Ways to Align Patient Characteristics of Progressive Multiple Sclerosis Trials With Clinical Reality: Robert J. Fox, MD

WATCH TIME: 2 minutes

"The lower proportion of patients with gadolinium enhancing lesions in the CALLIPER trial compared [with] other progressive MS trials actually is closer to what we see in practice than those other previous progressive MS trials."

Research indicates that progressive multiple sclerosis (MS) leads to continuous neurological disability, with few treatment options available. Prominent clinical trials, including ORATORIO (NCT01194570), EXPAND (NCT01665144), MS-STAT2 (NCT03387670), and HERCULES (NCT04411641), have investigated therapies for progressive forms of MS. The CALLIPER trial (NCT05054140), a phase 2, randomized, placebo-controlled study, is examining vidofludimus calcium, a selective DHODH inhibitor and Nurr1 activator, for its potential neuroprotective effects in secondary progressive MS (SPMS) and primary progressive MS (PPMS).

At the 2025 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, held from February 27 to March 1 in West Palm Beach, Florida, lead author Robert J. Fox, MD, a staff neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic, presented an analysis comparing baseline characteristics of patients in the CALLIPER trial with those from other major MS trials to understand how these differences may impact outcomes. Overall, the CALLIPER trial enrolled 278 patients, 59.5% of whom were diagnosed with nonactive SPMS, 7.9% with active SPMS, and 35.2% with PPMS.¹

Although baseline characteristics such as age, sex, and EDSS scores were similar across trials, differences in focal inflammation were observed, with fewer CALLIPER patients showing gadolinium-enhancing (Gd+) lesions compared with other trials. Specifically, 17.8% of CALLIPER’s patients with PPMS had Gd+ lesions, compared with 26.5% in ORATORIO, and 6.8% of patients with nonactive SPMS had Gd+ lesions, compared with12.6% in HERCULES. These findings suggest that vidofludimus calcium may target compartmentalized CNS pathology, which could affect disability progression. Topline results from the study, as noted by the authors, are expected in April 2025.

In a recent interview with NeurologyLive^®, Fox elaborated on the potential implications of the CALIPER trial's findings for the design of future trials in progressive MS. He discussed how the trial’s results might influence patient selection criteria, emphasizing the importance of aligning trial populations with the clinical realities seen in practice. Fox also highlighted key factors to consider when evaluating the effectiveness of therapies for progressive MS, such as the specific mechanisms of action of different treatments. He pointed out that the diverse mechanisms, like those of DHODH inhibitors and BTK inhibitors, could shape how trial results are interpreted, suggesting that lessons learned from one class of therapy may not be universally applicable to others without direct evidence supporting such conclusions.

Click here for coverage of 2025 ACTRIMS Forum.

REFERENCES
1. Fox R, Sciacca V, Wolf C, et al. Baseline Characteristics Across Major Clinical Trials in Progressive Multiple Sclerosis: Insights from ORATORIO, EXPAND, MS-STAT2, HERCULES, and CALLIPER. Presented at ACTRIMS Forum 2025; February 27 to March 1; West Palm Beach, Florida. P102.