Rituximab for multiple sclerosis

 

What is rituximab for MS?

Multiple sclerosis (MS) is a condition in which the immune system erroneously launches an inflammatory attack that damages the myelin sheath, a fatty coating around nerve cells that helps them send electrical signals. A type of immune cells, called B-cells, is thought to play a central role in this inflammatory attack.

Rituximab is an antibody-based therapy that works to deplete B-cells. It is not approved as a treatment for MS, but the medication is commonly used off-label to reduce relapse risk and delay disability progression in MS patients.

In the U.S. and elsewhere, rituximab is approved to treat certain blood cancers and some autoimmune diseases, including rheumatoid arthritis, ANCA-associated vasculitis, and pemphigus vulgaris, a condition characterized by painful skin blisters.

Brand names and biosimilars

Rituximab is marketed under the name Rituxan in the U.S., Canada, and Japan; elsewhere, it is marketed as MabThera. The brand-name medication is sold by Genentech (a Roche company) and Biogen in the U.S., and by Roche in most other places.

Several biosimilars of rituximab, such as Truxima, Ruxience, and Riabni, are now widely approved for the same indications as the original product.

A biosimilar is a biological medicine with a high degree of similarity — in terms of quality, safety, and efficacy — to an already-approved reference therapy. Much like generics of chemical compounds, biosimilars are typically less expensive than the original medication.

Therapy Snapshot

Treatment Name:	Rituximab
Administration:	Being tested in MS in intravenous formulation
Clinical Testing:	In Phase 3 clinical trials for relapsing and progressive forms of MS

 

How does rituximab work in MS?

B-cells are immune cells responsible for making antibodies and for activating many other players of the immune system, including inflammatory T-cells. In MS, they are believed to be a main driver of the inflammation that contributes to nervous system damage.

Rituximab is a monoclonal antibody that targets a protein on the surface of B-cells, called CD20. By targeting CD20, rituximab can kill these inflammatory cells, ultimately reducing MS-driving inflammation.

In addition to being found on B-cells, CD20 has been identified on a small subset of T-cells. Research has suggested that rituximab can deplete these cells in people with MS, but it remains unclear if such depletion contributes to the medication’s beneficial effects.

Rituximab works much like other anti-CD20 monoclonal antibodies that have been approved to treat MS, including Kesimpta (ofatumumab) and Ocrevus (ocrelizumab) — the latter of which also is sold by Roche and is structurally very similar to rituximab.

How is rituximab administered in MS?

Rituximab is given intravenously, or via an infusion into the bloodstream. Some MS clinical trials have explored administering rituximab intrathecally, or via an injection through the spine, but this is not routinely done in clinical practice.

Because it is not officially approved as a treatment for MS, there is no single standardized dosing regimen for rituximab for the neurodegenerative disorder. The most commonly used current treatment schedule is 500 or 1,000 mg, administered via a single infusion every six months. =

Several other dosing schedules have been explored in clinical trials, including 500 or 1,000 mg given two weeks apart, with or without additional infusions every six months. Another dose that’s been tested in trial is 375 mg per square meter (mg/m²) given weekly for four weeks.

Common side effects of rituximab in MS

The most common side effects of rituximab in MS clinical trials are infusion-related reactions, or IRRs. These typically occur within 30 minutes to two hours of starting the first infusion with rituximab. Common symptoms of IRRs include:

• fever
• chills
• nausea and vomiting
• itchiness (pruritus)
• nasal congestion
• swelling (angioedema)
• throat irritation
• high or low blood pressure
• hives (urticaria)
• headache
• muscle pain
• dizziness
• wheezing or breathing difficulty due to spasms in the airway (bronchospasm)

Infusion reactions usually are mild to moderate in severity, and can typically be managed by slowing or stopping the infusion and/or giving appropriate treatments to ease specific symptoms. Taking anti-inflammatory medicines like corticosteroids or antihistamines prior to infusion may reduce the risk of IRRs.

