Slide 1: SPRINT-MS/NN 102 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 R.J. 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. Ecklund, E. Klinger, M. Koepp, S. Natarajan, B. Thornell, J. Yankey, R.A.
Slide 2: Disclosures
Disclosures Dr. Fox has received consulting fees from Biogen Idec, GlaxoSmithKline, Novartis, Questcor, Teva, and Xenoport; research support from Novartis. Dr. Coffey has received consulting fees from ZZ Biotech, LLC. Dr. Cudkow icz has received consulting fees from Astra Zenica, Cytokinetics, Bioha
Slide 3: Acknowledgements
Acknowledgements • Thanks to the staff at the Clinical Coordinating Center (Mass General Hosp.), Data Coordinating Center (U. of Iowa), Protocol Steering Committee, all of the site investigators, NINDS, and NMSS for support throughout the study. • Participant protection: Independent Medical Monitor
Slide 4: Ibudilast (MN-166, AV411)
Ibudilast (MN-166, AV411) N CH3 • Orally-available small molecule N • Macrophage migration inhibitor factor (MIF) inhibitor CH3 • Phosphodiesterase(PDE)-4 and PDE-10 inhibitor O • Toll-like receptor 4 inhibitor H3C • Approved in Japan in 1989 CH3 • Bronchial asthma • Post-stroke dizziness • Reduces
Slide 5: Study Overview
Study Overview 28-site, phase II trial NIH-sponsored NeuroNEXT network 3T MRIs – GE, Siemens • Inclusion: • Age 18-65 years • PPMS or SPMS • Typical MS lesions on brain MRI (Swanton’s Criteria) • EDSS 3.0-6.5 • Disability progression in the preceding 2 years (EDSS, 25FW, 9HPT) • Concurrent tre
Slide 6: Study Endpoints
Study Endpoints • Primary: • Brain atrophy – Brain Parenchymal Fraction (BPF) • Safety – AEs, SAEs • Tolerability – early discontinuation • Secondary • Magnetization Transfer Ratio – normal-appearing tissue • Diffusion Tensor Imaging – descending pyramidal tracts • Optical Coherence Tomography - ret
Slide 7: Study Endpoints
Study Endpoints • Primary: • Brain atrophy – Brain Parenchymal Fraction (BPF) • Safety – AEs, SAEs • Tolerability – early discontinuation • Secondary • Magnetization Transfer Ratio – normal-appearing tissue • Diffusion Tensor Imaging – descending pyramidal tracts • Optical Coherence Tomography - ret
Slide 8: Design and Analysis
Design and Analysis • 1:1 Randomization • Ibudilast (60, 80, or 100mg/d, as tolerated) • Matching placebo • Stratified by disease (PPMS/SPMS) and DMT (untreated or on IFN/GA) • Modified Intent-to-Treat • Randomized, received ≥1 dose study medication, ≥1 MRI efficacy assessment • Sensitivity analysis
Slide 9: Baseline characteristics
Baseline characteristics Placebo Ibudilast P-value (n = 126) (n = 129) Age (yrs) 57 (6.5) 55 (7.8) 0.02 Females 69 (55%) 67 (52%) 0.71 Caucasian 114 (91%) 122 (95%) 0.79 Disease type (% SPMS) 60 (48%) 61 (47%) 0.96 Disease duration (yrs) 11.7 (9.0) 12.2 (9.3) 0.65 EDSS 5.38 (1.09) 5.43 (1.09) 0.74 O
Slide 10: Participant Disposition
Participant Disposition Randomized: placebo Randomized: ibudilast N = 126 N = 129 3 Early Terminations 8 Early Terminations before mITT before mITT Participants Reaching Week 24 or Participants Reaching Week 24 or on-study MRI (early termination) on-study MRI (early termination) N = 123 N = 121 (N =
Slide 11: Primary Objective 1: BPF
Primary Objective 1: BPF Estimated Rate of Annual BPF Change Treatment Estimate Group (90% CI) P-Value -0.00105 Ibudilast 0.040 (-0.00160, -0.00049) -0.00202 Placebo (-0.00256, -0.00147) Primary results show significant difference in slope of BPF over time. Treatment with ibudilast was associated wi
Slide 12: Primary Objective 1: BPF (Per Protocol Analysis)
Primary Objective 1: BPF Estimated Rate of Annual BPF Change Treatment Estimate Per Protocol Analysis: Group (90% CI) -0.00101 P-Value Ibudilast 0.045 (-0.00159, -0.00043) -0.00200 Placebo (-0.00258, -0.00143) Results of sensitivity analysis are consistent with findings from primary analysis.
