No remyelinating effects of bazedoxifene in postmenopausal MS patients

In the placebo-controlled phase 2 ReWRap trial, bazedoxifene failed to demonstrate remyelinating effects in postmenopausal women with relapsing MS (RMS). The treatment was well tolerated, but no primary or secondary endpoints were met. Nonetheless, the findings provide important insights for the design of future remyelinating trials.

Therapeutic strategies capable of slowing down or potentially reversing immune-mediated demyelination in MS remain a major unmet need in MS. Dr Riley Bove (University of California San Francisco, CA, USA) noted that most remyelination trials in MS have raised more questions than answers, particularly regarding optimal molecule selection, target population, study design, and outcome measures [1]. “Two molecules have demonstrated a signal consistent with remyelination: clemastine [2] and bexarotene [3]. There is a need for more remyelinating treatments that are tolerable and have different mechanisms of action.”

Bazedoxifene, a selective oestrogen receptor modulator (SERM), was investigated as a candidate remyelinating therapy. Given its regulatory approval for postmenopausal osteoporosis, postmenopausal women with MS were selected as the target population.

ReWRap (NCT04002934) was a double-blind phase 2 trial enrolling ambulatory women aged 45–60 years (>40 if postmenopausal) with RMS of less than 25 years’ duration and an Expanded Disability Status Scale (EDSS) score of 0–6. Participants were randomised to either 6 months of bazedoxifene 40 mg daily (early-start group; n=33) or 3 months of placebo followed by 3 months of bazedoxifene (delayed-start group; n=33). The primary endpoint was the change in myelin water fraction (MWF) within the corpus callosum on MRI, a quantitative biomarker of myelin content.

No significant between-group differences in MWF were observed at 3 or 6 months. Similarly, changes in the Multiple Sclerosis Functional Composite (MSFC) score did not differ between groups. Study retention and completion rates were high (91.3%). No clinical relapses or new gadolinium-enhancing (Gd+) T2 lesions were recorded during the study period. Adverse events were comparable between groups, and no severe adverse events were reported.

In retrospect, Dr Bove suggested that future studies of SERMs in MS might consider enrolling younger patients (e.g., 45–50 years) and limiting treatment duration to 1 year. She also proposed that combining bazedoxifene with metformin could enhance remyelination by promoting responsiveness of oligodendrocyte precursor cells (OPCs).

Bove R, et al. ReWrap: A phase II delayed start myelin repair RCT. LB1.1, ACTRIMS Congress 2026, 4–7 February, San Diego, California, USA.
Green AJ, et al. Lancet. 2017;390(10111):2481-2489.
Brown WL, et al. Lancet Neurol. 2021;20(9):709-720.