Results of compounds in late stages of development

MD1003 (high-dose pharmaceutical-grade biotin) did not meet any of the primary or secondary endpoints in patients with progressive multiple sclerosis (MS) in the SPI2 trial [1]. There were positive phase 2b trial results of the Bruton’s tyrosine kinase (BTK) inhibitor SAR442168 [2], and positive phase 3 results of oral diroximel fumarate (DRF) [3].

In the SPI2 trial, 642 patients were randomised to MD1003 (n=326) or placebo (n=316) [1]. Of the participants, 64.6% had secondary progressive MS; mean Expanded Disability Status Scale (EDSS) was 5.4, mean Timed 25-Foot Walk (TW25) 11.6 seconds. The double-blind period was 15-27 months. The primary endpoint, the proportion of patients with improvement in EDSS or TW25 (>20%), was not significantly different. The rate of EDSS or TW25 responders was 12.0% in the MD1003 group versus 9.2% in the placebo group (OR 1.35; 95% CI 0.81-2.26). In a subgroup analysis, there was a trend favouring MD1003, but not a single subgroup for whom MD1003 was clearly beneficial. There were no differences in times to 12-week confirmed EDSS progression, clinical global impression after 15 months, or change from baseline in TW25. MD1003 was generally well tolerated. The annualised relapse rate was very low in both groups (0.0362 vs 0.0478). These results did not confirm the beneficial effect of MD1003 on MS disability previously reported in the phase 3 MS-SPI study.

SAR442168, a central nervous system (CNS)-penetrating BTK inhibitor, was well tolerated at a dose of 60 mg and effectively lowered MRI lesions in relapsing MS patients [2]. A total of 130 relapsing MS patients were enrolled in this phase 2b study, with a median EDSS score of 2.5 at baseline. After 12 weeks, a dose-response relationship was established. Compared with placebo, the 60-mg dose resulted in an 85% relative reduction in the number of new gadolinium+ lesions, as well as an 89% relative reduction in the number of new/enlarging T2 lesions. Exploratory endpoints in terms of effects on the CNS, potentially on microglia, were still under investigation and could not yet be shared. SAR442168 was well tolerated over 12 weeks, with 129/130 patients (99%) completing the core study. There were no early safety signals, and only one serious adverse event occurred, which was hospitalisation for an MS relapse. These positive results of the DRI15928 study support further development in phase 3 studies.

The ongoing, open-label phase 3 study EVOLVE-MS-1 evaluates long-term safety, tolerability, and treatment effect of oral DRF in adults with relapsing-remitting (RR)MS. Two-year efficacy outcomes were presented of patients who: A) had newly diagnosed RRMS (≤1 year since diagnosis and treatment-naïve; n=109), or B) were most recently treated with interferon-β or glatiramer acetate (n=327) [3]. Adjusted annualised relapse rate was 0.13 (95% CI 0.07-0.23) and 0.17 (95% CI 0.12-0.23) in group A and B, respectively: a reduction of 88.6% (95% CI 79.8-93.6; P<0.0001) and 73.2% (95% CI 63.1-80.6; P<0.0001) compared to the 12 months before study entry. Mean EDSS scores remained stable at week 96 compared to baseline: 2.00 (n=60) versus 2.02 (n=108) in group A and 2.55 (n=100) versus 2.64 (n=310) in group B. More patients were free of gadolinium+ lesion at week 96 compared to baseline: 86.9% versus 54.1% (n=61) in group A; 93.9% versus 78.6% (n=98) in group B.

1. Cree BAC, et al. Abstract O2033, EAN 2020.
2. Reich DS, et al. Abstract O4010, EAN 2020.
3. Jasińska E, et al. Abstract EPR2124, EAN 2020.