Pharmacological Approaches to the Management of Secondary Progressive Multiple Sclerosis

Abstract

It is well recognised that the majority of the impact of multiple sclerosis (MS), both personal and societal, arises in the progressive phase where disability accumulates inexorably. As such, progressive MS (PMS) has been the target of pharmacological therapies for many years. However, there are no current licensed treatments for PMS. This stands in marked contrast to relapsing remitting MS (RRMS) where trials have resulted in numerous licensed therapies. PMS has proven to be a more difficult challenge compared to RRMS and this review focuses on secondary progressive MS (SPMS), where relapses occur before the onset of gradual, irreversible disability, and not primary progressive MS where disability accumulation occurs without prior relapses. Although there are similarities between the two forms, in both cases pinpointing when PMS starts is difficult in a condition in which disability can vary from day to day. There is also an overlap between the pathology of relapsing and progressive MS and this has contributed to the lack of well-defined outcomes, both surrogates and clinically relevant outcomes in PMS. In this review, we used the search term 'randomised controlled clinical drug trials in secondary progressive MS' in publications since 1988 together with recently completed trials where results were available. We found 34 trials involving 21 different molecules, of which 38% were successful in reaching their primary outcome. In general, the trials were well designed (e.g. double blind) with sample sizes ranging from 35 to 1949 subjects. The majority were parallel group, but there were also multi-arm and multidose trials as well as the more recent use of adaptive designs. The disability outcome most commonly used was the Expanded Disability Status Scale (EDSS) in all phases, but also magnetic resonance imaging (MRI)-measured brain atrophy has been utilised as a surrogate endpoint in phase II studies. The majority of the treatments tested in SPMS over the years were initially successful in RRMS. This has a number of implications in terms of targeting SPMS, but principally implies that the optimal strategy to target SPMS is to utilise the prodrome of relapses to initiate a therapy that will aim to both prevent progression and slow its accumulation. This approach is in agreement with the early targeting of MS but requires treatments that are both effective and safe if it is to be used before disability is a major problem. Recent successes will hopefully result in the first licensed therapy for PMS and enable us to test this approach.

Antibody signatures in patients with histopathologically defined multiple sclerosis patterns

“…Also, the question of whether an increased risk of MS is associated with varicella and zoster infections remains under discussion [45,46,66]. Pattern III lesions are characterized by an oligodendrocyte apoptosis [42], which together with neurons are target cells for VZV infection within the CNS [33,55]. However, we did not find clinical or histological evidence of VZV infection in pattern III lesions.…”

Phenotypic and functional alterations of myeloid‐derived suppressor cells during the disease course of multiple sclerosis

“…With time, most patients’ progress to secondary progressive MS (SPMS) associated with the predominance of neurodegeneration and accumulation of physical and cognitive disability . Mechanisms regulating transition from RRMS to SPMS are poorly understood and current immunomodulatory treatments for MS have a limited effect on disability progression in SPMS …”

“…2 Mechanisms regulating transition from RRMS to SPMS are poorly understood and current immunomodulatory treatments for MS have a limited effect on disability progression in SPMS. 3 Myeloid-derived suppressor cells (MDSCs) have emerged as a new immune cell population with important immunoregulatory functions. 4 In the murine system, MDSCs are defined as cells expressing the myeloid cell lineage differentiation antigen Gr-1 and are further subdivided according to expression levels of the epitopes Ly-6G and Ly6C.…”

Blinded sample size reestimation in event‐driven clinical trials: Methods and an application in multiple sclerosis

“…It is the most common neurological disorder in younger adults affecting up to 2.5 million people worldwide . While for the earlier stages (relapsing‐remitting MS), a variety of treatment options are available now, there is a high unmet medical need for the later stages of the disease, namely secondary progressive MS (SPMS), although a number of attempts have been undertaken over the past decades to develop an efficacious treatment for SPMS . Siponimod (BAF312) is a selective sphingosine 1‐phosphate receptor modulator, which is a similar drug class as fingolimod.…”