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may discuss goals, intentions and expectations as to future plans, trends, events, results of operations or fina
Slide 3: Agenda
Agenda Introduction and NGN-401 Program Overview Rett Syndrome Overview and Natural History NGN-401 Phase 1/2 Clinical Trial Design Baseline Characteristics and Safety Data Interim Low-Dose Cohort Efficacy Data NGN-401 Next Steps Q&A 3
Slide 4: E | ate
E | ate A y we
Slide 5: Compelling Interim Clinical Data in Low-Dose Cohort Shows Gains of Function
Compelling Interim Clinical Data in Low-Dose Cohort Shows Gains of Function Across Core Domains and Improvements in Autonomic Function 5 NGN-401 Durable improvements observed across multiple scales, incl. two-point improvement in CGI-I in all participants, with concordance of benefit across scales C
Slide 6: Leveraging START and RMAT to Accelerate Program to Registration
Leveraging START and RMAT to Accelerate Program to Registration; New Adult Cohort Underway 6 START Program participation provides clear channel of communication with FDA to accelerate registrational planning RMAT designation provides eligibility for an Accelerated Approval pathway and rolling BLA an
Slide 7: Rett Syndrome Overview and Natural History
Rett Syndrome Overview and Natural History 7
Slide 8: Rett Syndrome is Defined By Regression Period in Early Development
Rett Syndrome is Defined By Regression Period in Early Development 8 Pini G, et al. Orphanet Journal of Rare Diseases (2016) 11:132. C lin ic al fu nc tio n ~6 mos. to ~18 mos. ~1 to 4 years ~4 to 10 years Normal Adolescence to Adulthood Developmental Regression Early Onset Disease Progression“Relat
Slide 9: Simple Skills Are Generally Acquired but Majority Are Lost During Regression
Simple Skills Are Generally Acquired but Majority Are Lost During Regression; More Complex Skills are Generally Not Acquired 9Data from the RNHS; N=200 female subjects with classic RTT, age 4-10 years, CGI-S score of 4 to 6 at baseline, confirmed genetic mutation Raking Grasp (~85%) Transferred Obje
Slide 10: NGN-401 Phase 1/2 Trial Design and Interim Results
NGN-401 Phase 1/2 Trial Design and Interim Results
Slide 11: NGN-401 Phase 1/2 Clinical Trial Design in Females with Rett Syndrome
NGN-401 Phase 1/2 Clinical Trial Design in Females with Rett Syndrome 11 Cohort 1 prophylactic immunosuppression regimen includes corticosteroids Cohorts 2 and 3 prophylactic immunosuppression regimen includes a targeted regimen of rituximab, sirolimus and shorter course of corticosteroids Trial Des
Slide 12: Baseline Characteristics of Dosed Participants Range from Moderate to Severe Disease
12 Baseline Characteristics of Dosed Participants Range from Moderate to Severe Disease Low-Dose Cohort 1 (1E15 vg) High-Dose Cohort 2 (3E15 vg) Participant 1 (LD:1) Participant 2 (LD:2) Participant 3 (LD:3) Participant 4 (LD:4) Participant 5 (LD:5) Participant 1 (HD:1) Participant 2 (HD:2) Age at D
Slide 13: Baseline Presentations of Participants Across Core Domains
13Images are representative of skills and are not photos of participants in the NGN-401 clinical trial LD:1 Baseline - 7 Years Old LD:2 Baseline - 4 Years Old LD:3 Baseline - 6 Years Old LD:4 Baseline - 7 Years Old Hand Function / Fine Motor • Raking grasp • Limited ability to feed herself • Dropped
Slide 14: NGN-401 Has a Favorable Safety and Tolerability Profile
14 As of data cut-off date of 17 October 2024 TEAE = Treatment-emergent adverse event; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ULN= Upper limit of norma NGN-401 Has a Favorable Safety and Tolerability Profile in 7 Participants Dosed (5 Low Dose and 2 High Dose) Low-Dose Num
Slide 15: Consistent Improvement Across Key Rett Syndrome Scales
Consistent Improvement Across Key Rett Syndrome Scales, Bolstered by Functional Improvements in Core Clinical Domains 15 As of data cut-off date of 17 October 2024 *Each participant achieved a 2-point improvement from “no change,” or a score of 4 CGI-I CGI-S Total Score RSBQ Improved? How many point
Slide 16: Understanding the CGI-I with Rett Syndrome Specific Anchors
Understanding the CGI-I with Rett Syndrome Specific Anchors 16*Clinical Review Report: Brexpiprazole (Rexulti), 2017. Neul J, et al. J Child Neurol (2015) 30(13):1743–1748 • Clinician-rated scale assessing improvement from baseline • 1-point improvement considered clinically meaningful (score ≤ 3)*
Slide 17: All Treated Participants Achieved CGI-I Rating of Much Improved
All Treated Participants Achieved CGI-I Rating of “Much Improved” CGI-I Score ≤ 3 = Clinically Meaningful Improvement LD:1 3 – Minimally Improved 2 – Much Improved 2 – Much Improved 2 – Much Improved 2 – Much Improved LD:2 2 – Much Improved 2 – Much Improved 2 – Much Improved 2 – Much Improved LD:3
