Significant Associations Identified Between MRI Biomarkers and Clinical Functions in MS

Ritobrato Datta, PhD

A recent analysis of the phase 3 OPTIMUM study (NCT02425644) investigating 20 g of ponesimod (Ponvory; Janssen) showed significant associations between MRI features at baseline and clinical functions such as upper limb dexterity, mobility, cognition, and disability but not fatigue, supporting the relevance of MRI biomarkers in multiple sclerosis (MS).¹

At the conclusion of the analysis, all the clinical scales used were significantly associated with the MRI features except for Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS)(P <0.01). Notably, the most significant associations with MRI features were observed in 9-Hole Peg Text (9-HPT), Multiple Sclerosis Functional Composite (MSFC) and Symbol Digit Modalities Test (SDMT).

Presented at the 9th Congress of the European Academy of Neurology, held July 1-4, in Budapest, Hungary, lead author Ritobrato Datta, PhD, principal scientist, Janssen Research & Development at Johnson and Johnson, and colleagues had patients assigned randomly into 2 groups, A (n = 427) and B (n = 428). In the analysis, each patient’s MRI feature set consisted of 1010 measures at baseline and week 108 while clinical assessments comprised of the FSIQ-RMS, timed 25-foot walk (T25FW), SDMT, paced auditory serial-addition test (PASAT), Expanded Disability Status Scale (EDSS), MSFC, and 9-HPT.

All told, the data from baseline data in group A was “used to derive regression models for each of the clinical scales as a function of the first 3 principal components of each MRI feature group including volume, myelination, and tract damage,” the authors wrote. Additionally, resultant models were tested on data from group B at baseline, group A at week 108, and B at week 108. In both groups A and B, the amount of variance (r2) in the clinical scale explained by the MRI features were 0.1-0.33 at baseline and 0.01-0.27 at week 108, with no association observed between change in MRI features and change in clinical scores.

In the original OPTIMUM trial, 1133 patients with MS were randomly assigned 1:1 to 20 mg of ponesimod or 14 mg of teriflunomide (Aubagio; Sanofi) once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg, and were assessed at a follow-up period of 30 days. Originally reported in early 2021, the study’s main finding showed that ponesimod reduced annualized relapse rate (ARR) by 30.5% relative to teriflunomide.

Secondary end points such as the FSIQ-RMS was lower for fatigue symptoms in the ponesimod group than in the teriflunomide group at week 108, with least square means of 0.01 vs 3.56 (P = .002). In addition, treatment with ponesimod was associated with a 56% reduction in the cumulative number of combined unique active lesions (P <.001). The most common adverse events (AEs) recorded in OPTIMUM were nasopharyngitis, headache, upper respiratory tract infections, and an increase in alanine aminotransferase.

In March 2021, the FDA approved ponesimod for the treatment of adults with relapsing MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.² Ponesimod was developed to inhibit lymphocytes from leaving lymph nodes, thus rapidly reducing circulating blood lymphocyte counts and preventing the infiltration of lymphocytes into the targeted tissues.

The MS therapy is also being assessed in the ongoing phase 3 POINT trial (NCT02907177), which is comparing the S1P modulator in a 20-mg dose in measurements of efficacy, safety, and tolerability compared who placebo in those with MS who are currently being treated with twice-daily dimethyl fumarate (Tecfidera, Biogen).

The primary outcome of POINT is the confirmed relapses per subject-year as compared to placebo. Secondary end points include confirmed disability accumulation, time to first confirmed relapse, combined unique active lesions per post-baseline scan, longitudinal change over time in fatigue-related symptoms, and longitudinal percent change from baseline over time in brain volume.

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REFERENCES
1. Datta R, Wang T, Turkoz I, et al. MRI Biomarkers in Multiple Sclerosis are Associated with Clinical Scales: Results from the Phase-3 OPTIMUM Study. Presented at: EAN 2023. July 1-4, 2019; Budapest, Hungary. EPR-094.
2. Janssen Announces U.S. FDA Approval of PONVORY™ (ponesimod), an Oral Treatment for Adults with Relapsing Multiple Sclerosis Proven Superior to Aubagio® (teriflunomide) in Reducing Annual Relapses and Brain Lesions. News release. March 19, 2021. Accessed July 5, 2023.https://www.prnewswire.com/news-releases/janssen-announces-us-fda-approval-of-ponvory-ponesimod-an-oral-treatment-for-adults-with-relapsing-multiple-sclerosis-proven-superior-to-aubagio-teriflunomide-in-reducing-annual-relapses-and-brain-lesions-301250985.html