Medicinova, Inc. · NASDAQ:MNOV
Medicinova — International Symposium on ALS/MND 2017
44 slides from Medicinova's conference presentation, 2017
Slide 1: Ibudilast Bi-modal Therapy with Riluzole in Early and Advanced ALS Patients
NCT02238626 Ibudilast Bi-modal Therapy with Riluzole in Early and Advanced ALS Patients Adaptive Design Single Center Phosphodiesterase Type 4 (PDE4) Inhibitor – Ibudilast (MN-166) Phase 1b / 2a Clinical Trial [ NCT02238626 ] for Amyotrophic Lateral Sclerosis (ALS) Patients [1] Not Requiring Non- In
Slide 2: Disclosures
NCT02238626 Disclosures Benjamin Rix Brooks MD received grant support from Medcinova, Cytokinetics, Allexion, ITF Pharma, Avanir, Biogen, RTI Research, Center for Disease Control. Elena K Bravver MD received grant support from Medicinova, Allexion, Donna C Graves MD received grant support from Medic
Slide 3: NCT02238626
NCT02238626 Ibudilast - Glial Pathology MS, ALS, Glioblastoma Treatment Development Ibudilast Pharmacology - Target Engagement Adaptive Protocol - Early Cohort (EC) - Advanced Non-Invasive Ventilation Cohort (ANC) - Vital Status post Ibudilast Washout Un-Blinded Tolerability and Safety Analysis - 0-
Slide 4: Glial activation and ibudilast mechanism in MS and ALS
“t Inhibit microglia Glial (inhibit glial activation: 3- activation isobutyryl-2- isopropylpyrazolo-[1,5- a]pyridine] (Ibudilast) Microglia Pro-inflammatory, cytokines Inhibit toll-like receptors -N YN X NN —~ trocyte 0 PAR-2 antagonist: N1-3- methylbutyryl-N4-6- aminohexanoyl- piperazine (ENMD-1068
Slide 5: SPRINT-MS Phase II Trial of Ibudilast in Progressive MS: Top-Line Results
SPRINT-MS/NN 102 Phase II Trial of Ibudilast in Progressive MS: Top-Line Results » Neuro genes MG RJ. Fox, C.S. Coffey, M.E. Cudkowicz, T. Gleason, A. Goodman, E.C. Klawiter, K. Matsuda, M. McGovern, R. Conwit, R. Naismith, A. Ashokkumar, D. Eckund, E. Klinger, M. Koepp, S. Natarajan, B. Thornell, J
Slide 6: Challenges of molecular targeted therapies for glioblastoma
The Carolinas Neuromuscular g —— MEDICINOVA Zs @ MDA Carolinas Medical Center ‘J Neroamcal (2016) 127:427.434 DOT 10.1007411060-016-2030-6 wrt The challenges associated with molecular targeted therapies for glioblastoma Toni Rose Jue’ » Kerrie L. McDonald’ Received: 30 September 2015 / Accepted: 15
Slide 7: Ibudilast Pharmacology Target Engagement
NCT02238626 Ibudilast Pharmacology Target Engagement
Slide 8: Background: Riluzole Pharmacology
NCT02238626 Background Riluzole Pharmacology Riluzole currently slows the rate of loss of ALSFRS-R by 25-28% when administered at 50mg-twice-daily to achieve levels of 30- 1552 ng/mL corresponding to 0.15-6.6 μM ( Groeneveld, 2003 ). Tissue levels are 10-fold higher ( Milane, 2009 ) providing in viv
Slide 9: Background: Enhance Riluzole Pharmacology
NCT02238626 Background Enhance Riluzole Pharmacology Both riluzole and some PDE inhibitors reduce infarct size following transient cerebral artery occlusion ( O’Neill, 1997 ). Ibudilast, achieves this reduced infarct size at serum levels achievable in humans ( Lee, 2011 ). Decreased Cytokine Product
Slide 10: Ibudilast Pharmacology - Target Engagement
