Neuren Pharmaceuticals Limited · ASX:NEU
Neuren Pharmaceuticals — 6th Annual TBI Conference, Washington DC (May 2016)
34 slides from Neuren Pharmaceuticals's conference presentation, May 13, 2016
Slide 1: INTREPID: A Randomized, Double-Blind, Placebo-Controlled Study of NNZ-2566 in TBI
INTREPID: INvestigating TREatments for the Prevention of secondary Injury and Disability following TBI For personal use only A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study of NNZ-2566 in Patients with Traumatic Brain Injury 6th Annual TBI Conference, Washington DC 12 May 2016
Slide 2: Disclosures
Disclosures For personal use only • The INTREPID study was funded by Neuren Pharmaceuticals Ltd. and by grants from the U.S. Army Medical Research & Materiel Command (W81XWH-09-1-0496 and W81XWH-08-2-0014). • Opinions, interpretations, conclusions and recommendations are those of the presenter and a
Slide 3: Trofinetide (NNZ-2566)
Trofinetide (NNZ-2566) For personal use only
Slide 4: Primary and Secondary Objectives
4 Primary and Secondary Objectives For personal use only Primary: Evaluate safety and tolerability • AEs through 1 month (4-6 wks) or discharge • SAEs through 3 months (12-14 wks) • C-SSRS: Suicidality assessed at discharge or at 1 and 3 months using the Columbia Suicide Severity Rating Scale Se
Slide 5: Exploratory Objectives
5 Exploratory Objectives For personal use only – Biologic Activity/Efficacy • Improvement in cognitive and neuropsychological functioning at 1 month (4-6 wks) and 3 months (12-14 wks): TMT Grooved CPT-II Trail Making Test Peg Board Conner’s Continuous Performance Test II POMS RPSQ RBANS Profile of R
Slide 6: Exploratory Objectives (continued)
6 Exploratory Objectives (continued) For personal use only – Pharmacokinetics (PK): • Blood concentration of NNZ-2566 in patients with TBI when administered as a 10 minute bolus followed by a 72 hour maintenance infusion at 1, 3 or 6 mg/kg/h – Explore the relationship between PK and: • Biomarker tra
Slide 7: Study Design & Dose Escalation
7 Study Design & Dose Escalation For personal use only Loading Maintenance Total Active: Cohort N Dose Dose Dose Placebo 20 mg/kg 1 mg/kg/hr 1 30 92 mg/kg 2:1 (10–minute infusion) for 72 hr --- DSMC Review --- 20 mg/kg 3 mg/kg/hr 2 30 236 mg/kg 2:1 (10–minute infusion) for 72 hr --- DSMC Review ---
Slide 8: Composite Baseline Severity Score (CBSS)
8 Composite Baseline Severity Score (CBSS) For personal use only TBI clinical outcomes are associated with severity of patient condition at baseline as measured by various parameters predictive of outcomes. Baseline measures are not available for GOS-E and MPAI-4. CBSS was calculated as a comp
Slide 9: Analysis Populations by Cohort & Treatment
9 Analysis Populations by Cohort & Treatment For personal use only Cohort 1 Cohort 2 Cohort 3 All Analysis Not Population Placebo Active Placebo Active Placebo Active Treated Total 10 20 11 17 63 130 10 261 ITT (100%) (100%) (100%) (100%) (100%) (100%) (100%) 10 20 11 17 63 130 251 mITT (100%) (100%
Slide 10: Baseline Patient Characteristics: PA-GOSE
10 Baseline Patient Characteristics: PA-GOSE by Cohort & Treatment For personal use only Cohort 1 Cohort 2 Cohort 3 Placebo Active Placebo Active Placebo Active Total N 9 19 11 17 57 114 227 Sex: M 9 (100%) 19 (100%) 11 (100%) 17 (100%) 52 (91%) 92 (82%) 201 (89%) F 0 (0%) 0 (0%) 0 (0%) 0 (0%) 5 (9%
Slide 11: Baseline CBSS Components (PA-GOSE)
11 Baseline CBSS Components (PA-GOSE) by Cohort & Treatment Cohort 1 Cohort 2 Cohort 3 For personal use only Placebo Active Placebo Active Placebo Active Total N 9 19 11 17 57 114 227 GCS Mean 7.0 7.8 6.4 6.8 7.6 7.0 7.2 Median 7.0 8.0 6.0 7.0 7.0 7.0 7.0 N 9 19 11 17 57 114 227 GFAP Mean 7018.47 65
Slide 12: Baseline CBSS Components (PA-MPAI)
