CervoMed Inc. · NASDAQ:CRVO
CervoMed — CTAD 2019
19 slides from CervoMed's conference presentation, December 2019
Slide 1: Efficacy and safety results of REVERSE-SD phase-2b study of neflamapimod in early AD
Efficacy and safety results of REVERSE-SD, phase-2b clinical study of the selective p38α kinase inhibitor neflamapimod in early-stage Alzheimer’s disease (AD) Philip Scheltens1, John Alam2, John Harrison1,3, Kelly Blackburn2, Niels Prins1,4 for the REVERSE-SD investigators and study team. (1) Depart
Slide 2: Disclosures
Disclosures • Philip Scheltens is a consultant to EIP Pharma, Vivoryon, Biogen, Toyama, Green Valley, Novartis, • Niels Prins consultant to EIP Pharma, Boehringer Ingelheim, Vivoryon, and Fuji Film Toyama Chemical. He serves on the DSMB of Abbvie’s M15-566 trial. He is CEO and co-owner of the Brain
Slide 3: Background
Background • Neflamapimod is a potent, oral selective small molecule inhibitor of the alpha isoform of the intracellular signal transduction enzyme p38 MAP kinase (p38⍺) • p38⍺ implicated in oligomeric Aβ and IL-1β impairment of synaptic plasticity • Also implicated in βCTF mediated induction of Rab
Slide 4: Neflamapimod: Prior Experience
Neflamapimod: Prior Experience • Preclinical • Reversed spatial learning deficits, as assessed in Morris-Water-Maze test, in aged rats(1) • Prevents oligomeric Aβ-induced dendritic spine loss in mouse hippocampal neurons (2) • Rescues neurodegenerative phenotype in Ts2 Down Syndrome transgenic mice
Slide 5: Overview of Phase 2b Trial in Early AD
Overview of Phase 2b Trial in Early AD Endpoints Patients • 1º: episodic memory (Hopkins Verbal Learning • MCI or mild AD 24 WEEK TREATMENT Test) • Documented memory 40 mg or placebo twice daily • 2º: Wechsler Memory deficit Scale (WMS), Clinical • MMSE 20 to 28 Dementia Rating Scale, MMSE, CSF biom
Slide 6: Patient Disposition
Patient Disposition 477 Screened 316 Screen Failures. Most common reasons: § 119 for not meeting CSF criteria § 79 for not meeting MMSE criteria § 40 withdrawal by subject Placebo NFMD (N=83) 161 (N=78) Enrolled from March 2018 to January 2019 Randomized 5 Early Discontinuations 5 Early Discontinuat
Slide 7: Enrollment By Country
Enrollment By Country Number of Number of Subjects Number of Subjects (%) on Background Country Sites Enrolled AD Therapy USA 16 73 44 (60%) UK 11 52 30 (58%) Netherlands 3 20 10 (50%) Czech Republic 5 9 9 (100%) Denmark 3 7 4 (57%) Note: “Background Therapy” consists of cholinesterase inhibitor (85
Slide 8: Reverse-SD Study Baseline Characteristics
Reverse-SD Study Baseline Characteristics Placebo (N=83) Neflamapimod (N=78) Age 72.6 (0.8) 70.8 (0.7) Female 52% 47% CDR 0.5/1.0 75%/25% 81%/19% CDR Sum of Boxes 3.2 (0.18) 3.1 (0.15) MMSE 23.6 (0.3) 23.7 (0.3) HVLT Total Recall 15.3 (0.6) 16.4 (0.7) % on Background AD Therapy 61% 59% ApoE4+ (heter
Slide 9: Safety
Safety • Neflamapimod well tolerated with only 2 discontinuations (vs. 2 in placebo) for adverse events, one for nausea and one for diagnosis of myeloma • Two SAEs in neflamapimod patients (vs. three in placebo), hypokalemia and myeloma; both considered unrelated. • Most common adverse events were u
Slide 10: REVERSE-SD safety profile compares favorably with prior experience at higher dose
