N E W T O N Nimodipine microparticles to Enhance recovery While reducing TOxicity after subarachnoid hemorrhage Phase 1/2a Multicenter, Controlled, Randomized, Open Label, Dose Escalation, Safety, Tolerability, and Pharmacokinetic Study Comparing EG-1962 and Nimodipine in Patients with Aneurysmal Subarachnoid Hemorrhage Hänggi D, Etminan N, Macdonald RL, Steiger HJ, Mayer SA, Aldrich F, Diringer MN, Hoh BJ, Mocco J, Strange P, Faleck HJ, Miller M for the NEWTON Investigators Department of Neurosurgery, University Medical Center Mannheim, Ruprecht-Karls-University Heidelberg, Germany Director: Univ. Prof. Dr. Daniel Hänggi
Disclosure PI worldwide Scientific advisor / consultant: Edge Therapeutics 2
Aneurysmal SAH Overview Aneurysmal subarachnoid hemorrhage Day 0 Day 7 3
EG-1962 Nimodipine PLGA 70 µm microparticles Biodegradable polymer Single intraventricular injection Sustained-release formulation Nimodipine release for 21 days Targeted delivery 4
EG-1962 5
NEWTON Study Design Phase 1/2 study: Safety, tolerability and pharmacokinetics of EG-1962 with enteral nimodipine Identify maximum tolerated / feasible dose for pivotal phase 3 study Screening period Randomization Treatment period Follow-up period Aneurysmal SAH (3:1 randomization EG-1962 or enteral nimodipine) Clinical outcome at Day 90 (GOSE) Angiographic vasospasm, DCI, delayed cerebral infarction Use of rescue therapy ICU, hospital length of stay Standard of care Enteral nimodipine Clipping or coiling EG-1962 Enteral nimodipine CT-scan Secondary Objective: Plasma C SF concentrations GOSE mrs MoCA Barthel NIHSS TICS Day 0 Day 1 21 Day 30 Day 90 Trial registration: www.clinicaltrials.gov: NCT01893190 Hänggi D et al. Neurocrit Care, 2015 6
NEWTON Demographics EG-1962 Cohorts 1 to 6 Demographic Variable Age Mean Sex, n (%) Male Enteral nimodipine 100 mg 200 mg 400 mg 600 mg 800 mg 1200 mg Total (N=18) (N=9) (N=9) (N=9) (N=9) (N=9) (N=9) (N=54) 56 (+/-2) 5 (28%) 64 (+/-3) 1 (11%) 54 (+/-3) 3 (33%) 49 (+/-5) 5 (56%) 56 (+/-4) 6 (67%) 52 (+/-4) 7 (78%) 54 (+/-3) 2 (22%) 55 (+/-8) 24 (44%) Female 13 (72%) 8 (89%) 6 (67%) 4 (44%) 3 (33%) 2 (22%) 7 (78%) 30 (56%) N = number of subjects randomized to treatment group and received treatment. 7
NEWTON Safety Group EG-1962 EG-1962 (n=54) Dose Deaths (unrelated) SAEs (related) Drug-related Hypotension 100 mg 0 0 0 0 200 mg 2 0 0 0 400 mg 0 1 (Allergic Reaction) 600 mg 0 0 0 0 800 mg 1 0 0 1200 mg 0 0 0 0 All 3 (6%) 1 (2%) 0 (0%) 0 DLTs 1 (ICP) 1 (ICP) Enteral nimodipine (n=18) 60 mg x 4 hours x 21 days 1 (6%) 0 (0%) 3 (17%) 8
Concentration of nimodipine (ng/ml) NEWTON Plasma nimodipine Concentration 30 25 20 EG-1962 (100 mg) EG-1962 (200 mg) EG-1962 (400 mg) EG-1962 (600 mg) EG-1962 (800 mg) Oral Enteral Nimodipine nimodipine 15 10 5 0 0 2 4 6 8 10 12 14 Days Note: Values are mean +/-. 9
NEWTON Clinical Outcome Glasgow Outcome Scale (GOSE) 90 Day Outcome Unfavorable Outcome Favorable Outcome 1 2 3 4 5 6 7 8 Dead Vegetative State Lower Severe Disability Upper Severe Disability Lower Moderate Disability Upper Moderate Disability Lower Good Recovery Upper Good Recovery EG-1962 Active Control Cohort 1 (100 mg; N = 9) Cohort 2 (200 mg; N = 9) Cohort 3 (400 mg; N = 9) Cohort 4 (600 mg; N = 9) Cohort 5 (800 mg; N = 9) enteral nimodipine (N = 18) 56% Favorable Outcome (n = 5) 67% Favorable Outcome (n = 6) 78% Favorable Outcome (n = 7) 44% Favorable Outcome (n = 4) 56% Favorable Outcome (n = 5) Favorable Outcome (n = 5) 28% 0% EG-1962 related hypotension 17% (n = 3) related hypotension 10
NEWTON Clinical Outcome Glasgow Outcome Scale (GOSE) 90 Day Outcome Unfavorable Outcome Favorable Outcome 1 2 3 4 5 6 7 8 Dead Vegetative State Lower Severe Disability Upper Severe Disability Lower Moderate Disability Upper Moderate Disability Lower Good Recovery Upper Good Recovery EG-1962 Cohorts 1-5 (N = 45) Active Control enteral nimodipine (N = 18) 60% Favorable Outcome (n = 27) 0% EG-1962 related hypotension Favorable Outcome (n = 5) 28% 17% (n = 3) related hypotension 11
NEWTON Exploratory Outcomes EG-1962 Cohorts 1-5 (N = 45) Cohort 1 (100 mg; N = 9) Cohort 2 (200 mg; N = 9) Cohort 3 (400 mg; N = 9) Cohort 4 (600 mg; N = 9) Cohort 5 (800 mg; N = 9) Enteral nimodipine (N = 18) Vasospasm / DCI (N = ) (5) (2) (4) (2) (2) (11) Delayed Cerebral Infarction (N = ) (1) (0) (0) (0) (2) (2) Rescue Therapy (N = ) (4) (1) (3) (1) (2) (10) 56% 61% 56% 44% 44% 33% 22% 22% 22% 22% 22% 11% 0% 0% 0% 11% 11% 11% (N = 15; 33% ) (N = 3; 7% ) (N = 11; 24% ) 12
D AY S D AY S NEWTON Health Economics Reduced ICU Length of Stay (LoS) by 3.5 days Median ICU LoS Reduced Hospital LoS by 2.5 days Median Hospital LoS 10 Enteral nimodipine EG-1962 20 Enteral nimodipine EG-1962 12 14 13.5 (n=45) 22 24 25.0 22.5 (n=45) 16 17.0 26 (n=18) 18 (n=18) 28 13
NEWTON Study All endpoints met Improved clinical outcome MTD/MFD defined Less rescue therapy No safety concerns Reduced ICU and hospital length of stay 14
NEWTON Study Pivotal phase 3 study planned (US, Canada, Europe, Australasia) 15
N E W T O N Nimodipine microparticles to Enhance recovery While reducing TOxicity after subarachnoid hemorrhage Phase 1/2a Multicenter, Controlled, Randomized, Open Label, Dose Escalation, Safety, Tolerability, and Pharmacokinetic Study Comparing EG-1962 and Nimodipine in Patients with Aneurysmal Subarachnoid Hemorrhage http://www.umm.uni-heidelberg.de/inst/nch/ daniel.haenggi@medma.uni-heidelberg.de Department of Neurosurgery, University Medical Center Mannheim, Ruprecht-Karls-University Heidelberg, Germany Director: Univ. Prof. Dr. Daniel Hänggi