Understanding if and why Ocrevus might stop working

October 10, 2025 •

4 min read

According to a 2021 study, more than 60% of people with multiple sclerosis (MS) using ocrelizumab (Ocrevus) experience a "wearing-off" phenomenon, where symptoms increase before the next scheduled infusion. This common occurrence often leads patients to question: does Ocrevus stop working?

Quick Summary

This article explains the difference between the temporary 'wearing-off' phenomenon and genuine treatment failure for Ocrevus. It details common symptoms of the 'crap gap,' long-term efficacy data, and factors like anti-drug antibodies and disease activity that can affect treatment response.

Key Points

Wearing-off is common but not treatment failure: Many patients report increased symptoms like fatigue and brain fog before their next infusion, but studies suggest this "crap gap" does not reflect a loss of overall disease control.
Ocrevus is effective long-term: Ten-year clinical trial data shows that the majority of patients with relapsing MS and many with progressive MS maintain significant control over disability progression.
True treatment failure signs: Consistent increases in relapse rates, new MRI lesions, or persistent worsening of disability are clearer signs of potential treatment failure.
Addressing the wearing-off effect: For patients experiencing the "crap gap," options like adjusting the infusion interval may help alleviate symptoms.
Factors influencing efficacy: Higher BMI and comorbid fatigue have been linked to an increased risk of reporting the wearing-off effect, while developing anti-drug antibodies is a rare cause of true failure.
Switching therapies: If Ocrevus is truly failing, neurologists can consider alternative DMTs that work through different mechanisms.
Early treatment is key: Long-term studies show that initiating Ocrevus earlier is associated with better outcomes and a lower risk of future disability progression.

Ocrelizumab (brand name Ocrevus) is a highly effective disease-modifying therapy (DMT) for both relapsing forms of multiple sclerosis (RMS) and primary progressive MS (PPMS). For many patients, it is a long-term treatment option administered to target and deplete CD20-positive B cells, thereby reducing inflammation and slowing disease progression. However, some individuals, particularly closer to their next infusion, may notice a resurgence of symptoms, prompting concerns about the medication's ongoing effectiveness. Understanding the difference between this temporary 'wearing-off' phenomenon and genuine treatment failure is crucial for effective MS management.

The “Wearing-Off” Phenomenon vs. Treatment Failure

The 'wearing-off' phenomenon, sometimes colloquially referred to as the 'crap gap,' describes the return or worsening of MS-related symptoms in the weeks leading up to a new Ocrevus infusion. A 2021 study showed that 61% of participants reported this effect, with most experiencing symptoms one to four weeks before their next dose. The most commonly reported symptoms include:

Fatigue
Cognitive disability or "brain fog"
Sensory issues, such as numbness and tingling
Balance problems

While these symptoms can be concerning, multiple studies suggest that this phenomenon does not reflect a biological loss of disease control. Rather, it may relate to the gradual decline of medication levels in the body over the treatment period. For most, symptoms resolve soon after the next infusion. In contrast, true treatment failure involves a consistent increase in relapses, new or enlarging lesions on MRI, or a sustained worsening of disability that is unrelated to the infusion schedule.

Long-Term Efficacy Evidence for Ocrevus

Long-term clinical trial data, spanning over 10 years, provides strong evidence for Ocrevus's sustained efficacy. Presented at the American Academy of Neurology (AAN) 2024 Annual Meeting, the data from open-label extension studies demonstrated impressive long-term outcomes for patients with both RMS and PPMS.

Relapsing MS (RMS): After 10 years of continuous Ocrevus treatment, approximately 77% of patients remained free from disability progression, and nearly 92% could walk without a mobility aid.
Primary Progressive MS (PPMS): For PPMS patients treated continuously over 10 years, 36% were free from disability progression, and most (80%) still did not need a wheelchair.

These findings reinforce that Ocrevus offers sustained, long-term disease control for many patients. The research also highlighted the importance of early treatment, showing that patients who initiated Ocrevus earlier had a lower risk of long-term disability progression.

Potential Reasons for Perceived Failure

Beyond the temporary wearing-off effect, a few factors may contribute to a perceived or actual loss of effectiveness over time:

Natural MS Progression: Multiple sclerosis is an unpredictable disease, and progression can sometimes occur despite a highly effective DMT. This may manifest as new relapses, lesions, or increased disability.
Anti-Drug Antibodies: In rare cases, the body can develop neutralizing antibodies against the medication, which can reduce its effectiveness. If a loss of effectiveness is suspected, a doctor might test for these antibodies.
Comorbid Conditions: Other health issues can exacerbate MS-like symptoms, leading patients to mistakenly believe their Ocrevus is no longer working. It's important for patients to consider and report other factors to their healthcare providers.

