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Multiple Changes in NSMOD Treatment Tied to Poorer Outcomes

Multiple treatment transitions in patients with neuromyelitis optica spectrum disorder (NMOSD) for nonmedical reasons are associated with increased neurological harm, including relapse risk and disease progression, new research shows.

“For the first time, we were able to quantify clinical outcomes associated with treatment transitions in people with NMOSD. Our data highlight that aspects outside of therapeutic efficacy may be remarkably meaningful in the effective suppression of disease advancement,” senior investigator Darin T. Okuda, MD, professor of neurology and director of the neuroinnovation program at University of Texas Southwestern Medical Center in Dallas, told Medscape Medical News.

The findings were presented at the Consortium of Multiple Sclerosis Centers (CMSC) 2023 Annual Meeting.

Treatment Delayed?

NMOSD, an inflammatory syndrome of the central nervous system, can cause irreversible disability. As treatments have improved over time, transitioning from one medication to newer options has become increasingly common.

To better understand the effects of multiple treatment transitions, the researchers conducted a retrospective analysis of electronic medical records of 164 patients with aquaporin-4 IgG-positive NMOSD. Of these individuals, 89 met the study’s inclusion criteria.

Of the participants, 89% were female and the median disease duration was 10.1 years. Forty-two patients had switched therapies at least once; 26 switched at least twice; 12 switched at least three times; six switched four times; and three switched therapies five times or more for a total of 174 treatment transitions.

Patients were stratified into two groups — those who transitioned for medical reasons (53.4%), and those who switched because of nonmedical/tolerability reasons (46.6%).

Top reasons for transitioning in the medical category included clinical relapse and/or new MRI activity (29.9%), physician-directed transition (11.5%), and increased physical or clinical disability (4.0%). Leading reasons for nonmedical transitions were side effects (16.7%), adherence/persistence (8.1%), and cost/access (5.75%).

A recurrent event survival analysis showed that after just one transition for nonmedical or tolerability reasons, outcomes significantly improved, with the risk of hospitalization decreasing 40.3% (P = .005), the risk of relapse decreasing by 53.1% (P = .002), and the risk of advancement on MRI decreasing by 65.9% (P = .005).

Conversely, each additional drug discontinuation in the nonmedical group was associated with worse outcomes. These included a 25.2% increased risk of hospitalization (P = .0003), a 24.4% increase in relapse risk (P = .06), and a 41.9% increased risk of MRI advancement (P = .03).

In terms of transitions for medical reasons, there was a significantly increased risk of MRI advancement with the first switch (32.2%; P = .005). However, no significant increases in risk were associated with each additional transition (P = .33).

The median time spent on the first treatment was 306 days in the transition for medical reasons group and 378 days for the nonmedical/tolerability group.

The median duration of time spent between treatments during the initial transition was just 7 days among those transitioning for medical reasons vs 91 days for nonmedical reasons, with the median duration of additional transitions also substantially longer in the nonmedical reasons group, at 22 and 80 days, respectively.

“The median time spent on a first-line therapy regardless of [whether] that first transition was due to a medical or nonmedical tolerability reason was similar; however, the duration of that initial transition was 13 times longer if the transition had to do with a nonmedical or tolerability reason,” first author Alexander D. Smith, also of UT Southwestern Medical Center, told conference delegates.

“Similarly, each additional transition was almost four times longer if it had to do with a nonmedical or tolerability reason,” he said.

Okuda noted the longer window between treatment transitions may be a key factor in the different outcomes between the groups.

“A central theory involves the increased amount of time between treatments,” he told Medscape Medical News.

“The reasons for the delay in starting a new treatment may be related to a variety of factors, including laboratory testing required to start a new treatment, third-party administrator coverage, time for the resolution of adverse reactions, and/or personal factors from the individual undergoing treatment, etc.”

Another factor, Smith said in his talk, is that “when people are left miserable by a prior treatment exposure, they may simply be hesitant to get on the next therapy.”

The finding that only MRI advancement was associated with transitions due to medical reasons suggests that worsening disease activity is not necessarily behind increased transitions, with nonmedical reasons often the cause, and more likely to be associated with the worse outcomes.

With the time between treatments a possible culprit, Okuda said the clinical implications are that “treatment transitions, regardless of the reason, should occur as quickly as possible to reduce the risk for disease progression associated with NMOSD.”

Smith echoed the suggestion, adding that “it’s important that even if disease activity is not present, complacency should be avoided.”

“Clinicians and third-party administrators should work to ensure that people with NMOSD have accelerated switches on to their next therapy, even if that disease activity is not present. In a sense, rapid treatment transitions may have equitable benefits to the treatments themselves,” Smith added.

Important Research

Commenting on the study for Medscape Medical News, Shailee Shah, MD, an assistant professor in the Neuroimmunology Division at Vanderbilt University Medical Center, in Nashville, Tennessee, noted the findings are consistent with generally higher concerns around switching treatments for nonmedical reasons.

“In general, if a high-efficacy medication is started, it appears that patients are less likely to require a transition to a different medication. It is a little harder to predict who may have issues with tolerability or nonmedical reasons to transition medications, and many providers would likely agree that these transitions do raise some concerns about the risk of relapse or hospitalization in the interim,” she said.

Shah added that in her experience, patients who require multiple transitions are either started on lower-efficacy medications at treatment initiation or have highly refractory disease.

The study’s findings underscore that “identifying additional risk factors and underlying reasons for these findings will be imperative in the future,” Shah said.

The study was supported by Revert Health Inc., a corporation founded by Okuda. Okuda reports receiving personal compensation for consulting and advisory services from Alexion, Biogen, Celgene/Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Janssen Pharmaceuticals, Novartis, Osmotica Pharmaceuticals, RVL Pharmaceuticals, Inc., TG Therapeutics, Viela Bio, Inc., and research support from Biogen, EMD Serono/Merck, and Novartis. Shah reports that she has served on advisory boards for Horizon, Alexion, and Genentech.

Consortium of Multiple Sclerosis Centers (CMSC) 2023 Annual Meeting. Abstract #DMX01. Presented June 1, 2023.

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