Rituximab in clinical trials

Phase 1 trial in RRMS

The first study of rituximab in MS was a Phase 1 clinical trial that enrolled 26 people with relapsing-remitting MS (RRMS). Participants were given two infusions of rituximab at a dose of 1,000 mg, administered two weeks apart, followed by another two doses after six months, and were followed for up to 72 weeks (nearly 1.5 years). Results from the trial suggested that rituximab treatment reduced the relapse rate, with more than 80% of participants remaining relapse-free throughout the study. The treatment also lowered the number of inflammatory brain lesions and lessened the development of new lesions.

HERMES trial in RRMS

The pivotal Phase 2 HERMES clinical trial (NCT00097188) enrolled 104 adults with RRMS. Participants were randomly assigned to receive two infusions of 1,000 mg rituximab, or a placebo, given two weeks apart at the trial’s start. After a follow-up time of nearly a year (48 weeks), significantly fewer participants given rituximab than placebo had experienced a disease relapse (20.3% vs. 40%). At six months, brain lesions with active inflammation also were reduced by about 90% with rituximab compared with a placebo.

Other Phase 2 studies in RRMS

A Phase 2 clinical trial enrolled 30 people with RRMS who had evidence of actively inflamed brain lesions. Each had experienced at least one MS relapse in the prior 18 months despite treatment with an approved MS therapy. Participants were given four weekly infusions of rituximab, at a dose of 375 mg/m², as an add-on therapy.

After one year (52 weeks) of follow-up in the study, the proportion of patients without active inflammatory lesions in the brain rose from 26% at study initiation to 74%. Combining rituximab with other therapies was generally well tolerated in the study. The study was not designed to assess the effect of treatment on relapse rates; nevertheless, a marked reduction in average relapse rates was noted. In fact, the relapse rate dropped from 1.27 relapses per year before rituximab to 0.23 relapses per year in the study.

STRIX-MS trial

Another Phase 2 study, called STRIX-MS (2010-023021-38), enrolled 75 people with RRMS whose disease was stable on an approved therapy — specifically, an interferon treatment or glatiramer acetate — for at least six months. After a three-month run-in, patients were switched to treatment with rituximab, given in two doses of 1,000 mg two weeks apart.

Compared with values during the run-in period, rituximab significantly reduced the number of actively inflamed brain lesions after three and six months, and reduced the number of new or enlarging brain lesions after one year.  A single participant experienced a disease relapse on rituximab in the one year of follow-up, the data showed.

GATEWAYII trial

A third Phase 2 study called GATEWAYII (NCT01569451) enrolled 55 people with active RRMS or with clinically isolated syndrome (CIS). At the trial’s start, participants were given two infusions of 1,000 mg rituximab or a placebo, two weeks apart, as an induction therapy. All participants were then given daily treatment with glatiramer acetate starting at week five and for up to 144 weeks (nearly three years).

At the trial’s end, significantly more patients given rituximab than the placebo had no evidence of disease activity (44.4% vs. 19.2%), defined as no relapses, new MRI lesions, or sustained worsening in disability. Consistently, fewer participants given rituximab experienced treatment failure (37.04% vs. 69.23%), defined as at least two new lesions, relapses, and/or sustained disability worsening.

Additionally, the time to treatment failure was longer on average in rituximab-treated participants (23.32 vs. 11.29 months). Safety outcomes were similar in both groups.

Clinical trials in SPMS

RIVITaLISe (NCT01212094), a Phase 1/2 study sponsored by the National Institute of Neurological Disorders and Stroke (NINDS), tested rituximab, given both intrathecally and intravenously, in 43 people with SPMS. The trial was terminated early, however, after biomarker data suggested that the treatment did not adequately deplete B-cells within the central nervous system.

A Phase 2/3 study (NCT03315923) in Iran then enrolled 84 participants with SPMS who were randomly assigned to treatment with rituximab (1,000 mg every six months), or a standard regimen of glatiramer acetate, for one year. Results from the trial showed that both treatments were similarly effective at reducing relapse rates and inflammatory brain and spinal cord lesions. However, neither treatment demonstrated an ability to prevent disability progression, as measured by Expanded Disability Status Scale (EDSS) scores.

