Review: Ocrevus best of 4 antibody therapies for progressive MS

Drug found most effective also only one approved for PPMS by FDA

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Among four antibody-based therapies for multiple sclerosis (MS), Ocrevus (ocrelizumab) works best to prevent disability progression and other measures of disease activity in people with PPMS, or primary progressive MS, a review study found.

However, the medication is associated with an increased risk of infection, data suggested.

Most of the studies in the review focused on Ocrevus — found to be “primarily effective” for this form of MS. Meanwhile, the results for the other medications ranged from “not completely reassuring” to having “conflicting outcomes,” according to researchers.

“In summary, studies investigating [Ocrevus] in patients with PPMS suggest that the treatment effectively reduces disability progression, decreases the risk of [needing to use a wheelchair], and improves upper extremity impairment,” the researchers wrote, adding that, despite the infection risk, the therapy “did not pose any significant safety concerns.”

The review study, “A systematic review of the safety and efficacy of monoclonal antibodies for progressive multiple sclerosis,” was published in the journal International Immunopharmacology.

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A first investigation of antibody-based therapies in PPMS

MS is a chronic inflammatory disease characterized by the loss of the myelin sheath, a protective coating around nerve fibers that facilitates nerve signal transmission. Myelin loss, called demyelination, results in further inflammation that damages nerve cells, triggering the onset of the disease’s symptoms.

Most MS patients are initially diagnosed with relapsing-remitting disease (RRMS), in which periods of symptom worsening called relapses are interspersed by times when symptoms ease or disappear entirely. As the disorder progresses, most people with RRMS will eventually transition to secondary progressive MS (SPMS), in which disability continuously accumulates even in the absence of relapses.

There are also about 10% of patients who, from the disorder’s onset, experience continuous disease progression without relapses. These individuals have a form of the disease called PPMS — primary progressive multiple sclerosis.

Self-reactive immune T-cells and antibody-producing B-cells are known to drive inflammation in MS. As a result, several monoclonal antibody-based disease-modifying therapies have been developed to suppress the activity of these immune cells. Only one, Ocrevus, is approved for PPMS; most are used for RRMS.

“To the best of our knowledge, there is no systematic investigation of the safety and efficacy of monoclonal antibodies for PMS [progressive forms of MS, including PPMS and SPMS],” the researchers wrote.

To address that, researchers at the Tabriz University of Medical Sciences, in Iran, conducted a systematic analysis of studies reporting data from clinical trials in which at least one of the antibody-based therapies was examined in people with PPMS or SPMS.

Following a search of medical databases, the team selected 13 placebo-controlled clinical studies for analysis, each involving from 23 to 732 participants, ages 39-60.

Eight studies evaluated Ocrevus, a therapy designed to deplete mature B-cells by targeting the CD20 protein. In particular, all eight examined data from the ORATORIO Phase 3 trial (NCT01194570), whose data supported the approval of Ocrevus for PPMS patients.

The studies showed that early Ocrevus treatment was associated with the greatest benefits. The therapy effectively reduced the progression of disability and improved arm function. It also decreased the risk of reaching an Expanded Disability Status Scale (EDSS) score of 7 or more, at which point patients are mostly confined to a wheelchair or worse.

Infusion-related reactions, or reactions that develop during or shortly after drug administration, were mild to moderate and were controlled. Common infections included influenza, urinary tract infections, and the common cold.

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Rituximab, Tysabri, Lemtrada all found not as effective

Two studies assessed rituximab, another anti-CD20 antibody that’s sometimes used off-label to treat people with MS. One study found no significant difference between the treatment and a placebo regarding time to disability progression, but MRI scans showed improvement in the volume of lesions. Infections were the same as those seen with Ocrevus.

The second study was stopped because there were no significant changes in disease-related biomarkers and not enough effects on B-cells in the brain and spinal cord. “Further research is needed to better understand its potential benefits and limitations,” the researchers wrote, naming rituximab as the treatment not completely reassuring in its results.

Tysabri (natalizumab), approved for nearly two decades in the U.S., was tested in two clinical studies that included both RRMS and SPMS patients. Given by intravenous (into-the-vein) infusion, the therapy binds to alpha-4-beta-1-integrin protein on immune cells, which prevents their entry into the brain and spinal cord.

Treatment reduced relapse rates and prevented the development of active brain lesions, particularly in patients with higher relapse rates and active lesions before starting Tysabri. Its impact on disease progression was limited, but the therapy reduced the decline in arm function. Common adverse events included urinary tract infections, the common cold, and falls.

The fourth therapy reviewed was Lemtrada (alemtuzumab), which had been tested in an open-label study in SPMS patients using MRI as an outcome measure. This monoclonal antibody binds to the CD52 protein on the surface of T- and B-cells, suppressing their activation and migration.

While treatment decreased the number and volume of active lesions, it also led to brain and spinal cord shrinkage, as well as black hole lesions, or lesions with permanent nerve damage. Also, some patients showed worse progressive disability.

These findings “revealed conflicting outcomes,” the researchers wrote, adding that, as such, “careful monitoring and more research are necessary to fully understand the risks and benefits of this treatment option for PMS.”

Based on our findings, [Ocrevus] is the most efficient monoclonal antibody for [PPMS], although it is associated with a higher risk of infection.

Overall, according to the team, Ocreveus proved to be the most effective of the four antibody-based treatments for people with primary progressive MS.

“Based on our findings, [Ocrevus] is the most efficient monoclonal antibody for [PPMS], although it is associated with a higher risk of infection,” the researchers concluded, adding, however, “While other monoclonal antibodies did not show significant promise in treating PMS, more research is necessary.”