Slide 13: Primary Objective 2: Safety
Primary Objective 2: Safety Treatment Emergent Adverse Events: Placebo Ibudilast p-value Any Adverse Event 88% 92% 0.26 Gastrointestinal System Organ Class 39% 51% 0.050 - Nausea 15% 27% 0.020 - Diarrhoea 7% 16% 0.027 - Abdominal Pain 0% 5% 0.030 - Abdominal Pain, Upper 0% 4% 0.060 - Vomiting 2% 7%
Slide 14: Primary Objective 2: Safety
Primary Objective 2: Safety Treatment Related Adverse Events: Placebo Ibudilast p-value Any Adverse Event 48% 67% 0.002 Gastrointestinal SOC 20% 41% 0.0003 - Nausea 9% 23% 0.004 Investigations SOC 6% 14% 0.05 Nervous System SOC 8% 16% 0.064 Skin & Subcutaneous Tissue SOC 4% 9% 0.097 Other - Fatigue
Slide 15: Primary Objective 2: Safety
Primary Objective 2: Safety Serious Adverse Events – 58 SAEs (in 44 participants) Assessment by Independent Medical Monitor 2 Related & Anticipated • 1 Placebo (Thrombocytopenia) • 1 Ibudilast (Ataxia) 0 Related & Unanticipated 22 Not Related & Unanticipated: 12 Placebo: 10 Ibudilast: Atrial F
Slide 16: Primary Objective 2: Safety
Primary Objective 2: Safety Serious Adverse Events – 58 SAEs (in 44 participants) Assessment by Independent Medical Monitor 2 Related & Anticipated • 1 Placebo (Thrombocytopenia) • 1 Ibudilast (Ataxia) 0 Related & Unanticipated 22 Not Related & Unanticipated: 12 Placebo: 10 Ibudilast: Atrial F
Slide 17: Primary Objective 2: Tolerability
Primary Objective 2: Tolerability Placebo Ibudilast p-value Discontinue Treatment - Any Reason 25% 30% 0.39 - Due to AE 12% 18% 0.18 Early Study Terminations - Any Reason 11% 16% 0.28 - Due to AE 4% 8% 0.29 Early Drug Withdrawal - Any Reason 16% 18% 0.74 - Due to AE 9% 12% 0.42
Slide 18: Major Secondary Objective: MTR
Major Secondary Objective: MTR Normal-appearing Brain Tissue Estimated Rate of Change Per 1 Yr Treatment Estimate Group (90% CI) P-Value -0.00558 Ibudilast 0.047 (-0.02297, 0.01181) -0.03064 Placebo (-0.04767, -0.01362) Significant difference in slope in both MTR measures. Normal-appearing Gray Matt
Slide 19: Major Secondary Objective: DTI
Major Secondary Objective: DTI Transverse diffusivity Estimated Rate of Change Per 1 Yr Treatment Estimate Group (90% CI) P-Value Ibudilast -0.00157 0.15 (-0.00417, 0.00102) Placebo 0.00160 (-0.00096, 0.00416) No significant difference observed in either DTI Longitudinal diffusivity measure. Estimat
Slide 20: Overall Conclusions
Overall Conclusions • Compared to placebo, ibudilast treatment was associated with 48% slowing in the rate of atrophy progression • A similar benefit was seen with MTR, but not DTI • Treatment-related adverse events were mostly gastrointestinal, as well as rash, depression, and fatigue • No increase