Brain Volume Loss Reductions Offer Comparative Tool for DMTs in Relapsing MS

Different disease-modifying therapies (DMTs) have differing impacts on brain volume loss in patients with relapsing multiple sclerosis (RMS), according to a new study.

The report shows how using brain volume loss as an end point can affect comparisons of DMTs, but it also highlights the need for more research into brain volume loss as a clinical trial end point.¹ The study was published in BMC Neurology.

People with multiple sclerosis (MS) have detectable brain volume loss even at the earliest stages of the disease, noted corresponding author Alexander J. Keenan, MA, of Janssen Pharmaceuticals, and colleagues.

People with multiple sclerosis have detectable brain volume loss even at the earliest stages of the disease. | Image Credit: © DedMityay - stock.adobe.com

“This marker of degeneration has been reliably correlated with future physical and cognitive disability, and has been suggested as a key mechanism by which disease-modifying therapies can prevent or delay disability progression,” they wrote.

For instance, a 2020 study evaluating outcomes in patients treated with teriflunomide (Aubagio) found patients with the least brain volume loss were less likely to have confirmed disability worsening at key timepoints compared with patients with the most brain volume loss.² The authors of that study suggested that brain volume loss might be a meaningful way to assess the efficacy of MS therapies.

Yet, while Keenan and colleagues said brain volume loss is now commonly assessed in phase 3 clinical trials, relatively little data has been published directly comparing how different DMTs affect brain volume loss.¹ They said the use of indirect treatment comparison methods can facilitate such comparisons using data from different clinical trials. In the new study, the investigators used 2 such methods, model-based meta-analysis and network meta-analysis, to see how different DMTs affected brain volume loss.

Keenan and colleagues identified 5 DMTs that significantly reduced brain volume loss at 2 years compared with placebo; however, the rates of reduction varied from therapy to therapy.

In the model-based meta-analysis, ponesimod (Ponvory) reduced brain volume loss by a mean difference (MD) of 0.71 (95% CI, 0.48-0.95); alemtuzumab (Lemtrada) reduced it by an MD of 0.38 (95% CI, 0.10-0.67); teriflunomide also had an MD of 0.38 (95% CI, 0.20-0.55); ozanimod (Zeposia) had an MD of 0.26 (95% CI, 0.12-0.41; and fingolimod (Gilenya) had an MD of 0.25 (95% CI, 0.15-0.36). The investigators said the network meta-analysis yielded similar findings.

“Across both analyses, the DMTs which significantly outperformed placebo included fingolimod, teriflunomide, and ponesimod, where the latter always ranked first,” they wrote.

Interferons and natalizumab (Tysabri) performed most poorly, the investigators said.

Keenan and colleagues said traditionally, lesion burden has been used as a surrogate marker for disease activity in RMS, but they said the link between that marker and clinical findings has been “weak to modest.”

“In contrast to lesion counts, BVL [brain volume loss] is a measure of whole-brain atrophy,” they wrote. “Notably, both lesion load and atrophy (including that of white matter and grey matter) have been correlated with disability status in MS.”

A report from 2013 found the effect of treatment on brain atrophy correlated with disability progression, independent of the effect of lesions.³

Considering the links between brain volume loss and disability, Keenan and colleagues argue a better understanding of the effect of particular therapies on brain volume loss may be helpful to clinicians and decisions-makers.¹

The investigators cautioned that there are inherent limitations to indirect treatment comparison analyses, such as heterogeneity across studies. There were also differences in how brain volume loss was measured across the time periods covered by the studies.

“Nevertheless, the differentiation of various DMTs substantiates the importance of evaluating BVL [brain volume loss] as a clinical endpoint in future trials, as a complement to traditional measures of disability,” they concluded.

References:

1. Zivadinov R, Keenan AJ, Le HH, et al. Brain volume loss in relapsing multiple sclerosis: indirect treatment comparisons of available disease-modifying therapies. BMC Neurol. 2024;24(1):378. doi:10.1186/s12883-024-03888-6
2. Sprenger T, Kappos L, Radue EW, et al. Association of brain volume loss and long-term disability outcomes in patients with multiple sclerosis treated with teriflunomide. Mult Scler. 2020;26(10):1207-1216. doi:10.1177/1352458519855722
3. Sormani MP, Arnold D, De Stefano N. Combined MRI measure of active lesions and brain atrophy as a surrogate for disability in multiple sclerosis: a meta-analysis of randomized trials (P07.096). Neurology. 2013;80(7_supplement). doi:10.1212/wnl.80.7_supplement.p07.096