Ocrelizumab: A Comprehensive Patient Guide to Multiple Sclerosis Treatment

Table of Contents

• Understanding Multiple Sclerosis and Ocrelizumab
• How Ocrelizumab Works
• Effectiveness in Relapsing Multiple Sclerosis
• Effectiveness in Primary Progressive MS
• Long-Term Treatment Results
• Safety and Side Effects
• Practical Treatment Information
• Study Limitations
• Patient Recommendations
• Source Information

Understanding Multiple Sclerosis and Ocrelizumab

Multiple sclerosis (MS) is a chronic autoimmune disorder that affects the central nervous system, causing inflammation, damage to the protective nerve covering (myelin), and eventually irreversible nerve damage. Approximately 85% of patients begin with relapsing-remitting MS (RRMS), characterized by periods of symptom flare-ups (relapses) followed by recovery. The remaining 10-20% have primary progressive MS (PPMS), where disability worsens steadily from disease onset without remission periods.

Ocrelizumab (marketed as Ocrevus®) is an intravenous monoclonal antibody treatment approved for both relapsing forms of MS and primary progressive MS. This medication represents a significant advancement in MS treatment, particularly for PPMS where no other disease-modifying therapies were previously approved. The treatment works by targeting specific immune cells called B cells, which researchers now understand play a crucial role in MS progression.

How Ocrelizumab Works

Ocrelizumab selectively targets and depletes CD20+ B cells through several mechanisms including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and apoptosis (programmed cell death). This targeted approach spares the body's ability to reconstitute B cells later and preserves existing immunity while effectively modulating the immune response that drives MS progression.

The medication reduces CD19+ B cells (a marker for CD20+ B cells) to negligible levels within 14 days after infusion, with this depletion maintained throughout treatment in 96% of patients. After stopping treatment, the median time for B cells to return to normal levels is 72 weeks (ranging from 27-175 weeks). The treatment also significantly reduces cerebrospinal fluid B cells and neurofilament light chain levels (markers of nerve damage) in both relapsing and progressive forms of MS.

Ocrelizumab has a terminal elimination half-life of 26 days and is primarily cleared through natural breakdown processes in the body. No dosage adjustments are needed based on liver or kidney function, and no special adjustments are required for patients over 55 years of age.

Effectiveness in Relapsing Multiple Sclerosis

The effectiveness of ocrelizumab for relapsing MS was demonstrated in two pivotal phase III trials called OPERA I and OPERA II, which included 1,656 patients total. These studies compared ocrelizumab against interferon β-1a over 96 weeks (approximately 2 years). Patients were aged 18-55 with Expanded Disability Status Scale (EDSS) scores of 0-5.5, and approximately 75% had not received any disease-modifying therapy in the 2 years before screening.

Ocrelizumab demonstrated remarkable effectiveness, reducing annualized relapse rates by 46% in OPERA I and 47% in OPERA II compared to interferon β-1a. Specifically, the relapse rate was 0.16 with ocrelizumab versus 0.29 with interferon in both trials, representing a highly statistically significant difference (p < 0.001). These benefits were consistent across most patient subgroups regardless of age, sex, body mass index, baseline disability level, or MRI findings.

The treatment also significantly improved multiple other important measures:

• Disability progression: Reduced risk of confirmed disability progression at 12 weeks by 40% (9.1% vs 13.6% with interferon)
• Disability improvement: Increased the proportion of patients showing disability improvement by 33% (20.7% vs 15.6%)
• MRI activity: Reduced gadolinium-enhancing lesions by 94-95% (0.02 vs 0.29-0.42 lesions per scan)
• New lesions: Reduced new or enlarging T2 lesions by 77-83% (0.32-0.33 vs 1.41-1.90 lesions)

Additional studies including ENSEMBLE (treatment-naïve patients), ENCORE (patients previously treated with natalizumab), CHORDS and CASTING (patients with suboptimal response to prior therapies) all consistently showed significant benefits with ocrelizumab treatment.

Effectiveness in Primary Progressive MS

The ORATORIO trial specifically evaluated ocrelizumab in 732 patients with primary progressive MS over at least 120 weeks (approximately 2.5 years). Patients had EDSS scores of 3.0-6.5 at screening, and 88% had not used any disease-modifying therapy in the previous 2 years.

Ocrelizumab demonstrated significant benefits in slowing disease progression in PPMS, reducing the risk of 12-week confirmed disability progression by 24% compared to placebo (hazard ratio 0.76; 95% CI 0.59-0.98; p = 0.03). The treatment also showed greater effects in certain subgroups, particularly patients with gadolinium-enhancing lesions at baseline (35% risk reduction) and those aged 45 years or younger (36% risk reduction).