12 Baseline CBSS Components (PA-MPAI) by Cohort & Treatment Cohort 1 Cohort 2 Cohort 3 For personal use only Placebo Active Placebo Active Placebo Active Total N 8 19 10 15 50 97 199 GCS Mean 7.0 7.8 6.5 7.1 7.6 7.2 7.3 Median 7.0 8.0 6.5 7.0 7.0 7.0 7.0 N 8 19 10 15 50 97 199 GFAP Mean 7608.29 6576
Slide 13: Baseline CBSS by Dichotomized 3 month GOS-E
13 For personal use only GOS-E (5-8) GOS-E (1-4) Favorable Unfavorable Baseline CBSS by Dichotomized 3 month GOS-E (PA-GOSE)
Slide 14: Baseline CBSS by Treatment Cohort (PA-GOSE)
14 Baseline CBSS by Treatment Cohort 3 (PA-GOSE) For personal use only Placebo Active
Slide 15: Summary of top-line safety and efficacy results
Summary of top-line safety and efficacy results For personal use only No treatment-related or dose-dependent trends in adverse events or laboratory results No significant difference between active and placebo assessed by the 3 core efficacy measures: GOS-E, MPAI- 4 and survival – Overall and wit
Slide 16: GOS-E, MPAI-4 and RBANS at 3 months
GOS-E, MPAI-4 and RBANS at 3 months Primary Analysis Populations (PA) Cohort 3 Adjusted for CBSS For personal use only GOS-E MPAI-4 RBANS Placebo Active Placebo Active Placebo Active N 32 56 29 51 27 44 CBSS < median LSmean 5.6 5.4 23.0 31.6 81.5 81.0 SE 0.38 0.29 5.33 4.01 2.55 2.00 Median 6.0 6.0
Slide 17: Incidence of Treatment Emergent AEs and SAEs
17 Incidence of Treatment Emergent AEs and SAEs (ITT Population) For personal use only Treatment Emergent AEs Cohort 1 Cohort 2 Cohort 3 Placebo Active Placebo Active Placebo Active Total * Reported at 10 20 10 15 54 102 211 least one (100%) (100%) (91%) (88%) (86%) (78%) (81%) event Treatment Emerg
Slide 18: Incidence of Out of Range ECG Parameters
18 Incidence of Out of Range ECG Parameters (ITT Population) For personal use only Cohort 1 Cohort 2 Cohort 3 QTc>450ms Placebo Active Placebo Active Placebo Active Total * 0 1 0 0 1 0 3 Screening (5%) (2%) (1%) QTc>480ms 1 2 3 Day 1-2 (2%) (2%) (1%) 1 1 2 Day 2-3 (2%) (<1%) (<1%) 1 4 5 Day 3-4 (2%)
Slide 19: Difference in drug distribution in Fragile X Syndrome and TBI Patients
Difference in drug distribution in Fragile X Syndrome and TBI Patients For personal use only Bodyweight (kg) Central Volume (L) Clearance (L/h) Cmax (µg/mL) Fragile X TBI Fragile X TBI Fragile X TBI Fragile X TBI 35 70 1 3 6 35 70 1 3 6 35 70 1 3 6 35 70 1 3 6 mg/kg mg/kg/h mg/kg mg/kg/h mg/kg mg/kg
Slide 20: Effect of body weight on exposure
Effect of body weight on exposure For personal use only
Slide 21: Pharmacokinetic conclusions
21 Pharmacokinetic conclusions For personal use only • NNZ-2566 showed linear pharmacokinetics across the dose range evaluated in TBI patients • No accumulation, metabolic inhibition or induction was observed during the course of treatment • Body weight has a significant effect on clearance and volu
Slide 22: PK/PD Analysis
22 PK/PD Analysis For personal use only • Hypotheses: • Exposure to NNZ-2566 (dose, duration or both) was not sufficient to demonstrate clinical benefit vs. placebo • Noise level at baseline due to highly variable severity impacted treatment effect detection • Methodology: evaluate high dose treatme
Slide 23: PK/PD Analysis Details
23 PK/PD Analysis Details For personal use only • For high dose group, evaluate association between GOS-E, MPAI4, and RBANS and AUC stratified by baseline severity (CBSS) • Descriptive evaluation • Selected quantitative evaluation • For RBANS responders evaluate relationship between RBANS, GOS-E, an
Slide 24: 3 Month GOS-E vs. AUC
24 3 Month GOS-E vs. AUC Cohort 3 - Active (PA-GOSE) For personal use only 8 GOS-E 3 Month 7 6 5 4 3 2 <=median CBSS >median CBSS 1 1000 1500 2000 2500 3000 3500 4000 4500 AUC Note: For subjects alive at 3 months. Excludes GOS-E of 1 (dead).
