Neuren Pharmaceuticals Limited · ASX:NEU
Neuren Pharmaceuticals — RettSyndrome.org 2016 Rett Syndrome Symposium
27 slides from Neuren Pharmaceuticals's conference presentation, 2016
Slide 1: The Treatment of Rett Syndrome with Trofinetide (NNZ-2566): Past, Present, Future
The Treatment of Rett Syndrome with Trofinetide (NNZ-2566): Past, Present, Future Daniel Glaze, MD Baylor College of Medicine
Slide 2: Multicenter Trials of Trofinetide
Multicenter Trials of Trofinetide • Past: Neu-2566-RETT-001 Phase 2 in Adolescents and Adults with RTT • Present: Neu-2566-Rett 002 Phase 2, Children with RTT • Future: Anticipated Phase 3 Trial, Pediatric and Adult RTT Sponsor: Neuren Pharmaceuticals Rett 001 and 002 partially funded by RettSyndrom
Slide 3: Trofinetide (NNZ-2566)
Trofinetide (NNZ-2566) • IGF-1 is a naturally occurring growth factor in the brain • Glypromate (GPE) separates from IGF-1 in the brain • IGF-1 and GPE maintain and restore equilibrium in trofinetide the brain
Slide 4: Trofinetide (NNZ-2566)
Trofinetide (NNZ-2566) Trofinetide is a synthetic analogue of GPE • Able to cross blood brain barrier • Suitability as an oral medication: 50-60% bioavailable • Influences processes underlying response to injury trofinetide and synaptic plasticity
Slide 5: Trofinetide (NNZ-2566)
Trofinetide (NNZ-2566) Trofinetide is a synthetic analogue of GPE • Potentially targets a range of neurological conditions • Does not bind to IGF1 receptor • Provides good brain levels trofinetide in animal models
Slide 6: Trofinetide: Effects in Mecp2 Mouse Model
Trofinetide: Effects in Mecp2 Mouse Model • Enhanced mecp2 knockout model long-term potentiation • Increased dendritic length and arborization • Improved longevity
Slide 7: Trofinetide (NNZ-2566): In Sum
Trofinetide (NNZ-2566) In Sum: These suggest potential application to treat Rett syndrome. Oral liquid formulation: good safety profile in adult healthy volunteers and Rett 001
Slide 8: Rett Trial in Adolescents and Adults
Rett 001 Trial in Adolescents and Adults Phase 2, randomized, double-blind, placebo-controlled, dose-escalation clinical trial of trofinetide in RTT Primary Outcome: Safety Secondary Outcomes: Efficacy
Slide 9: Participants
Participants Females ages 15.9-44.2 yr. (mean 25.3) Met diagnostic criteria for typical RTT and MECP2 mutation CGI-S score ≥ 4
Slide 10: Dosing Cohorts of Oral Trofinetide vs Placebo
Dosing Cohorts of Oral Trofinetide vs Placebo Cohort 0 35mg/kg BID or 2:1 Randomization 14 Days Treatment N=9 Placebo Cohort 1 35mg/kg BID or 2.1 Randomization 28 days treatment N=18 Placebo Cohort 2 70mg/kg BID or 2:1 Randomization 28 days of treatment N=29 Placebo
Slide 11: Safety Measures
Safety Measures • Adverse events • ECGs • Laboratory blood tests (chemistry, hematology, thyroid, HgA1C) • Physical exams • Vitals signs • Caregiver report/seizure diary
Slide 12: Core Efficacy Measures
Core Efficacy Measures Efficacy Domain Core Outcome Measure Efficacy Domain 1: 1. Rett Syndrome Motor-Behavior Clinician-completed syndrome- Assessment (MBA) specific measures 2. Rett Clinical Severity Scale (CSS) Efficacy Domain 2: 3. Clinical Global Impression of Clinician-completed syndrome- Impr
Slide 13: Pre-Specified Criteria for Efficacy
Pre-Specified Criteria for Efficacy
Slide 14: Participant Characteristics (mITT)
Participant Characteristics (mITT) Placebo 35 mg/kg 70 mg/kg (Combined) N 20 18 17 Age (yr.) 27.41 23.74 24.52 CSS (mean) 23.7 23.5 24.5 CGI-S (mean) 5.1 4.9 5.2
Slide 15: Results: Safety
Results: Safety Achieved its primary endpoint - both dose levels of trofinetide were well-tolerated after 28 days of treatment and no safety concerns were identified. As measured by adverse events, ECGs, vitals, physical exams and lab values
