Ocrelizumab: The Only Proven Therapy for Primary Progressive Multiple Sclerosis
Ocrelizumab is the only disease-modifying therapy with proven clinical efficacy for primary progressive multiple sclerosis (PPMS), demonstrating a 24% risk reduction in 12-week confirmed disability progression compared to placebo, while natalizumab has failed to show efficacy in PPMS populations. 1
Evidence for Ocrelizumab Efficacy in PPMS
Pivotal Trial Data (ORATORIO)
The FDA-approved indication for ocrelizumab in PPMS is based on Study 3 (ORATORIO), a randomized, double-blind, placebo-controlled trial that enrolled 732 patients with PPMS 1. This landmark study demonstrated:
- 32.9% of ocrelizumab-treated patients experienced 12-week confirmed disability progression versus 39.3% on placebo (24% risk reduction, p=0.0321) 1
- Mean reduction in T2 lesion volume of -0.39 cm³ with ocrelizumab versus +0.79 cm³ increase with placebo (p<0.0001) at Week 120 1
- Treatment duration extended for at least 120 weeks (approximately 2.3 years minimum) 1
Regulatory Recognition
Ocrelizumab received FDA approval in March 2017 and European Medicines Agency approval in November 2017 as the first and only disease-modifying therapy approved for PPMS 2, 3. This represents a paradigm shift, as PPMS previously had no approved treatment options 2.
Real-World Confirmation
Multiple real-world studies have validated the clinical trial findings:
- A German compassionate use programme involving 489 PPMS patients confirmed ocrelizumab's tolerability and safety profile in clinical practice 4
- A Dutch retrospective cohort study (n=21) demonstrated that disability worsening rate while on ocrelizumab was significantly lower than pre-treatment period (Z=-2.81, p≤0.01), with 3 of 17 patients showing clinically relevant improvement 5
- Long-term data extending beyond 7.5 years of treatment show maintained clinical benefits with no new safety signals 3
Mechanism and Patient Selection
The ORATORIO trial specifically enrolled patients with:
- Baseline EDSS of 3.0 to 6.5 1
- EDSS pyramidal functional system score ≥2 due to lower extremity findings 1
- Mean time since symptom onset of 6.7 years 1
- 26% had gadolinium-enhancing lesions at baseline, indicating some inflammatory activity 1
PPMS patients with early and inflammatory active disease represent the optimal treatment population, as recommended by the 2025 ECTRIMS/EBMT guidelines 6.
Evidence Against Natalizumab in PPMS
Failed Clinical Trials
The 2020 MAGNIMS consensus explicitly documents natalizumab's failure in PPMS:
- The ASCEND trial in secondary progressive MS (SPMS) showed no benefit: natalizumab versus placebo over 24-96 weeks demonstrated "None" as the treatment favored 6
- While ASCEND technically studied SPMS, the progressive phenotype shares pathophysiological mechanisms with PPMS (compartmentalized inflammation, neurodegeneration predominating over focal inflammation) 6
Mechanistic Rationale for Failure
Natalizumab is a high-efficacy DMT for relapsing MS that works by preventing lymphocyte migration across the blood-brain barrier 6. However:
- Progressive MS is characterized by compartmentalized inflammation behind an intact blood-brain barrier, making natalizumab's mechanism less relevant 6
- The 2025 ECTRIMS guidelines classify natalizumab among high-efficacy DMTs effective for relapsing forms but do not recommend it for progressive MS without active inflammatory disease 6
- A registry-based study mentioned in the 2025 guidelines found no differences in MS relapse or disability outcomes when comparing AHSCT and natalizumab for primary progressive and secondary progressive MS 6, suggesting natalizumab provides no meaningful benefit in progressive phenotypes
Comparative Trial Evidence
The MAGNIMS consensus table systematically documents treatment outcomes across MS phenotypes 6:
- Natalizumab trials (AFFIRM, SENTINEL) enrolled only RRMS patients, with no PPMS trials conducted 6
- No natalizumab trial has ever been designed or conducted specifically for PPMS, in stark contrast to ocrelizumab's dedicated ORATORIO trial 6, 1
Clinical Implications
Ocrelizumab Remains Unique
Ocrelizumab is explicitly recognized as the only DMT approved for PPMS in multiple authoritative sources 2, 3, 7. The 2022 Cochrane systematic review states: "Ocrelizumab is the only disease-modifying therapy (DMT) approved for PPMS" 2.
Treatment Algorithm for PPMS
Based on the evidence:
- First-line therapy: Ocrelizumab 600 mg IV every 24 weeks (initial dose as two 300 mg infusions 2 weeks apart) 1
- Patient selection criteria: EDSS 3.0-6.5, evidence of inflammatory activity (gadolinium-enhancing lesions preferred), disease duration <10 years, age <55 years 6, 1
- Monitoring: Neurological assessments every 12 weeks, MRI at baseline and periodically (Weeks 24,48,120 in pivotal trial) 1
Critical Distinction from Relapsing MS
The 2025 ECTRIMS guidelines emphasize that high-efficacy DMTs including natalizumab are effective when initiated early in relapsing MS 6, but progressive MS requires different therapeutic approaches targeting compartmentalized inflammation and neurodegeneration 6. Ocrelizumab's B-cell depletion mechanism addresses the pathophysiology of PPMS more effectively than natalizumab's mechanism 2, 3.
Safety Considerations
Ocrelizumab's safety profile in PPMS includes 1, 2:
- Most common adverse events: upper respiratory tract infections (49%), infusion reactions (40%), skin infections (14%), lower respiratory tract infections (10%)
- Serious adverse events occurred in similar proportions to placebo (no significant difference, RR 0.92,95% CI 0.68-1.23) 2
- Treatment discontinuation due to adverse events showed no significant difference versus placebo (RR 1.23,95% CI 0.55-2.75) 2
- Vigilance required for progressive multifocal leukoencephalopathy (PML), particularly in patients with prior natalizumab exposure 4