Slide 25: 3 Month MPAI-4 vs. AUC
25 3 Month MPAI-4 vs. AUC Cohort 3 - Active (PA-MPAI) For personal use only 80 <=median CBSS 70 >median CBSS 60 MPAI-4 3 Month 50 40 30 20 10 0 -10 1000 1500 2000 2500 3000 3500 4000 4500 AUC
Slide 26: 3 Month RBANS vs. AUC
26 3 Month RBANS vs. AUC Cohort 3 – Active PA (RBANS) For personal use only 110 105 100 95 RBANS 3 Month 90 85 80 75 70 65 <=median CBSS >median CBSS 60 1000 1500 2000 2500 3000 3500 4000 4500 AUC
Slide 27: GOS-E: Analysis Adjusted for AUC and CBSS
27 GOS-E: Analysis Adjusted for AUC and CBSS For personal use only • The mean treatment effect versus placebo evaluated for high dose at 1 month • If not adjusted for AUC and CBSS p=0.96 • When adjusted for AUC and CBSS • High dose 4.3 vs. 2.5 on placebo • p= 0.14 • Significance of each covariate in
Slide 28: 3 Month RBANS vs. 3 Month GOS-E
28 3 Month RBANS vs. 3 Month GOS-E Cohort 3 – Active RBANS Responder PA (RBANS) For personal use only 115 110 105 RBANS 3 Month 100 95 90 85 80 75 70 1 2 3 4 5 6 7 8 9 GOS-E 3 Month Values
Slide 29: 3 Month RBANS vs. 3 Month MPAI-4
29 3 Month RBANS vs. 3 Month MPAI-4 Cohort 3 – Active RBANS Responder PA (RBANS) For personal use only 115 110 105 RBANS 3 Month 100 95 90 85 80 75 -30 -10 10 30 50 70 MPAI-4 3 Month Values
Slide 30: PK/PD analysis: Conclusions
30 PK/PD analysis: Conclusions For personal use only • There appears to be an association of GOS-E, MPAI-4 and RBANS with AUC and CBSS • The association with AUC is stronger for patients with greater severity at baseline (higher CBSS) • The association with CBSS is very strong • For RBANS responders
Slide 31: Study conclusions from top-line results (1)
31 Study conclusions from top-line results(1) For personal use only • NNZ-2566 has a favorable safety profile • Baseline severity as measured by CBSS was strongly associated with all primary outcomes • Significant imbalance in baseline severity between active and placebo in all cohorts • No evidence
Slide 32: Study conclusions from top-line results (2)
32 Study conclusions from top-line results(2) For personal use only • Overall mortality rate was lower than reported in comparable TBI clinical trials, but difference between drug and placebo was not significant • Evidence of improvement for drug versus placebo in RBANS for patients with CBSS above
Slide 33: Next Steps
33 Next Steps For personal use only • Responder analysis • Biomarker trajectory analysis as a component of PK/PD • Explore adjustment of the analysis for covariates not included in CBSS (e.g., location of lesion, focal vs diffuse injury, comorbidities) • Evaluate utility of secondary endpoints for f
Slide 34: INTREPID Investigators
INTREPID Investigators Principle Investigator Site Frank Lucente Charleston Area Medical Center James Ecklund Inova Fairfax For personal use only Paul Vespa UCLA - Westwood Ross Bullock University of Miami - Miller School of Medicine Javed Siddiqi Arrowhead Regional Medical Center David Okonkwo Univ
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