Slide 16: Results: 70mg/kg b.i.d. Dose Demonstrates Evidence of Efficacy
RESULTS: 70mg/kg b.i.d. Dose of Trofinetide Demonstrates Evidence of Efficacy Higher dose exceeded the pre-specified criteria for improvement in core efficacy measures compared with placebo on group and subject level analysis MBA Change Index Subject-Level Score Top 3 Concerns CGI-I Least Squares me
Slide 17: Motor Behavior Assessment-Change Index: 70mg/kg b.i.d. group
Motor Behavior Assessment-Change Index:70mg/kg b.i.d. group EOT Direction of benefit: decrease in score. Lsmeans: Adjusted for Baseline when Baseline p<0.1. End of treatment=EOT
Slide 18: Caregiver Top Concerns: 70mg/kg b.i.d. group
Caregiver Top 3 Concerns: 70mg/kg b.i.d. group EOT Direction of benefit: decrease in score. Lsmeans: Adjusted for Baseline when Baseline p<0.1. End of treatment=EOT
Slide 19: Clinical Global Impression of Improvement: 70mg/kg b.i.d. group
Clinical Global Impression of Improvement:70mg/kg b.i.d. group EOT Direction of benefit: decrease in score. Lsmeans: Adjusted for Baseline when Baseline p<0.1. End of treatment=EOT
Slide 20: Conclusion
Conclusion Oral trofinetide safe and well tolerated Higher dose exceeded pre-specified criteria for evidence of clinical benefit in the core symptoms of RTT. Results provide initial evidence of effectiveness of trofinetide as a potentially viable treatment for the core signs and symptoms of Re
Slide 21: Current Study: Rett 002
Current Study: Rett 002 Phase 2, randomized, double-blind, placebo- controlled, clinical trial of trofinetide in RTT Outcomes Primary: Safety/PK Secondary: Efficacy Blinded treatment with trofinetide or placebo as a strawberry flavored liquid medication Randomized to placebo, 50 mg/kg, 1
Slide 22: Inclusion / Exclusion Criteria
Inclusion / Exclusion Criteria Dx of classical Rett with MECP2 mutation Females 5 to 15 years-old Weight at screening 15-100 kg At least moderate overall severity in clinical symptoms (CGI-S ≥ 4, CSS 10-36) Medication and behavioral therapies stable Stable pattern of seizure activity I
Slide 23: Efficacy Assessments
Efficacy Assessments Clinician Completed Measures Motor Behavior Assessment; Clinical Global Impression (Severity and Improvement – Anchored with Training on RTT Cases); Clinician Rated Concerns-VAS, Clinical Severity Scale (screening) Caregiver Completed Measures Caregiver Top Three Concerns-VA
Slide 24: Study Timeline and Current Progress
Study Timeline and Current Progress 11 week study with 8 study visits • Other sites in start up Target Enrollment: 64 • Study info and new sites opened on the Target Completion: Q4 2016 website: Planned Study Sites: 12 Enrolling Study Sites: www.Rettstudy.org University of Alabama, Birmi
Slide 25: What is next?
What is next? Received meaningful guidance on the development program and outcome measures from FDA Reached agreement with FDA on the construct of the primary outcome measure considered acceptable for use in pivotal registration trial Subject to the results from the Rett 002 pediatric trial, a
Slide 26: Trials of Trofinetide in RTT: Contributions to Progress in the Field
Trials of Trofinetide in RTT: Contributions to Progress in the Field Development and validation of RTT-Specific outcome measures will be an important component to support clinical trials development Development of RTT-specific measures relevant to assessing treatment outcome in trials Clinical
Slide 27: Acknowledgements
Acknowledgements Rett 002 Study Sites and PIs Drs. A. Percy, J. Neul, D. Glaze Rettsyndrome.org Neuren Larry Glass Nancy Jones, PhD Special thanks to the participating families
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