Management of progressive MS with approved DMT

In an invited lecture, Prof. Xavier Montalban (Vall d’Hebron University Hospital, Spain) discussed the management of primary and secondary progressive MS (PPMS and SPMS) with approved disease-modifying treatment (DMT) highlighting their limitations and reasons they have failed [1]. For PPMS in particular, current treatment options are limited to ocrelizumab, but the ongoing trials were discussed.

Drugs considered for active SPMS in the 2018 ECTRIMS/EAN MS treatment guidelines are interferon-1a or -1b, taking into account the dubious efficacy as well as the safety and tolerability profile [2]. Other options mentioned for active SPMS are mitoxantrone, ocrelizumab, or cladribine. Possible additions to this list are siponimod and ozanimod, which were recently approved for relapsing MS, and ofatumumab, which was approved for active SPMS (among others) by the FDA in August 2020.

For PPMS, only 1 DMT has been approved specifically, which is ocrelizumab. Prof. Montalban pointed out several reasons why drugs fail in PPMS trials. First, pathogenic mechanisms in the progressive phase are completely different from the relapsing phase. Second, patient populations included in PPMS trials are generally not appropriate. Third, generally used clinical outcome measures are not sensitive enough, meaning clinical trials are not “smart” enough to detect PPMS worsening over a relatively short time span. Among drugs that failed to show any effect on PPMS are fingolimod and glatiramer acetate.

Natalizumab could have a role in the treatment of SPMS “for specific cases of very active disease,” according to Prof. Montalban. In the phase 3 trial ASCEND, natalizumab did not reduce progression on the primary multicomponent disability endpoint over 2 years, but it did reduce progression on its upper limb component, the 9-Hole Peg Test (9-HPT) [3]. Siponimod is an example of an MS drug showing some efficacy in SPMS patients who have a particular profile. Response is better in patients with prior relapses, rapidly evolving disease, active baseline MRI, younger age, shorter disease duration, no prior treatment, and a lower EDSS score [4].

More DMTs have been tested in SPMS in the past decade, ranging from interferon-β to agents that are not registered for any form of MS. For example, MD1003 (biotin) showed very positive results that could, unfortunately, not be replicated in a second pivotal phase 3 trial [5,6]. A phase 3 trial of high-dose simvastatin in SPMS (n=1,180) is ongoing. A potentially promising therapy in both PPMS and SPMS is ibudilast [7]. The potential benefit of opicinumab is less clear [8]; an additional phase 2b trial is underway. Clemastine showed short-term improvement in visual evoked potentials [9], but the clinical relevance of these results is as yet unclear. Amiloride, fluoxetine, and riluzole yielded basically negative results in the MS-SMART study [10]. Lipoic acid showed a “very important” 68% reduction in annualised percent change brain volume [11], but these results have to be replicated in a larger trial.

Prof. Montalban stressed that a major complicating factor in treating progressive MS is the lack of consensus on the definition of treatment failure. In active progressive MS, is it persistence of relapses, or disability worsening? In non-active PPMS, is it disability worsening and/or appearance of relapses? How long should the time on treatment be when evaluating efficacy? Can only improvement be considered as proof of efficacy? All these questions are still waiting to be answered.

1. Montalban X, et al. Management of Progressive MS with Approved DMT. MSVirtual 2020, Abstract PS05.02.
2. Montalban X, et al. Mult Scler. 2018;24(2):96-120.
3. Kapoor R, et al. Lancet Neurol. 2018;17(5):405-15.
4. Kappos L, et al. Lancet. 2018;391(10127):1263-73.
5. Tourbah A, et al. Mult Scler. 2016;22(13):1719-1731.
6. Coulome L, et al. Mult Scler. 2019;1352458519894713.
7. Fox RJ, et al. N Engl J Med. 2018 Aug 30;379(9):846-855.
8. Cadavid D, et al. Lancet Neurol. 2019 Sep;18(9):845-856.
9. Moghaddasi M, et al. Clin Neurol Neurosurg. 2020 Jun;193:105741.
10. Connick P, et al. BMJ Open. 2018 Aug 30;8(8):e021944.
11. Spain R, et al. Neurol Neuroimmunol Neuroinflamm. 2017 Jun 28;4(5):e374.

 

Posted on 25 November, 2020