Closing the Gaps: Therapeutic Performance and the Promise of Innovation

EP: 1.Understanding PIRA and Its Clinical Significance in MS

EP: 2.Measuring What Matters: Evidence and End Points That Define Disability in MS

Now Viewing

EP: 3.Closing the Gaps: Therapeutic Performance and the Promise of Innovation

EP: 4.Digging Deeper: Mechanisms of Progression and the Case for a Dual Therapeutic Approach

Video content above is prompted by the following:

Current therapeutic options for addressing disability progression in MS, particularly in progressive forms, remain severely limited and often inadequate. For primary progressive MS, only 1 FDA-approved treatment exists: ocrelizumab, a humanized anti-CD20 monoclonal antibody. Despite positive phase 3 trial results against placebo, ocrelizumab’s performance is modest—it slows but doesn’t stop progression, and its efficacy diminishes significantly after patients are aged 53 to 55 years. Notably, this systemic immune system–targeting antibody achieves only 0.1% CNS penetration, highlighting the challenge of addressing CNS-confined pathological processes.

The therapeutic landscape for secondary progressive MS faces similar challenges. While 1 second-generation S1P receptor modulator showed positive results in secondary progressive MS trials, FDA approval was limited to relapsing forms because the progression-slowing benefits primarily occurred in patients closer to the relapsing phase, rather than those with established progressive disease. This regulatory decision underscores the difficulty in developing treatments specifically for established progressive MS and the need for more targeted therapeutic approaches.

Emerging BTK inhibitors represent a promising new therapeutic class that may address these unmet needs. These oral agents target both B cells and myeloid cells (monocytes, macrophages) while offering crucial CNS penetration to impact microglia—a key component of the smoldering inflammation underlying progressive MS. The positive HERCULES trial results showed a 31% reduction in confirmed disability progression over 6 months compared with placebo in patients with nonrelapsing secondary progressive MS. Current phase 3 trials are testing distinct BTK inhibitors in primary progressive MS, with one comparing against placebo and another against ocrelizumab as the gold standard, potentially offering new hope for patients with limited treatment options.