Natalizumab Switch to Moderate-Efficacy DMT Increases Disability Risk

Nancy A. Melville

May 27, 2020

Patients with relapsing multiple sclerosis (MS) who switch from treatment with the highly effective disease-modifying therapy (DMT) natalizumab (Tysabri, Biogen) to a moderate-efficacy DMT show an increased risk of disability accumulation and disease activity over 2 years compared with switching to another highly effective DMT, new research shows.

"Owing to the vast number of available DMTs, not only understanding DMT performance but answering the question of what can come next if a patient needs to discontinue treatment due to safety or breakthrough disease is important," first author Carrie M. Hersh, DO, of the Lou Ruvo Center for Brain Health, Cleveland Clinic, in Las Vegas, Nevada, told Medscape Medical News.

The study shows that, "patients transitioning from natalizumab to another high-efficacy therapy have better inflammatory and disability outcomes compared to those who de-escalate their therapy to a moderate-efficacy DMT," she said.

Natalizumab offers significant benefits in the treatment of relapsing forms of MS, however, its long-term use is associated with safety concerns, notably an increased risk of progressive multifocal leukoencephalopathy (PML).

Although the risk can be reduced with a switch to a different DMT, the transition can have risks of its own, including a rebound of disease activity that could prove to be worse than the pre-natalizumab treatment period, and there is a lack of consensus on the safest avenues for switching to another DMT following discontinuation of natalizumab.

In research presented as part of the 2020 Virtual Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC), Hersh and colleagues explored the issue in a real-world population of 556 patients discontinuing natalizumab at two MS centers.

Of these, 270 switched to a moderate DMT (dimethyl fumarate, n = 130; or fingolimod, n = 140) and 130 switched to a highly effective DMT (ocrelizumab, n = 106; rituximab, n = 17; or alemtuzumab, n = 7).

Reasons for switching included a PML risk for 54.9%, breakthrough disease for 15.3%, and adverse effects for 17.3%.

At 24-month follow-up after the switch and after adjustment for propensity score matching, no differences were seen between the moderate and highly effective DMT groups in terms of the annualized relapse rate (ARR; P = .33) or the time to first relapse (P = .09).

However, significantly higher proportions of patients switching to moderate DMTs showed new T2 lesions (odds ratio [OR], 2.15; P = .01), as well as new gadolinium-enhancing lesions (OR, 1.99; P = .02), and a 20% worsening of the timed 25-foot walk test (T25FW; OR, 1.83; P = .04) and 9-hole peg test (9-HPT; OR, 1.81; P = .04)

Those switching to moderate DMTs also had significantly lower rates of absence of disease activity over the 24 months (OR, 0.41, P = .004), and they had a higher risk of earlier time-to-first gadolinium-enhancing lesion (hazard ratio [HR], 6.67, P = .002) compared with those switching to a high-efficacy DMT.

Other factors that have previously been shown to be associated with rebounds that are worse than pre-natalizumab treatment include washout periods that are longer than 3 months.

The authors note that there were no significant differences between the groups in terms of mean washout duration, which were relatively short (moderate DMT = 1.4 months, highly effective treatment = 1.8 months; P = .34),

In addition, there were no significant differences between the groups in terms of the average duration of natalizumab treatment.

Hersh speculated that the lack of ARR differences may reflect that the measure is not as objective as the more specific determinants of performance.

"One could consider the comparable ARR as a little surprising, but relapse evaluation in a retrospective manner is limited," she explained.

"Historically, radiographic markers of new inflammation via brain magnetic resonance imaging (MRI) and neuroperformance measures (T25FW and 9-HPT) are more objective compared to assessing clinical relapses, especially in a retrospective cohort where relapses cannot be validated by a central agency or the principal investigator.

"Therefore, one can surmise that patients transitioning from natalizumab to another high-efficacy DMT fare better than de-escalating treatment to a moderate-efficacy DMT."

Hersh and her team plan a larger, multicenter study to investigate the short- and long-term effects of post-natalizumab DMT sequencing to help validate the current findings.

Commenting on the research, Stephen Kamin, MD, professor, vice chair and chief of service, Department of Neurology, Rutgers New Jersey Medical School in Newark, said the results are consistent with natalizumab's general profile.

"In general, natalizumab has been used in patients with highly active disease, so I would expect fewer patients with no evidence of disease activity when switched to a moderately active drug rather than a highly active one," he told Medscape Medical News.

Caveats of the findings include the trial's observational nature, meaning potential confounding factors of baseline characteristics among patients who switched regimens are not known, noted Kamin, who was not involved with the study.

"Also, the patients were switched to a variety of drugs and even within a class there may be differences in outcome," he explained.

Hersh reported consulting or research relationships with Biogen, Genentech, EMD Serono, Genzyme, Novartis, and PCORI. Kamin has received research support from Biogen, Novartis, and CMSC.

2020 Virtual Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC): Abstract #DMT01.

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