Another successful remyelination study: is progress in MS unstoppable? #MSBlog #ResearchSpeak
One of the big questions out there is how do we do remyelination and repair/neurorestorative trials? In phase 2, or early proof-of-concept, remyelination studies we have tended to rely on the optic nerve and an improvement in conduction speed using the so called visual evoked potential. Another strategy is anatomical and to study individual lesions with an MRI, or imaging, technique called MTR. MTR, or magnetization transfer ratio, is one technique that can be used to detect changes in the structural status of brain parenchyma that may, or may, not be visible with standard MR techniques. Use of MTR allow subcategorization of multiple sclerosis lesions into those with very low MTR (demyelinated lesions) and slightly decreased MTR (oedematous lesions) and it can show how these lesions evolve over time. If the a lesion with a low MTR improves over time this would indicate that it has been remyelinated.
In this proof-of-concept study below, of a novel compound that works by blocking histamine H3 receptors, the investigators show a small, but signficant improvement, in lesions in pwMS treated with the H3-blocker, compared to those treated with placebo. This trial therefore shows that H3-blockade using GSK239512 is able to improve the MTR of demyelinated MS lesions; the interpretation being that this drug may be be an effective remyelination therapy in MS.
Where to from here? Now that is the question we are trying to answer. As you are aware when Biogen moved from optic neuritis to MS with opicinumab, their anti-lingo-1 antibody, into a larger add-on phase 2b study the results were negative. Can we learn something from the negative opicinumab study? Yes, I am sure we can and let’s hope Biogen publish their results soon. In a similar way that not all people respond to certain drugs, not all pwMS with disabilities will have reversible disabiities as a result of demyelinated lesions. Some disabilities will be fixed due to axonal loss and not modfiable with remyelination. We are therefore going to have work out who is more likely to respond to a remyelination therapy and who is not. We simply don’t want to include the latter people in clinical trials as they won’t respond or be informative. Remyelination therapy may finally bring precision medicine to MS.
Background: Histamine H3 receptor blockade may enhance lesion remyelination in multiple sclerosis (MS).
Objective: The efficacy (using a magnetic resonance imaging marker of myelination, magnetisation transfer ratio [MTR]), safety and pharmacokinetics of GSK239512, a potent and brain penetrant H3 receptor antagonist/inverse agonist on lesion remyelination in relapsing-remitting MS (RRMS) were assessed.
Methods: This was a phase II, randomised, parallel-group, placebo-controlled, double-blind (sponsor-unblinded), international, multicentre study (NCT01772199). Patients aged 18-50 with RRMS, receiving intramuscular interferon-β1a or glatiramer acetate, were randomised 1:1 to once-daily oral GSK239512 or placebo, up-titrated over 4-5 weeks to a maximum tolerable dose up to 80 µg and maintained until Week 48. The co-primary endpoints were mean changes in post-lesion MTR in gadolinium-enhanced (GdE) or Delta-MTR defined lesions from pre-lesion values. Adverse events (AE) and withdrawals were monitored.
Results: Of the 131 patients randomised, 114 patients completed the study (GSK239512, n = 51; placebo, n = 63) and 27 (GSK239512) and 28 (placebo) patients contributed lesions to the primary analysis. GSK239512 was associated with positive effect sizes of 0.344 [90% confidence interval (CI) 0.018, 0.671] and 0.243 (90% CI -0.112, 0.598) for adjusted mean changes in the normalised MTR for GdE and Delta-MTR lesions, respectively. The overall incidence of AEs was similar between GSK239512 and placebo during the treatment phase although some AEs including insomnia were more common with GSK239512, particularly during the titration period.
Conclusions: A small but positive effect of GSK239512 on remyelination was observed. MTR assessment represents a promising method for detecting lesion remyelination in RRMS.