Jeffrey A. Cohen, P. Tesar
Dec 2, 2017
Citations
0
Influential Citations
10
Citations
Quality indicators
Journal
The Lancet
Abstract
The regulatory approval of 15 disease-modifying medications to reduce inflammatory lesion activity in relapsing multiple sclerosis illustrates the dramatic progress made in the treatment of this frequently disabling condition. None of these medications, however, directly promotes repair of the damaged CNS. As a result, therapies to prevent accumulation of permanent disability and, especially, to reverse preexisting disability represent major unmet needs. In The Lancet, Ari J Green and colleagues report the results of the ReBUILD trial, a double-blind, placebo-controlled, crossover phase 2 trial, which tested the antihistamine clemastine fumarate as a remyelinating drug. 50 patients with relapsing multiple sclerosis, mild neurological disability, and chronic optic neuropathy following optic neuritis were randomly assigned to receive oral clemastine fumarate 5·36 mg twice daily for 90 days followed by placebo for 60 days or placebo for 90 days followed by clemastine fumarate for 60 days. Clemastine fumarate treatment reduced visual-evoked potential (VEP) P100 latency, the primary outcome measure, by 1·7 msec/eye (95% CI 0·5 to 2·9; p=0·0048) in the preplanned analysis as a crossover trial and 3·2 ms/eye (1·8 to 4·7; p=0·0001) in a post-hoc analysis of the trial as a delayed-start design. The VEP results were supported by a trend for improvement in low-contrast letter acuity (LCLA) of 0·9 letters per eye (–0·1 to 1·9; p=0·085) in the preplanned crossover analysis and 1·6 letters per eye (0·2 to 3·0; p=0·022) in the post-hoc delayed-start analysis. MRI lesion analyses or several techniques, which have been proposed to measure myelin integrity (myelin water fraction, magnetisation transfer imaging, and diffusion tensor imaging), had no benefit. Clemastine fumerate treatment was associated with fatigue, an expected side-effect, but no serious adverse effects. Clemastine fumarate was identified as a potential remyelinating drug via high-throughput screening of drug libraries when looking for the ability to stimulate primary rodent oligodendrocyte progenitor cell (OPC) differentiation, extension of myelin membranes, and wrapping of micropillars in vitro. Clemastine fumarate was further evaluated by more clinically relevant testing to assess the ability to stimulate remyelination in rodent multiple sclerosis models in vivo and enhance the generation of oligodendrocytes from human OPCs in vitro. Other research groups used separate high-throughput screening assays with primary rat OPCs or pluripotent stem cell-derived OPCs and identified clemastine fumarate plus the muscarinic antagonist benzatropine and a functionally diverse array of additional candidates. The results of the ReBUILD trial validate the use of these approaches to identify candidate strategies to promote remyelination. Importantly, screening can include drugs for which there is previous knowledge in human beings and a known safety profile, allowing them potentially to be repurposed and thus accelerating their availability for clinical use. The positive results with clemastine fumarate in the ReBUILD trial were noteworthy. However, the average improvements detected by VEP and LCLA in this short trial were modest and probably not of a clinically meaningful magnitude. The clemastine fumarate dose tested in the trial was higher than that typically used in clinical practice to treat allergic symptoms. Longer treatment and further dose escalation might be difficult due to side-effects resulting from clemastine fumarate’s interaction with a variety of G-protein-coupled receptors. On the basis of their previous mechanistic studies in rodents, the investigators postulate that off-target antagonism of the muscarinic receptor by clemastine fumarate is responsible Published Online October 10, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)32639-9