OLYMPUS trial in PPMS

Genentech sponsored a Phase 2/3 trial called OLYMPUS (NCT00087529), which enrolled 439 people with primary progressive MS (PPMS). Participants were selected randomly to receive two infusions two weeks apart of 1,000 mg rituximab or placebo. The infusions were given every six months for about two years.

The trial failed to meet its main goal, which was to demonstrate that rituximab could lower the proportion of patients with confirmed disability progression, defined as an increase in EDSS scores that was sustained for at least three months.

While the proportion of patients with disability progression was somewhat lower with rituximab than with placebo (30.2% vs. 38.5%), the difference was not statistically significant. However, pre-specified analyses showed that rituximab did significantly slow disability progression in patients who were younger than 51 and/or had inflammatory brain lesions at the trial’s start.

In the overall study population, treatment with rituximab significantly lowered the total volume of lesions in the brain, and lessened the decline in a measure of walking ability, measured via the Multiple Sclerosis Functional Composite timed 25-foot walk test, according to the results.

Ongoing clinical trials

A number of ongoing studies are further evaluating the effectiveness and safety of rituximab in MS patients; these are mostly smaller studies being run by individual hospitals and academic centers. For instance, a Phase 1 trial (NCT05078177) run by St. Petersburg State Pavlov Medical University, in Russia, is evaluating intrathecal rituximab in about 40 MS patients.

A Phase 3 study now underway, called DanNORMS (NCT04688788), is evaluating whether there is a meaningful difference in treatment effectiveness between rituximab and Ocrevus in approximately 594 people with active MS. DanNORMS is sponsored by Rigshospitalet, in Denmark, and expected to run through 2028.

NOR-MS (NCT04121403), another Phase 3 trial, is comparing rituximab against the approved oral MS treatment Mavenclad (cladribine) in an estimated 264 people with relapsing disease. That trial, sponsored by Oslo University Hospital, in Norway, launched in 2019.

Boxed warning alerts for rituximab in approved indications

Infusion-related reactions

Severe, fatal IRRs, including anaphylactic allergic reactions and heart attack, have been reported in patients given rituximab, usually in response to the first infusion of the medication. It is recommended that patients be closely monitored while receiving the medicine, and the infusion should be stopped if a severe reaction occurs. 

Skin and mucosal reactions

Severe and sometimes fatal reactions of the skin and mucus membranes (those lining some organs and body cavities, such as the nose, mouth, lungs, and stomach) have been reported in patients on rituximab. Specific reactions can include:

• toxic epidermal necrolysis, a severe skin reaction with blistering or peeling of the skin
• paraneoplastic pemphigus, an autoimmune disease that mostly results in mucosal lesions
• ichenoid dermatitis, a form of eczema characterized by purple-tinted raised skin bumps
• vesiculobullous dermatitis, a blistering disease

If patients experience a severe mucocutaneous reaction, rituximab treatment should be stopped.

Infections

Because it works to lower the activity of the immune system, rituximab may increase the risk of new infections or cause existing infections to worsen. For this reason, vaccines that contain a live virus should not be given to patients currently on or about to start rituximab.

In people with an inactive hepatitis B virus (HBV) infection, rituximab may cause the infection to reactivate, which can result in liver failure and death. Patients should be screened for HBV prior to starting on rituximab and while on therapy; antiviral medications may be given to decrease the risk of reactivation in those with a known latent infection. If a reactivation of HBV does occur, rituximab should be immediately stopped, and appropriate care should be given.

Progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal viral infection of the brain, has been reported in patients on rituximab. The therapy should be stopped if patients develop PML.

Use in pregnancy and breastfeeding

Rituximab may cause harm to a developing fetus. It is recommended that patients with the capacity to become pregnant use effective contraception while taking rituximab, and for at least one year after their last dose.

The medication is detectable in human breast milk, but the clinical significance for the nursing child is unclear. Given the risk of harm to the baby, patients treated with rituximab should not breastfeed until at least six months after their last dose.

---

 is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.