NCT02238626 Ibudilast Pharmacology - Target Engagement Ibudilast Biochemistry IC50 Chronic daily oral administration of Ibudilast at 30mg twice-daily in humans can achieve peak [ PDE4A - 0.05 μM 0.25 μM ] and trough [ 0.15 μM ] serum levels ( PDE4B - 0.06 μM Yoon, 2009 ). Brain and spinal cord level
Slide 11: Protocol Outcome Measures: Adaptive Protocol
NCT02238626 Protocol Outcome Measures Adaptive Protocol Adaptive Protocol - Survival Follow-up 2 Week Safety Adaptive Protocol DB OLE Post OLE - Riluzole inclusion criteria - Advanced ALS on NIV
Slide 12: Protocol Milestones
NCT02238626 Protocol Milestones AAN 2015 MND 2015 AAN 2016 MND 2016 MND 2017
Slide 13: Inclusion/Exclusion Criteria
NCT02238626 Inclusion/Exclusion Criteria Inclusion: • Age 18-80 years • Diagnosis of familial or sporadic ALS • ALS with onset of 5 yrs for EC • SVC 60% • Currently on stable dose of Riluzole Exclusion: • Use of Tracheostomy, invasive mechanical ventilation, Non-invasive ventilation NIV • > 3% p
Slide 14: EC Baseline characteristics
NCT02238626 EC Baseline characteristics Placebo Ibudilast (N=17) (N=34) Age 57.5 59.2 Female 5 (29.4%) 11 (32.4%) Ethnicity •Caucasian 15 (88.2%) 31 (91.2%) •African American 2 (11.8%) 1 (2.9%) •Asian 0% 1 (2.9%) •Unknown 0% 1 (2.9%) Baseline ALSFRS-R 39.0 39.3 Baseline SVC 97.2 92.0 Baseline MIP/NI
Slide 15: CONSORT Diagram
NCT02238626 CONSORT Diagram DB - OLE -12 months
Slide 16: Early Cohort CONSORT
Early Cohort Screened = 55 Screen Failure = 4 NCT02238626 Randomized = 51 Placebo MN-166 N=17 N=34 Early Terminate 2 Early terminate 5 Month 6 completer Month 6 completer on study drug on study drug N= 15 N= 29 Early Terminate 3 Early Terminate 6 Month 12 completer Month 12 completer on study drug o
Slide 17: Study epochs and endpoints
DB OL WO PWO 1 3 6 7 E9 12 14 18-37 Months Post OLE DB OLE WO Post OLE Feasibility Feasibility Progression Progression Tolerability Tolerability NIV GT Survival NIV GT Survival Safety Safety MMT Modifiers AEs SAEs AEs SAEs ALS-FRS-R Age Sex Progression Progression SVC Site Onset NIV GT Survival NIV
Slide 18: EC Clinical Trial Endpoints
NCT02238626 EC Clinical Trial Endpoints Primary: • Tolerability – early discontinuation from study or drug • Safety – AEs, SAEs Secondary Clinical Endpoint Responsiveness • MMT( Manual Muscle Test ) DB | OLE epochs • ALSAQ-5 DB | OLE epochs • ALSFRS-R DB | OLE epochs • Survival DB | OLE epochs | Pos
Slide 19: EC Data Analysis Population
NCT02238626 EC Data Analysis Population ITT ( Intention-To-Treat) population = all randomized patients Total = 51 ( Placebo = 17; MN-166 = 34 ) PP (Per-Protocol) population = completed study Double-blind phase Total = 44 ( Placebo = 15; MN-166 = 29 ) Open Label Extension Total = 35 ( Placebo = 12; M
Slide 20: Primary Endpoints Tolerability / Safety
NCT02238626 Primary Endpoints Tolerability / Safety DB - OLE -12 months
Slide 21: Primary Endpoints: Tolerability
NCT02238626 Primary Endpoints : Tolerability EC Safety Analysis ITT Population # of subjects early study or drug termination Double-Blind Epoch (0 - 6 month) # of Subjects Placebo Ibudilast ( N = 17 ) ( N = 34 ) Early Study Termination 2 2 •Due to AEs 1 1 •Any Reason 1 1 Early Drug Termination 0 3 •
