Despite the plethora of therapies approved for relapsing multiple sclerosis (MS), there are few treatment options with demonstrated efficacy for progressive MS. Challenges in developing therapies for progressive MS include uncertain disease pathophysiology, lack of validated treatment response biomarkers, and insensitive clinical outcomes. These challenges hamper trial design because phase II trials rely on dynamic, disease-relevant biomarkers and phase III trials require thousands of patients to make definitive efficacy claims. With numerous potential therapies to evaluate, the latter is logistically challenging and prohibitively expensive. Many other neurologic disorders face similar challenges.