Newer Drugs in Multiple Sclerosis Management
High-Efficacy Monoclonal Antibodies
The most impactful newer drugs for MS are the anti-CD20 monoclonal antibodies ocrelizumab and ofatumumab, along with the sphingosine 1-phosphate receptor modulators siponimod, ozanimod, and ponesimod, all approved since 2018. 1, 2
Anti-CD20 Therapies
- Ocrelizumab is approved for both relapsing forms of MS and primary progressive MS, representing the first disease-modifying therapy specifically indicated for primary progressive disease 1, 2
- Ofatumumab is the first fully subcutaneous anti-CD20 therapy, eliminating the need for intravenous infusion and allowing self-administration at home 2
- Both ocrelizumab and ofatumumab are classified as high-efficacy therapies, with ofatumumab demonstrating efficacy comparable to established high-efficacy treatments 3
- These agents probably cause a trivial increase in treatment discontinuation due to adverse events compared to placebo 4
Sphingosine 1-Phosphate Receptor Modulators
- Siponimod is FDA-approved for relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease 5
- Ozanimod and ponesimod are second-generation S1P receptor modulators with more selective receptor binding, resulting in reduced off-target cardiac and pulmonary effects compared to fingolimod 2
- Siponimod is classified as moderate to high efficacy depending on the analytical approach used 3
- These oral formulations probably cause a trivial increase in discontinuation rates due to adverse events 4
Oral Disease-Modifying Therapies
Fumarates
- Diroximel fumarate is a second-generation fumarate with significantly reduced gastrointestinal side effects compared to dimethyl fumarate, improving tolerability while maintaining efficacy 2
Cladribine
- Cladribine is classified as high-efficacy therapy based on direct comparative trial results and network meta-analysis 3
- This oral therapy is administered in short treatment courses (typically 2 treatment courses over 2 years), offering a unique pulsed immunoreconstitution approach 1
Treatment Strategy for Newer Agents
Early Escalation Approach
- High-efficacy DMTs including ocrelizumab, ofatumumab, and cladribine should be initiated early in the disease course rather than using a stepped escalation approach 1, 6
- For patients with markers of aggressive disease (frequent relapses, incomplete recovery, high frequency of new MRI lesions, rapid disability onset), high-efficacy DMTs can be considered after failure of a single high-efficacy DMT following a meaningful treatment period 1
Specific Clinical Scenarios
- For active secondary progressive MS, siponimod is specifically indicated and should be prioritized 5
- For primary progressive MS, ocrelizumab remains the only approved disease-modifying therapy 1, 2
- For highly active MS refractory to high-efficacy DMTs, autologous hematopoietic stem cell transplantation (AHSCT) should be considered as an appropriate escalation therapy 1, 6
Safety Monitoring Requirements
Anti-CD20 Therapies
- Monitor for infusion reactions with ocrelizumab (though less common than with earlier anti-CD20 agents) 2
- Screen for hepatitis B before initiating therapy and monitor for reactivation 2
- Assess immunoglobulin levels periodically during treatment 2
S1P Receptor Modulators
- Perform baseline cardiac evaluation including ECG, as first-dose bradycardia can occur (though less pronounced with newer agents) 2
- Obtain baseline ophthalmologic examination and monitor for macular edema 2
- Monitor lymphocyte counts during treatment 2
MRI Surveillance
- Perform follow-up brain MRI at least annually with T2-weighted and contrast-enhanced T1-weighted sequences 1
- For patients at risk of progressive multifocal leukoencephalopathy (particularly those switching from natalizumab), increase monitoring frequency to every 3-4 months 1, 6
Comparative Efficacy
- Newer high-efficacy agents (cladribine, ocrelizumab, ofatumumab) reduce annualized relapse rates by approximately 50-68% compared to placebo or active comparators 7, 3
- The number of people with clinical relapses is probably trivially reduced with rituximab at 2 years and interferon beta-1b at 3 years, though these are not among the newest agents 4
- Evidence for disability progression prevention remains uncertain for most agents due to short follow-up periods in pivotal trials 4