Slide 22: Primary Endpoints: Safety
NCT02238626 Primary Endpoints : Safety EC Safety Analysis ITT Population Treatment Related AEs ( TRAEs ) # of subjects, # of events Double-Blind Epoch (0 – 6 month) # of Subjects or # of Events Placebo Ibudilast N=17 N=34 # of Subject with at Least one TRAEs n= 3 n= 4 Total events # of TRAEs 5 8 Sev
Slide 23: Primary Endpoints: Safety
NCT02238626 Primary Endpoints : Safety EC Safety Analysis ITT Population Treatment Related AEs ( TRAEs ) # of events Double-Blind Epoch ( 0 – 6 month) System Organ Code # of Events Placebo (n=3) Ibudilast (n=4) Gastrointestinal system 1 2 Nervous system disorder 3 0 Metabolism and Nutrition 0 4 Inve
Slide 24: Primary Endpoints: Safety
NCT02238626 Primary Endpoints : Safety EC Safety Analysis ITT Population Treatment Emergent AEs (TEAEs) # of subjects Entire Study ( 0-12 months ) # of Subjects Placebo Ibudilast N = 17 N = 34 At Least one TEAEs n = 17 n = 34 Severe or Life threatening TEAEs n= 2 n= 4 Serious Adverse Events n= 1 n=
Slide 25: Primary Endpoints: Safety
Primary Endpoints : Safety EC Safety Analysis ITT Population Serious Adverse Events Double-Blind and Open Label Extension ( 0- 12 months ) Subject Reference # SAEs Treatment related ? 022 DVT No 027 Leg fracture No 028 Dysphagia No Bowel obstruction 029 Ankle fracture No 049 Ureteral stone No 052 Pn
Slide 26: Secondary Endpoints Clinical Endpoint Responsiveness
NCT02238626 Secondary Endpoints Clinical Endpoint Responsiveness DB - OLE -12 months
Slide 27: Secondary Endpoints: Manual Muscle Testing MMT
NCT02238626 Secondary Endpoints Manual Muscle Testing MMT Responder = 0 unit loss or gain per 6 months change Non-Responder = > 1 unit loss per 6 months change DB - OLE -12 months
Slide 28: MMT score EC ITT population
NCT02238626 MMT score EC ITT population % of subjects stable or improved ( same or higher score ) on 6 months treatment Double-Blind Phase Open-Label Phase Ibudilast Ibudilast treatment combined Placebo Ibudilast 6-12 mon treatment ( N = 51 ) ( N = 17 ) ( N = 34 ) ( N = 17 ) 4 / 17 11 / 34 6 / 17 17
Slide 29: Secondary Endpoints: ALSAQ-5
NCT02238626 Secondary Endpoints ALSAQ-5 Responder = 0 unit loss or gain per 6 months change Non-Responder = > 1 unit loss per 6 months change DB - OLE -12 months
Slide 30: ALSAQ-5 score EC ITT population
NCT02238626 ALSAQ-5 score EC ITT population % of subjects stable or improved (same or lower score) on 6 month treatment Double-Blind Phase Open-Label Phase Ibudilast Ibudilast treatment combined 6-12 mon Placebo Ibudilast treatment ( N = 51 ) ( N = 17 ) ( N = 34 ) ( N = 17 ) 4 / 17 17 / 34 5 / 17 22
Slide 31: Secondary Endpoints: ALSFRS-R total
NCT02238626 Secondary Endpoints ALSFRS-R total Responder = < 1 unit loss per 6 months change Non-Responder = > 1 unit loss per 6 months change DB - OLE -12 months
Slide 32: ALSFRS-R Score EC ITT population
ALSFRS-R Score NCT02238626 EC ITT population % of subjects with less than 1 unit change in 6 months stable or improved on 6 or 12 months treatment Double-Blind Phase Open Label Phase Overall Placebo Ibudilast Ibudilast Ibudilast Ibudilast 0-6 mon 6-12 mon 0-12 mon treatment treatment treatment combi