Slide 18: Understanding the CGI-S with Rett Syndrome Specific Anchors
Score CGI-S 1 Normal, not at all ill 2 Borderline ill 3 Mildly ill 4 Moderately ill 5 Markedly ill 6 Severely ill 7 Extremely ill Understanding the CGI-S with Rett Syndrome Specific Anchors 18 • Clinician-rated scale of disease severity across 7 clinical domains • Communication, ambulation, and hand
Slide 19: CGI-S Clinical Domains Provide Insights Into Core Functional Areas
CGI-S Clinical Domains Provide Insights Into Core Functional Areas; Scale Was Not Designed as Clinical Outcome Measure 19*Treated participants to date have been stable with no seizures on study Neul J, et al. J Child Neurol (2015) 30(13):1743–1748 Clinical Domains CGI-S 3 CGI-S 4 CGI-S 5 CGI-S 6 Lan
Slide 20: Hand Function: All Participants Gained Meaningful Improvements
Hand Function: All Participants Gained Meaningful Improvements and Gained Skills that Deepened Over Time 20 LD:1 7 yrs. at dosing CGI-S Domain Score 4 4 4 4 4 4 Raking grasp; Limited self-feeding • More consistent self- feeding, able to take multiple bites of foods without dropping • Modified pincer
Slide 21: Ambulation and Gross Motor Improvements
21 LD:1 7 yrs. at dosing CGI-S Domain Score 4 4 3 3 4 3 Impaired, ataxic, unstable gait; Freezes often and walks on tip-toes; Unable to ascend or descend stairs independently • More fluid gait, more heel-to toe • Able to ascend stairs independently • Can get on and off bed independently • Ascends st
Slide 22: Communication: Improvement in Ability to Convey Choices (1 of 2)
Communication: All Participants Demonstrated Improvement in Ability to Convey Choices (Slide 1 of 2) 22 LD:1 7 yrs. at dosing CGI-S Domain Score 6 6 5 5 4 4 Makes choices 50% of time; Unable to follow commands • Some choice-making • Makes choices most of time; food 80–90% of time • Intermittently fo
Slide 23: Communication: Improvements in Ability to Express Themselves (2 of 2)
Communication: All Participants Experiencing Improvements in Ability to Express Themselves (Slide 2 of 2) 23 LD:1 7 yrs. at dosing CGI-S Domain Score 6 6 5 5 4 4 Vocalizations • Vocalizations • Vocalizations • Vocalizations • Babbles • Consistently waves “hello” on command • Shouts or yells to expre
Slide 24: Autonomic Function: Breathing Dysrhythmias Are Variable
Autonomic Function: Breathing Dysrhythmias Are Variable, Difficult to Assess Clinically Meaningful Improvements at Clinic Visits 24 LD:1 7 yrs. at dosing CGI-S Domain Score 5 5 3 4 4 5 Breathing dysrhythmias 50% of the time • Breathing dysrhythmias 50% of the time • No or minimal breathing abnormali
Slide 25: Understanding the Rett Syndrome Behavior Questionnaire (RSBQ)
Understanding the Rett Syndrome Behavior Questionnaire (RSBQ) • Caregiver-completed scale consisting of 45 items measuring behavior in females with RTT • Developed as a diagnostic tool to differentiate females with Rett syndrome from those with severe intellectual disability • Scale is limited due t
Slide 26: All Participants Have Experienced Improvement in RSBQ Score
All Participants Have Experienced Improvement in RSBQ Score C ha ng e fro m B as el in e in To ta l S co re 26 Participant Baseline CGI-S Score Baseline RSBQ Score Change from Baseline % Change LD:1 4 39 -10 -28% LD:2 5 62 -32 -52% LD:3 5 17 -5 -29% LD:4 5 29 -8 -28% RSBQ: Change from Baseline Reduc
Slide 27: All Participants Experienced Improvements in Autonomic Function
All Participants Experienced Improvements in Autonomic Function, as Measured by Objective Assessments 27Detailed data provided in Appendix • LD:1 and LD:2, who had sleep deficits at Baseline, experienced improvements in sleep parameters, as measured by a wearable device • LD:1 sleep efficiency incre
Slide 28: Participant Vignettes
Participant Vignettes
Slide 29: LD:1 From Pre-Treatment to 15 Months Post NGN-401
Hand Function / Fine Motor • Had a raking grasp, briefly held objects, dropping items quickly, with limited ability to self-feed Ambulation / Gross Motor • Walked independently, but would stay on her tip-toes, freeze often and required a parent to help her go up/down stairs or get on/off a bed Langu
Slide 30: LD:1 Multi-Domain Improvements Deepened Over Time
LD:1 Multi-Domain Improvements Deepened Over Time, and Not Expected Based on Rett Syndrome Natural History 30 Select LD:1 Developmental Skills Post-NGN-401 Months Post-NGN-401 3 6 9 12 15 Uses a pincer grasp Holds bottle or cup unpropped Uses spoon/fork to self-feed Transfers objects between hands H
Slide 31: LD:2 Pre-Treatment to Post NGN-401 Vignette
Hand Function / Fine Motor • Had no functional hand use, clenched hands, could not grab, reach, hold objects Ambulation / Gross Motor • Walked independently, but fell frequently, couldn’t stand up from seated position without being pulled up, couldn’t bend over Language / Communication • No babbling
