Slide 1: A Phase II Trial of Ibudilast in Progressive Multiple Sclerosis
A Phase II Trial of Ibudilast in Progressive Multiple Sclerosis 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, J. Barnes, D. Ecklund, E. Klinger, M. Koepp, S. Natarajan, B. Thornell, J. Yankey, R.A. Bermel
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. Cudkowicz has received consulting fees from Astra Zenica, Cytokinetics, Biohav
Slide 3: Progressive Multiple Sclerosis
Progressive Multiple Sclerosis • About half of people living with multiple sclerosis have progressive MS (primary and secondary progressive) • Manifests as gradual decline in neurologic function • Primary and secondary progressive MS are increasingly recognized as having more similarities than diffe
Slide 4: Progressive Multiple Sclerosis
Progressive Multiple Sclerosis • About half of people living with multiple sclerosis have progressive MS (primary and secondary progressive) • Manifests as gradual decline in neurologic function • Primary and secondary progressive MS are increasingly recognized as having more similarities than diffe
Slide 5: Ibudilast (MN-166, AV411)
Ibudilast (MN-166, AV411) N CH3 • Orally-available small molecule N • Phosphodiesterase PDE-4 and PDE-10 inhibitor CH3 • Macrophage migration inhibitor factor inhibitor O • Toll-like receptor 4 inhibitor H3C • Approved in Japan in 1989 CH3 • Bronchial asthma • Post-stroke dizziness • Slowed progress
Slide 6: NN102 / SPRINT-MS Trial Overview
NN102 / SPRINT-MS Trial Overview • 96-week, 28-site, phase II trial utilizing NIH-sponsored NeuroNEXT network • Inclusion: • Age 18-65 years • Primary or secondary progressive MS • Typical MS lesions on brain MRI • Expanded Disability Status Scale 3.0-6.5 • Disability progression in the preceding 2
Slide 7: Study Endpoints
Study Endpoints Brain atrophy Diffusion tensor imaging • Primary: • Whole brain atrophy – Brain Parenchymal Fraction (BPF) • Safety – Adverse events, Serious adverse events Magnetization transfer • Tolerability – early discontinuation ratio • Secondary Cortical atrophy • Diffusion Tensor Imaging in
Slide 8: Demographics
Baseline characteristics Characteristic Placebo (n = 126) Ibudilast (n = 129) P-value Age (yrs), mean (SD) 57 (6.5) 55 (7.8) 0.02 Females, n (%) 69 (55%) 67 (52%) 0.65 Demographics Race Caucasian, n (%) 114 (91%) 122 (95%) 0.79 Black / African American, n (%) 7 (6%) 4 (3%) Other, n (%) 1 (1%) 3 (2%)
Slide 9: Participant Disposition
Participant Disposition 86% overall retention rate through Week 96
Slide 10: Primary Outcome: Brain Atrophy
Primary Outcome: Brain Atrophy Compared to placebo, ibudilast treatment was associated with a 48% slowing in rate of atrophy progression • There was no evidence for outliers driving the overall result • A modified per-protocol sensitivity analysis was consistent with findings from the primary analys
Slide 11: Primary Outcome: Safety and Tolerability
Primary Outcome: Safety and Tolerability Adverse events more frequent in one group (p≤0.10) or reported in more than ≥10% Overall Placebo Ibudilast P value (N = 255) (N = 126) (N = 129) All Adverse Events 230 (90%) 111 (88%) 119 (92%) 0.26 Gastrointestinal Abdominal pain 6 (2%) 0 (0%) 6 (5%)* 0.03 A
Slide 12: Primary Outcome: Safety and Tolerability
Primary Outcome: Safety and Tolerability Adverse events more frequent in one group (p≤0.10) or reported in more than ≥10% Overall Placebo Ibudilast P value (N = 255) (N = 126) (N = 129) All Adverse Events 230 (90%) 111 (88%) 119 (92%) 0.26 Gastrointestinal Abdominal pain 6 (2%) 0 (0%) 6 (5%)* 0.03 A
Slide 13: Primary Outcome: Safety and Tolerability
Primary Outcome: Safety and Tolerability Adverse events more frequent in one group (p≤0.10) or reported in more than ≥10% Overall Placebo Ibudilast P value (N = 255) (N = 126) (N = 129) All Adverse Events 230 (90%) 111 (88%) 119 (92%) 0.26 Gastrointestinal Abdominal pain 6 (2%) 0 (0%) 6 (5%)* 0.03 A
Slide 14: Primary Outcome: Safety and Tolerability
Primary Outcome: Safety and Tolerability Adverse events more frequent in one group (p≤0.10) or reported in more than ≥10% Overall Placebo Ibudilast P value Overall Placebo Ibudilast 24 (19%) Subjects 20 (16%) Subjects P value All Serious 44 (17%) Atrial Fibrillation Asthenia 0.46 (N = 255) (N = 126)
Slide 15: Key Secondary Outcomes
Key Secondary Outcomes Change in transverse diffusivity in Change in magnetization transfer ratio in pyramidal tract normal-appearing brain tissue Change in cortical thickness Worse Worse Worse Change in longitudinal diffusivity in Ibudilast was associated with: pyramidal tract Change in retinal ner
Slide 16: Secondary Outcome - Disability
Secondary Outcome - Disability Sustained progression on Expanded Disability Status Scale • Progression of disability changed in a favorable direction with ibudilast but was not statistically significant • This phase 2 trial was not powered to detect benefit on clinical disability HR 0.74 (90% confid
Slide 17: Overall Conclusions
Overall Conclusions • Ibudilast treatment led to a 48% slowing in the progression of whole brain atrophy in progressive MS • Benefit was also seen with magnetization transfer ratio (81% reduction) and cortical atrophy (80% reduction), but not with diffusion tensor imaging or retinal nerve fiber laye
Slide 18: Acknowledgements
Acknowledgements Many thanks to: • Clinical Coordinating Center – Massachusetts General Hospital • Data Coordinating Center – University of Iowa • Coordinating Support - Mellen Center for Multiple Sclerosis • Protocol Steering Committee • Site investigators • NINDS and National MS Society for suppor