Summary
Anti-CD20 therapies are a class of monoclonal antibodies that bind to CD20 on the surface of B cells. They work by depleting peripheral B-cells. Four anti-CD20 antibodies are available for treating MS and are administered by intravenous or subcutaneous injection. The three licensed agents for treating relapsing forms of MS are ocrelizumab (Ocrevus), ofatumumab (Kesimpta) and ublituximab (Briumvi). In addition, ocrelizumab is the only anti-CD20 therapy with a license to treat primary progressive MS. In many countries, rituximab (MabThera) is used off-label. Rituximab will be increasingly used as it has recently been included on the WHO’s essential medicines list as a treatment for MS.
Most B-cell killing due to anti-CD20 is done through immunological processes that burst or lyse the cells, releasing their contents. This can cause a cell lysis syndrome or infusion reaction, which in the case of anti-CD20 therapies tends to be mild to moderate. The infusion reactions are typically managed by predosing with steroids, antihistamines and/or antipyretics (paracetamol/acetaminophen or a non-steroid anti-inflammatory such as ibuprofen). The doses and dosing schedules of the anti-CD20 therapies differ.
Ocrelizumab (600 mg), ublituximab (450 mg) and rituximab (1000 mg) are given as 6-monthly intravenous infusions and ofatumumab (20 mg) as monthly subcutaneous injections.
The anti-CD20 therapies are highly effective DMTs with a high rate of no evident inflammatory disease activity (NEIDA), slowing down disability worsening and brain volume loss. A recent real-world study suggests that ocrelizumab is more effective than rituximab. However, as these agents have yet to be compared head-to-head in a clinical trial, it is difficult to claim one is more or less effective than the others.
Rituximab and ublituximab are the least humanised of the anti-CD20s and are associated with a higher rate of antidrug antibodies (ADAs), which are usually neutralising antibodies (NAbs). It is reported that 6.4% of ublituximab-treated subjects and even more rituximab-treated patients develop ADAs. In comparison, 1 ̶ 2% of ocrelizumab-treated patients and fewer than 0.5% of ofatumumab-treated patients develop ADAs as these therapeutic antibodies are more humanised than the others and less likely to induce an antidrug immune response. The ADAs are important considerations when choosing between these products.
The most common adverse effects of anti-CD20 therapies are mild infusion-like reactions (generally not seen with subcutaneous ofatumumab), infections, low antibody levels in the blood (hypogammaglobulinaemia), blunted vaccine responses and (rarely) delayed neutropenia. In the ocrelizumab trials, the number of malignancies (including breast cancers) was increased. The incidence was, however, within the background rate expected for an MS population, and post-marketing studies have not shown an increased rate of malignancies.
Anti-CD20 therapies are generally available first line to treat DMT-naive patients. As a class, anti-CD20 therapies have transformed the management of MS by allowing the adoption of a treatment strategy of using high-efficacy DMTs as the first treatment, which I refer to as ‘flipping the pyramid’. Importantly, ocrelizumab has also ushered in the era in which we can treat some patients with primary progressive MS.
Trade names
Ocrevus, Kesimpta, Bonspri, Briumvi, MabThera.
Mode of action
Via peripheral B-cell depletion. It is hypothesised that anti-CD20 therapies work via several mechanisms involving the B cell and possibly through a small population of CD20-expressing T cells.
Efficacy
High, with a positive impact on annual relapse rate, 3-month disability progression, no evident disease activity (NEDA) rates and slowing of accelerated brain volume loss.
Class
Maintenance therapy – continuous B-cell depletion.
Immunosuppression
Yes, long-term.
Dosing
Ocrevus (ocrelizumab) dosing
600 mg administered as two infusions of 300 mg (with a 2-week gap). Subsequent doses of 600 mg ocrelizumab every 6 months.
Kesimpta/Bonspri (ofatumumab) dosing
20 mg administered by subcutaneous injection at weeks 0, 1 and 2, then monthly dosing from week 4.
Briumvi (ublituximab) dosing
150 mg intravenous infusion (first infusion); 450 mg intravenous infusion 2 weeks later. All subsequent doses are administered as a single 450 mg intravenous infusion every 24 weeks.
MabThera (rituximab) dosing
Generally, 1000 mg intravenously on days 1 and 15 then 1000 mg intravenously every 6 months. Rituximab is off patent and dosing regimens vary.
Pre-treatment and prophylaxis treatment
100 mg of corticosteroid is administered intravenously before infusion to help manage infusion reactions; this may not be needed with later infusions. Premedication is not necessary with subcutaneous ofatumumab. Prophylactic antivirals or antibiotics are not required.
Main adverse events
- Infections, usually minor, are the most common adverse event. Herpes infections are reported more frequently than with other DMTs.
- Infusion-related reactions are relatively common with the first and second infusions. The risk of anaphylaxis is very low.
- Laboratory abnormalities such as decreased antibody levels, lymphopaenia or neutropaenia are associated with a higher risk of infection.
- Standard breast cancer screening measures are mandated for women aged 50 ̶ 70 years.
Pharmacovigilance monitoring requirements
- Standard blood tests and comprehensive screening for infection, pregnancy and blood pressure are done at baseline.
- Vaccine review is recommended, followed by vaccination where indicated.
- Follow-up blood tests are not mandated, but our centre performs them every 6 ̶ 12 months.
- A rebaseline MRI scan should be done ~6 months after starting an anti-CD20 therapy, ideally including Gd-enhancement. A monitoring MRI is performed annually after that.
- In the event of pregnancy, the next infusion should be delayed until after delivery.
- In general, the anti-CD20 therapies are safe when breastfeeding, except during weeks 2 ̶ 3 post-partum when colostrum is produced.