Slide 32: LD:2 Multi-Domain Improvements from Severe Impairments at Baseline
LD:2 Multi-Domain Improvements from Severe Impairments at Baseline Deepened Over Time, and Not Expected Based on Rett Syndrome Natural History 32 Data from the RNHS; N=200 female subjects with classic RTT, age 4-10 years, CGI-S score of 4 to 6 at baseline, confirmed genetic mutation As of data cut-o
Slide 33: LD:3 From Pre-Treatment to 9 Months Post NGN-401
Hand Function / Fine Motor • Raking grasp, required caregiver to spoon feed all meals due to inability to swallow anything safely other than pureed food Ambulation / Gross Motor • Could not sit, stand, or walk independently due to poor core strength and lower extremity weakness Language / Communicat
Slide 34: LD:3 Multi-Domain Improvements Not Expected Based on Natural History
LD:3 Multi-Domain Improvements Not Expected Based on Rett Syndrome Natural History 34 Select LD:3 Developmental Skills Months Post-NGN-401 3 6 9 Uses a pincer grasp Able to self-feed Sits independently Data from the RNHS; N=200 female subjects with classic RTT, age 4-10 years, CGI-S score of 4 to 6
Slide 35: LD:4 From Pre-Treatment to 3 Months Post NGN-401
Hand Function / Fine Motor • Raking grasp, able to use adaptive utensils to self-feed, unable to hold or use regular utensils Ambulation / Gross Motor • Could not stand or walk independently Language / Communication • No babbling, unable to follow commands, laughed out of context 35 Images are repre
Slide 36: LD:4 Early Improvements in Hand Function
LD:4 Early Improvements in Hand Function Not Expected Based on Rett Syndrome Natural History 36 Select LD:4 Developmental Skills Months Post- NGN-401 3 Uses a pincer grasp Can use utensils to self-feed (without assistance) Data from the RNHS; N=200 female subjects with classic RTT, age 4-10 years, C
Slide 37: Neurogene: Differentiated Clinical-Stage Company Utilizing EXACT Technology
Neurogene: Differentiated Clinical-Stage Company Utilizing EXACT Technology to Treat Complex Neurological Diseases 37 • Potential best-in-class efficacy: Durable and concordant improvements observed across multiple scales, incl. two-point improvement in CGI-I in all participants • Consistent gains o
Slide 38: Next Steps
Next Steps
Slide 39: Key Upcoming Anticipated Milestones and Pipeline Developments
Key Upcoming Anticipated Milestones and Pipeline Developments Rett syndrome (NGN-401) Expand ongoing Phase 1/2 clinical trial in 1H:24 to enroll a larger cohort of pediatric patients Interim Phase 1/2 clinical data in pediatrics in 4Q:24 Complete low-dose enrollment in pediatrics in 4Q:24 (N=8
Slide 40: Thank You
Thank You
Slide 41: Presentation Appendix
Presentation Appendix
Slide 42: NGN-401 Designed to be Best-in-Class Gene Therapy for Rett Syndrome
NGN-401 Designed to be Best-in-Class Gene Therapy for Treatment of Rett Syndrome 42 Full-length human MECP2 gene maximizes potential for efficacy EXACT designed to fine- tune transgene expression to deliver consistent levels across wild type and deficient cells without overexpression toxicity Intrac
Slide 43: LD:1 Autonomic Function: Improvements in Sleep Parameters and Constipation
LD:1 Autonomic Function: Objective Improvements Observed in Sleep Parameters and Constipation 43 Total sleep time increased from 6.6 to 7 hrs./night Number of position changes decreased from 37 to 18 per night Sleep efficiency* increased from 83% to ~90% (95% is ideal) Improvements in All Sleep Para
Slide 44: LD:2 Autonomic Function: Improvements in Sleep Parameters and Constipation
0% 20% 40% 60% 80% 100% Month 0 Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 None Type 1 - Separate hard lumps, like nuts Type 2 - Sausage-like, but lumpy Type 3 - Like a sausage or snake, smooth and soft Type 4 - Fluffy pieces with ragged edges, a mushy stool Type 5 - Watery, no solid pieces LD:
Slide 45: LD:3 Autonomic Function: Improvement in Swallowing and Self-feeding
Beginning 3 months post-NGN-401, LD:3 could swallow liquids, such as clear soup and water from a sippy cup, and chew and swallow soft items, such as meatballs and cooked carrots, without choking At 9 months post-NGN-401, she is now able to grasp food such as apple slices and self-feed At Baseline, L
Slide 46: LD:4 Autonomic Function: Improvement Observed in Constipation
LD:4 did not have Baseline deficits in autonomic category of sleep Sleep quality maintained post-treatment LD:4 Autonomic Function: Objective Improvement Observed in Constipation 46 Constipation Improved in Month 4, as Measured by Stool Consistency and Frequency* *As measured by Caregiver on modifie