Additional benefits included:

• Walking speed: 29% reduction in worsening of timed 25-foot walk performance
• Upper extremity function: 44-45% reduction in risk of 9-hole peg test progression
• MRI measures: Significant reductions in brain volume loss (33.8% reduction) and T2 lesion volume (3.4% vs 7.4% increase with placebo)

Long-Term Treatment Results

Long-term extension studies have demonstrated that the benefits of ocrelizumab are maintained over extended treatment periods. After the initial 2-year OPERA trials, 89% of patients continuing ocrelizumab and 88% of patients switching from interferon completed 3 additional years of treatment (5 total years).

At 5 years of treatment, patients receiving continuous ocrelizumab showed near-complete suppression of MRI disease activity with gadolinium-enhancing lesion rates of 0.006 per year (compared to 0.017 at year 2) and new/enlarging T2 lesion rates of 0.031 per year (compared to 0.063 at year 2). Patients continuously treated with ocrelizumab also had significantly less brain atrophy than those who switched from interferon.

After 7.5 total years of follow-up (5.5 years in the extension period), the annualized relapse rate remained very low at 0.03 in both continuous ocrelizumab patients and those who switched from interferon. Patients who received continuous ocrelizumab had a 23% lower risk of disability progression and 35% lower risk of requiring a walking aid compared to those who switched from interferon.

Safety and Side Effects

Ocrelizumab is generally well-tolerated with a safety profile consistent across clinical trials and real-world experience. The most common adverse events include:

• Infusion-related reactions: Occurring in 34-40% of patients during the first infusion, decreasing to 20-25% with subsequent infusions, and mostly mild to moderate in severity
• Infections: Mostly upper respiratory tract infections and urinary tract infections, typically mild to moderate
• Other effects: Including cough, fatigue, and skin problems

Serious infections occurred in 1.3-5.5% of ocrelizumab patients compared to 0.8-2.9% with comparator treatments. No increased risk of malignancies was observed compared to interferon or placebo groups. Regular monitoring is recommended due to the immunosuppressive effects of treatment.

Practical Treatment Information

Ocrelizumab is administered by intravenous infusion every six months, providing convenient dosing compared to many other MS treatments. The initial dose is given as two 300 mg infusions separated by 14 days, followed by single 600 mg infusions every 24 weeks. The infusion time is approximately 2 hours for the 600 mg dose after the initial infusion.

Important considerations for patients include:

1. Vaccinations: Non-live vaccines should be administered at least 2-4 weeks before starting treatment when possible
2. Live vaccines: Not recommended during treatment or until B cells have recovered after discontinuation
3. Pregnancy: Infants born to mothers treated with ocrelizumab should not receive live vaccines until B cell recovery occurs
4. Other medications: Concurrent use with other immunosuppressive therapies is generally not recommended

Before starting treatment, patients should undergo appropriate screening for hepatitis B and other infections, as well as complete any necessary vaccinations.

Study Limitations

While the clinical trial data for ocrelizumab is extensive and compelling, several limitations should be considered. The OPERA trials compared ocrelizumab against interferon β-1a rather than placebo, which while ethically appropriate, makes direct comparison to other newer treatments more challenging. The ORATORIO trial in PPMS was not powered to detect differences in all patient subgroups, limiting some of the subgroup analyses.

Additionally, while long-term extension data is available for up to 7.5 years, even longer-term safety and effectiveness data will be important as patients may remain on treatment for decades. Real-world evidence, while consistent with clinical trial results so far, continues to accumulate and will provide additional insights into the medication's performance in diverse patient populations.

Patient Recommendations

Based on the comprehensive clinical evidence, ocrelizumab represents an important treatment option for both relapsing and primary progressive multiple sclerosis. For patients with relapsing forms of MS, ocrelizumab provides high efficacy with convenient six-month dosing. For those with primary progressive MS, it offers the first approved disease-modifying therapy that can meaningfully slow disability progression.

Patients considering ocrelizumab should:

• Discuss their complete medical history with their neurologist, including any history of infections or cancer
• Complete all recommended vaccinations before starting treatment when possible
• Understand the infusion process and potential side effects
• Commit to regular monitoring and follow-up appointments
• Report any signs of infection promptly to their healthcare provider

The convenience of six-month dosing, combined with strong efficacy data and a generally manageable safety profile, makes ocrelizumab a valuable treatment option that many patients can incorporate successfully into their long-term MS management plan.

Source Information

Original Article Title: Ocrelizumab: A Review in Multiple Sclerosis
Author: Yvette N. Lamb
Publication: Drugs (2022) 82:323–334
DOI: https://doi.org/10.1007/s40265-022-01672-9
Accepted: 12 January 2022 / Published online: 22 February 2022

This patient-friendly article is based on peer-reviewed research and aims to accurately represent the original scientific findings while making them accessible to educated patients. The information provided should be discussed with healthcare professionals when making treatment decisions.