Neurotrope — Technical Presentation (January 2018)
20 slides from Neurotrope's technical presentation, Jan 8, 2018
Slide 1: Phase 2 Trial Evidence that Bryostatin Improves Cognitive Function in Advanced Alzheimer's Patients
Neurotrope Phase 2 Trial Evidence that Bryostatin Improves Cognitive Function in Advanced Alzheimer’s Patients January 7, 2018 1
Slide 2: Bryostatin Phase 2 Trial Design
Bryostatin Phase 2 Trial Design 2 • Double - blind, randomized, controlled , exploratory trial • Moderate to severe patients (MMSE 4 - 15) • Stable background therapy with cholinesterase inhibitors and/or memantine • Three arms (1:1:1) 20µg, 40µg and control • 7 doses over 12 weeks: 0, 1, 3, 5, 7, 9
Slide 3: Scientific Review Summary
Scientific Review Summary 3 Top Line Results of 150 Patients Exploratory Phase 2 Trial: • Safe, sustained improvement in SIB (Severe Impairment Battery) in 20µg dosing arm (but not the 40µg*) compared to control group through week 13 • The primary efficacy endpoints with SIB were pre - specified to
Slide 4: Pre-Clinical Studies: PKC ε Signaling Pathways Integral to Memory and Learning
Pre - Clinical Studies: PKC ε Signaling Pathways Integral to Memory and Learning * Increased red, green (yellow) overlapping of presynaptic & postsynaptic staining indicates increased synaptic formation Sen A et al. J Biol Chem. 2012;287(19):15947 - 15958. Sen A et al. J Biol Chem . 2016;291(32):164
Slide 5: Bryostatin SIB Improvement by Visit (Completers): Increasing Bryostatin Benefit
5 Last dose @week 11 D = 6.36 D = 4.09 Control Bryo 20µg Bryo 40µg SIB Change from baseline Last dose @week 11 D = 2.6 SIB: Thru Week 13 SIB: Thru Week 15 SIB: Thru Week 15, OFF - memantine Bryostatin SIB Improvement by Visit (Completers) Increasing Bryostatin Benefit N=38 N=33 N=42 38 32 42 37 33 4
Slide 6: Topline Phase 2: SIB Change From Baseline mITT & Completer (CAS) Analyses at Week 13
Topline Phase 2: SIB Change From Baseline mITT & Completer (CAS) Analyses at Week 13 6 -2.5 -2 -1.5 -1 -0.5 0 0.5 1 1.5 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Completers -2.5 -2 -1.5 -1 -0.5 0 0.5 1 1.5 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 mITT Control 20µg 40µg Change from baseline in SIB Change from basel
Slide 7: 30 Day Post-Dosing Data – Exploratory Endpoint: Evidence for Persistent, Enhanced Benefit
30 Day Post - Dosing Data – Exploratory End Pt. Evidence for Persistent, Enhanced Benefit 7
Slide 8: SIB by Visit: 30 Day Post Dosing in mITT Group
-2.5 -2 -1.5 -1 -0.5 0 0.5 1 1.5 2 0 2 4 6 8 10 12 14 16 44 46 38 43 38 42 34 33 SIB by Visit: 30 Day Post D osing in mITT Group 8 • Consistent SIB effect across time points, increased D at week 15 * for all subjects who were not re - randomized Last dose @ week 11 • Cognitive improvement sustained
Slide 9: SIB by Visit: 30 Days Post Dosing in Completers (CAS)
• Consistent SIB Effect across time points, increasing D at week 15 * SIB by Visit: 30 Days P ost D osing in Completers ( CAS) -2.5 -2 -1.5 -1 -0.5 0 0.5 1 1.5 2 0 2 4 6 8 10 12 14 16 Control Bryo 20ug Control 13-15 Bryo 20ug 13-15 * for all subjects who were not re - randomized Week 15 data show in
Slide 10: Post-Hoc Analyses: Evidence of Memantine's Negative Impact on Bryostatin's Therapeutic Benefits
Post - Hoc Analyses: Evidence of Memantine’s Negative Impact on Bryostatin’s Therapeutic Benefits 10
Slide 11: PKC, Activated by Bryostatin, Regulates NMDA Receptor Function in Multiple Pathways
