Off-label DMT Use for Progressive MS May Be as Effective as On-label

'Small' difference in disability worsening at 2 years seen across 5 trials

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Off-label use of high-efficacy disease modifying therapies (DMTs) for people with progressive forms of multiple sclerosis (MS) appear to be as effective as on-label, or approved, DMTs for this MS patient group, a review study from Brazil suggests.

The meta-analysis, which included data from controlled clinical trials, found that rates of disability worsening after two years were similar among patients using on- or off-label treatments when compared with those given a placebo.

“The use of these off-label drugs may be a cost-reducing strategy to improve access to immunotherapy,” the researchers wrote, noting that the two DMTs approved for progressive MS are often not available to patients in low- and medium-income countries.

The study, “Is there a role for off-label high-efficacy disease-modifying drugs in progressive multiple sclerosis? A network meta-analysis,” was published in Acta Neurologica Scandinavica

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Progressive forms of MS — primary progressive MS (PPMS) and secondary progressive MS (SPMS) — are characterized by continuous symptom worsening and have proven more difficult to treat.

Many high-efficacy DMTs that have emerged in recent years are designed to treat relapsing MS types. Only two high-efficacy DMTs are approved for progressive forms of MS: Mayzent (siponimod) and Ocrevus (ocrelizumab).

Access can be an issue for 2 approved progressive MS DMTs

Novartis’ Mayzent is approved in the U.S., Europe, Canada, Australia, and several other countries for adults with active SPMS, characterized by the presence of relapses or brain lesions with active inflammation. Genentech’s Ocrevus is the only DMT for PPMS, approved in the U.S., Europe, and various other countries.

Still, “in clinical practice, access to these drugs for patients with primary progressive and secondary progressive MS is difficult,” the researchers wrote. “Furthermore, in some countries, being labeled as having progressive MS requires the cessation of DMDs use.”

Off-label use of other high-efficacy DMTs may offer a way of lowering treatment costs and increasing access for these patients, but the effectiveness of such treatments — relative to on-label options — has not been directly evaluated in appropriately controlled clinical trials.

Researchers at the University of São Paulo retrospectively analyzed published studies up to December 2021 reporting results of controlled trials comparing a high-efficacy DMT against a placebo in people with a form of progressive MS.

The final meta-analysis included five studies, each testing one of five high-efficacy DMTs: on-label Mayzent or Ocrevus, and off-label rituximab, Gilenya (fingolimod), or Tysabri (natalizumab). Gilenya and Tysabri are approved to treat active SPMS in the U.S., but not in Europe and other countries, including Brazil.

While each of the five DMTs have distinct modes of administration and mechanisms of action, all work, one way or another, by modulating the immune system. This is expected to suppress the abnormal immune responses that drive inflammation and neurodegeneration in MS.

These studies involved 4,526 progressive MS patients: 2,654 who received a DMT and 1,872 who were given a placebo. Mayzent and Tysabri were tested in SPMS patients, whereas Ocrevus, Gilenya, and rituximab were evaluated in PPMS.

The researchers’ main goal was to establish the effects of these on- or off-label therapies on three-month confirmed disability progression, as measured by the expanded disability status scale, after two years of treatment.

‘Similar effect on disability progression at 2 years’

Results showed that across all studies, 30% of patients given a DMT experienced a confirmed disability worsening, compared with 35% of those in placebo groups.

A median of 29% of progressive patients receiving on-label DMTs — Ocrevus and Mayzent — experienced confirmed disease progression compared with 33% of those in their corresponding placebo groups.

With off-label DMTs, 36% of treated patients and 39% of their respective placebo groups showed confirmed disability worsening.

Overall, the effect of DMTs on confirmed disability worsening was “small,” the researchers noted. On- and off-label DMTs were associated with a similar effect on disability progression over a placebo.

These data “reinforce our hypothesis that on-label and off-label high-efficacy [DMTs] have a similar effect on disability progression at 2 years in patients with [progressive MS],” the researchers wrote.

Detecting similar benefits with DMTs with different modes of action suggests “the effect of progression is mainly driven by the control of chronic inflammation and not a specific mechanism of action of any drug,” the team added.

“Our findings provide reassurance to many neurologists in clinical practice in maintaining MS patients on treatment with high-efficacy [DMTs], including off-label drugs, even when they evolve to secondary progressive [forms] of the disease,” the researchers concluded.

The team noted, however, that these findings were based on indirect comparisons, and that future studies directly comparing different DMTs in progressive MS patients are needed to allow strong conclusions to be drawn.

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