Multiple sclerosis (MS) is a chronic inflammatory condition of the central 
nervous system with heterogeneous features. Primary progressive (PP) MS is a 
rare disease subtype characterized by continuous disability worsening from 
onset. No disease-modifying therapy is currently approved for PP MS due to the 
negative or inconsistent results of clinical trials conducted on a wide range of 
interventions, which are reviewed in the present paper. Areas covered: The 
features and results of randomized trials of disease-modifying treatments for PP 
MS are discussed, including immunosuppressants, immunomodulators, monoclonal 
antibodies, and putative neuroprotective agents. Expert commentary: The recent 
encouraging results of the ocrelizumab trial in PP MS, the first to reach the 
primary disability endpoint, indicate B cells as a promising therapeutic target 
to prevent disease progression. Other emerging treatment strategies include cell 
metabolism modulation and inflammatory pathways inhibition, which are being 
investigated in several ongoing phase II and III placebo-controlled trials. 
Future PP MS trials will need to systematically include efficacy endpoints other 
than physical disability alone, such as cognition, quality of life, advanced MRI 
measures and molecular biomarkers.