A Comparison of Ocrevus and Other Multiple Sclerosis Treatments

Compared to many other DMTs, Ocrevus offers high efficacy with a relatively convenient dosing schedule, contributing to superior adherence rates.


Feature	Ocrevus (Ocrelizumab)	Oral DMTs (e.g., Fingolimod)	Injectable DMTs (e.g., Interferons)
Mechanism	Anti-CD20 monoclonal antibody; depletes B-cells	Various; some modulate lymphocyte migration	Various; immunomodulatory
Administration	Administered via IV infusion	Oral pill, typically daily	Injectable, frequency varies
Persistence Rate	Very high persistence over 12-18 months in real-world studies	Lower persistence due to more frequent dosing	Lower persistence due to more frequent dosing and side effects
Efficacy	High efficacy; showed superiority to interferon in trials	High to moderate efficacy; varies by medication	Moderate efficacy; varies by medication

When to Discuss Treatment Concerns with Your Doctor

It is important to have an open discussion with your neurologist if you experience any changes in your MS symptoms or feel your medication is not working as well as it used to. Key signs that warrant a conversation include:

An increase in relapse frequency
Worsening or new symptoms that persist beyond the 'wearing-off' period
MRI scans showing new or enlarging lesions
Higher neurofilament light chain (pNfL) levels, which can indicate increased neuroaxonal damage

What are the Next Steps if Ocrevus Isn't Working?

If your neurologist determines that Ocrevus is truly failing to control your MS, several options are available:

Adjusting Infusion Timing: For patients experiencing the 'wearing-off' effect, some neurologists may consider adjusting the timing between infusions to maintain more consistent drug levels. This intervention has been shown to improve or resolve symptoms in some patients.
Switching Therapies: There are many other DMTs available that act on different parts of the immune system. Your doctor will determine the best alternative based on your specific MS type, disease activity, and overall health.
Symptom Management: It's important to remember that while DMTs treat the underlying disease activity, many MS symptoms require separate management. This can include physical therapy, medication for specific symptoms like pain or fatigue, and lifestyle adjustments.

Conclusion

While many people on Ocrevus experience a "wearing-off" phenomenon as they approach their next infusion, this is generally not an indication that the medication has stopped working. Long-term clinical data demonstrates sustained efficacy and safety for Ocrevus over a decade for a majority of patients. True treatment failure is possible but less common and is typically defined by consistent disease progression, not temporary symptom fluctuations. Open and consistent communication with your neurologist, regular MRI monitoring, and considering all aspects of your health are the best ways to ensure your MS is being managed effectively over the long term.

Learn more about Ocrevus and its long-term clinical data from the Neurology® Journal.

Frequently Asked Questions

This is often the "wearing-off" phenomenon, where symptoms like fatigue and cognitive issues worsen as drug levels decline toward the end of the treatment cycle. It does not typically indicate that the medication has stopped working, as symptoms often improve after the next dose.

Clinical trials and long-term extension studies, with data spanning over 10 years, have shown that Ocrevus maintains sustained efficacy over the long term for many patients, helping to control relapses and slow disability progression.

True resistance, where the body develops neutralizing antibodies against the drug, can occur but is rare. This differs from the common "wearing-off" effect. Your doctor may order tests to check for anti-drug antibodies if treatment failure is suspected.

Signs of true treatment failure include an increase in the frequency of relapses, new or enlarging lesions visible on MRI scans, and a sustained, progressive worsening of disability that is not related to the infusion schedule.

If the symptom fluctuations are significantly impacting your quality of life, your neurologist might consider adjusting the timing between infusions. This intervention has been shown to resolve or improve wearing-off symptoms for many patients.

If your doctor confirms that Ocrevus is no longer effectively controlling your disease, they may recommend switching to another disease-modifying therapy (DMT). There are many options available that target different aspects of the immune system.

Yes. While Ocrevus addresses the underlying disease progression, many MS symptoms like pain and fatigue need separate management strategies. This can include symptomatic medications, physical therapy, or other supportive treatments.