Slide 33: ALSFRS-R Score EC PP population
ALSFRS-R Score NCT02238626 EC PP population % of subjects with less than 1 unit change in 6 months stable or improved on 6 or 12 months treatment Double-Blind Phase Open Label Phase Overall Placebo Ibudilast Ibudilast Ibudilast Ibudilast 0-6 mon 6-12 mon 0-12 mon treatment treatment treatment combin
Slide 34: ALSFRS-R Responder Analysis - Comparison
NCT02238626 ALSFRS-R Responder Analysis - Comparison 0-6 or 6-12 month Non-Decline ITT 6 month Non-Decline PP 3 / 17 = 17.6 % pbo 0-6 mon 3 / 15 = 20.0 % pbo 0-6 mon 10 / 34 = 29.4 % Ibd 0-6 mon 10 / 29 = 34.5 % Ibd 0-6 mon 6 / 17 = 35.3 % pbo-Ibd 6-12 mon 6 / 12 = 50.0 % pbo-Ibd 6-12 mon 3 * / 34 =
Slide 35: Distribution of ALSFRS-R score
Distribution of ALSFRS-R score
Slide 36: ALSFRS-R Total over months post randomization
@ NCT02238626 Mono os ALSFRS:R Total 0 3 6 9 12 Months post Randomization
Slide 37: Adaptive Protocol Per Protocol Analysis Survival
NCT02238626 Adaptive Protocol Per Protocol Analysis Survival OLE and Post OLE
Slide 38: Survival probability: per-protocol completers vs non-completers
(-) Me Cyatins Neuronal ) ALS MDACanter NCT02238626 MEDICINOVA 4s @ BADR 100 Survival probability (%) === Per-Protocol Completers non Per-Protocol Completers 1 iT i iT iT i i 10 15 20 25 30 35 40 Months post Randomization a ° aL Te Number at risk Group: Per-Protocol Completers 35 35 34 30 21 14 5 oO
Slide 39: Survival by ALSFRS-R responder status
a NCT02238626 weno Ase : 100 pm mmm 400 Pte, mu, 90} 3 : = 90 — te, L sor om 4 80 = 7ol- H -s—) _ + = . 1 = 70 2 tc = cot 1 ay 2 a . a] 3 60 s 1 & S sof 4 t-. g ES Es = atestent | = 50 EZ aob 1 ' g E iz 5 B 30 aor Ge 40 --. Per-Protocol Completers 4 20 c77_non Per-Protocol Completers | 30 ALSFRSR Re
Slide 40: Clinical Trial Conclusions
NCT02238626 Clinical Trial MN-166 ( Ibudilast ) bi-modal therapy with riluzole in ALS subjects is - feasible, tolerable, and safe, - is associated with the proportion of subjects with no decline in ALSAQ - riluzole-ibudilast responders - is associated with the proportion of subjects with little or n
Slide 41: Clinical Trial Conclusions: further evaluation
NCT02238626 Clinical Trial MN-166 ( Ibudilast ) bi-modal therapy with riluzole in ALS subjects needs further evaluation to assess the potential effect of ibudilast treatment protocols on function and survival in ALS patients and to explicitly exclude biased selection. The novel statistical analysis
Slide 42: Carolinas Neuromuscular / ALS-MDA Center
Carolinas Neuromuscular / ALS-MDA Center
Slide 43: Supported by
NCT02238626 Supported by CMC - Neurology Carolinas Neuromuscular / ALS-MDA Center Logistical and Statistical Support CMC - Neurology Research Division Clinical Study Drug and Placebo CHS - Office of Clinical and Translational Clinical Trials Grant Research CHS - Dickson Advanced Analytics DA2 Clinic
Slide 44: Benjamin Rix Brooks MD contact details
NCT02238626 Benjamin Rix Brooks MD Carolinas Neuromuscular / ALS-MDA Center CMC - Department of Neurology benjamin.brooks@carolinashealthcare.org + 1 704-446-1900