REVERSE-SD safety profile compares favorably with prior experience at higher dose Incidence of Adverse Event By Study Adverse Events Rheumatoid Arthritis Study REVERSE-SD (250 mg BID Twice Daily for (40 mg BID Twice 12 weeks) Daily for 24 weeks) Diarrhea, Abdominal 20% <5% Pain ALT/AST elevation to
Slide 11: Immediate and Delayed Recall Composites
Primary Objective: Improve Episodic Memory Function Primary Endpoint: Secondary Endpoint: Hopkins Verbal Learning Test Wechsler Memory Scale Least Square Mean (s.e.m.) Change in Combined 0.1 20 Immediate and Delayed Recall Composites Combined Z-score of Total and Delayed Recall 0.05 Least Square Mea
Slide 12: Mean Change from Baseline in Secondary Clinical Endpoints
Mean Change from Baseline in 2o Clinical Endpoints: Full Efficacy Population CDR Sum of Boxes MMSE 2 1.5 1.8 Worse 1.6 1 1.4 1.2 0.5 1 0 Worse 0.8 0.6 -0.5 0.4 0.2 -1 0 Week 12 Week 24 -1.5 Week 12 Week 24 Placebo (N=82) NFMD (N=78) Placebo (N=82) NFMD (N=78) Mixed Effects Repeated Measures Model di
Slide 13: CSF Biomarkers: Full Efficacy Population
CSF Biomarkers: Full Efficacy Population LS mean (s.e.m.) absolute change (pg/mL) from baseline to week 24 Placebo Neflamapimod Difference in Change P-value (N=68) (N=62) (95% CI) Total tau 11.1 (6.91) -7.7 (7.4) -18.9 (-36.0, -1.8) 0.03 p-tau181 1.0 (0.6) -1.1 (0.7) -2.0 (-3.6, -0.5) 0.012 Neurogra
Slide 14: Pharmacokinetic-Pharmacodynamic (PK-PD) Analyses
Pharmacokinetic-Pharmacodynamic (PK-PD) Analyses • As only one dose level was utilized, PK-PD analyses included in Statistical Analysis Plan to evaluate the results for potential dose-dependency. • Blood obtained immediately prior to first dose on Day 21 for determination of trough plasma drug conce
Slide 15: Relationship Between Plasma Drug Concentration and Primary Endpoint
Relationship Between Plasma Drug Concentration (CTROUGH) and Primary Endpoint Individual Patient Change From Baseline to Week 24 Placebo NFMD NFMD (N=82) < 75th Percentile > 75th Percentile Combined Z-score of Total and Delayed Recall 0.35 (N=52) (N=18) Least Square Mean (s.e.m.) Change in 0.25 0.15
Slide 16: Change in Wechsler Memory Scale Composite by Plasma Drug CTROUGH
Change in Wechsler Memory Scale Combined Immediate and Delayed Recall Composite by Plasma Drug CTROUGH All Patients Patients on Background Therapy Placebo NFMD NFMD Placebo NFMD NFMD (N=78) < 75th %ile > 75th %ile (N=51) <75th %ile > 75th %ile 25 (N=52) (N=18) 25 (N=29) (N=13) 20 20 15 15 Improvemen
Slide 17: Summary
Summary • No improvement in episodic memory in full efficacy patient population. • Statistically significant effect of neflamapimod treatment relative to placebo on CSF ptau and total tau, and trend on CSF neurogranin, levels in full efficacy population. • PK-PD analysis shows arent improvement in t
Slide 18: Conclusions
Conclusions • The CSF biomarker effects of neflamapimod demonstrate (1) target engagement and (2) p38⍺ inhibition impacts the AD disease process (i.e. provides proof-of-mechanism). • The CSF biomarker effects, combined with the episodic memory effects in patients with the highest blood concentration
Slide 19: Acknowledgements
Acknowledgements • All participating patients and caregivers • Study staff of Worldwide Clinical Trials Inc., Anoixis Corporation and EIP Pharma Inc. • All participating sites: USA UK Netherlands Arnold, Massachusetts General Hospital Asher, MAC Clinical Research Manchester Prins, Brain Research Cen