Protein kinase C (PKC), which is activated by mGluR5 receptor stimulation, phosphorylates NMDA receptors to increase the cationic conductance of this receptor. PKC can also phosphorylate mGluR5 receptors to modulate their function. PKC, Activated by Bryostatin, Regulates NMDA Receptor Function in Mu
Slide 12: SIB By Visit: OFF-Memantine Patients in mITT Group at Weeks 13 and 15
SIB By Visit: OFF - Memantine patients in mITT Group at weeks 13 and 15 D = 5.93 p < . 0576 weeks D = 20 μ g treatment effect minus control SIB Change from baseline N=17 N=14 17 14 15 13 16 13 14 11 12 Last dose @ week 11 Control
Slide 13: SIB By Visit: Comparison of OFF vs. ON-Memantine in mITT Group
-2 -1.5 -1 -0.5 0 0.5 0 4 8 12 16 Control Bryo 20ug -3 -2 -1 0 1 2 3 4 5 6 0 2 4 6 8 10 12 14 16 Control Bryo 20ug SIB By Visit: Comparison of OFF vs. ON - Memantine in mITT Group at Weeks 13 and 15 SIB - OFF - Memantine D = 5.93 SIB Change from baseline weeks weeks SIB Change from baseline N=17 N=1
Slide 14: SIB By Visit: OFF-Memantine Completers (CAS) at Weeks 13 and 15
-3 -2 -1 0 1 2 3 4 5 6 7 0 2 4 6 8 10 12 14 16 Control Bryo 20ug SIB By Visit: OFF - Memantine Completers (CAS) at Weeks 13 and 15 D = 6.36 p < 0.0488 Last dose @week 11 14 SIB Change from baseline D = 20 μ g treatment effect minus control weeks SIB - OFF - Memantine N=16 N=13 16 13 15 13 16 13 14 1
Slide 15: SIB By Visit: Comparison of OFF vs. ON-Memantine in Completers
-3 -2 -1 0 1 0 2 4 6 8 10 12 14 16 Control Bryo 20ug -3 -2 -1 0 1 2 3 4 5 6 7 0 2 4 6 8 10 12 14 16 Control Bryo 20ug SIB By Visit: Comparison of OFF vs. ON - Memantine in Completers at Weeks 13 and 15 *Results from Week 15 are from a model that included all visits, all other results are consistent
Slide 16: Memantine Blocks Bryostatin SIB Improvement
Memantine Blocks Bryostatin SIB Improvement SIB 20 μg bryostatin vs. control mITT Completer (CAS) Off m emantine On m emantine Off m emantine On m emantine Week 5 D 4.48 1.96 5.38 2.94 p - value* 0.0857 0.1973 0.0487 0.1016 Week 9 D 2.08 0.09 2.66 0.90 p - value* 0.2597 0.4847 0.2071 0.3522 Week 13
Slide 17: Top Line: SIB Improvement at Weeks 5, 9 & 13 Was Significantly Correlated for the 20µg Dose
Top Line: SIB Improvement at Weeks 5, 9 & 13 Was Significantly C orrelated for the 20 m g Dose Change from baseline in SIB Change from baseline in SIB • S ignificant correlations (p <.001) between SIB values for 20µg (vs. control) at successive weeks – 5, 9,13 • Shows that the same patients who impr
Slide 18: Bryostatin Dose Further Validated as Effective by Body Surface Area (BSA) Analysis
Bryostatin - 20 μ g Dose Further Validated as Effective by Body Surface Area (BSA) Analysis F - ratio for 20µg vs. 40µg variance of 3.97 and a corresponding 2 - sided p - value of <0.0001, supported a conclusion of unequal variances between the two dosage groups. Narrow Dose Response Distribution ar
Slide 19: Concluding Observations
Concluding Observations: Change from baseline in SIB Change from baseline in SIB 1. 20µg bryostatin showed evidence of safely produced, sustained cognitive improvements (SIB scores) in advanced AD patients 2. These improvements, not just reduction in the rate of decline, persisted at week 15 (30 day
Slide 20: Next Steps in Clinical Development Program
Next Steps in Clinical Development Program A confirmatory t rial in advanced AD, non - memantine p atients 1. Leverage Phase II data by incorporating memantine - free patients into the study 2. Confirm marked improvement in SIB scores among memantine - free patients 3. Draw conclusions on possible l