How far away from having an effective treatment option for progressive multiple sclerosis are we?

KEYWORDS:

• Clinical trials
• multiple sclerosis
• primary progressive
• progression
• secondary progressive

1. Introduction

The availability of numerous disease-modifying drugs for relapsing-remitting (RR) multiple sclerosis (MS) is one of the greatest successes of the last 30 years of neurology history. Unfortunately, this story has a dark side, represented by progressive forms of the disease, still without an effective treatment. A total of 15% of MS patients show a progression form onset, while secondary progression is developed by about 80–90% of RR patients after long-standing disease. Clinical differences between primary progressive (PP) and secondary progressive (SP) forms are well known; nevertheless, these two entities share so many pathological mechanisms and characteristics [1] that seem warranted considering them as part of the same spectrum.

The prominence of neurodegeneration over inflammation, with microglial activation, chronic axonal demyelination mediated by oxidative injury, and axonal mitochondrial dysfunction, translates in high disability levels that have deep consequences on patients’ quality of life and give rise to significant familiar, social, and economic burden. It is easy to understand why finding an answer to such a disabling disease represents a priority for scientific community.

2. Past and present of clinical trials

In the last 30 years, many drugs have been unsuccessfully tested in phase II and III trials, with some exceptions [2,3]. Studies involving classical immunosuppressants, such as azathioprine, cyclophosphamide, and cyclosporine, reflected the first attempts to act on residual inflammatory aspects of the disease. In particular, the positive results of mitoxantrone trial for worsening RR MS and SP MS [4] offered a therapeutic option for transitional MS phases with signs of activity, without real impact on pure progression. It is important to point out safety issues, primarily related to cardiotoxicity and leukemic risk [5]. The most widely experimented medications have been borrowed from RR MS. Interferon-beta failed to demonstrate an effect on reducing Expanded Disability Status Scale (EDSS)-confirmed progression in SP patients, with only one positive trial [6] that differed from the others for enrolling a considerable percentage of patients with evidence of recent clinical or MRI disease activity. A favorable long-term outcome was not evident in the 10-year follow-up of the study [7]. Similarly, phase III trials of glatiramer acetate (PROMISE) [8] and fingolimod (INFORMS) [9] in PP patients were negative, as well as SP MS trials of MPB8298 (MAESTRO [10]) and natalizumab (ASCEND [11]). Rituximab, a chimeric anti-CD20 monoclonal antibody, demonstrated its efficacy on disability progression only in a subgroup of patients (≤51 years, with gadolinium-enhancing lesions at baseline) [12]. Acting on the same molecular target, the phase III ocrelizumab trial (ORATORIO) for PP MS met its primary end point, with an approximately 25% risk reduction of disability progression in treated patients versus placebo [13]. This study represents a milestone, being the first to prospect a possible treatment for a previously orphan disease subtype. GZ402668, a novel anti-CD-52 (NCT02977533), and dimethyl fumarate (NCT02959658) are currently under investigation. Encouraging results have been announced for the phase III placebo-controlled EXPAND study, where BAF312 (siponimod) demonstrated to reduce the risk of 3-month confirmed disability progression by more than 20% in treated SP MS patients [14]. Siponimod, a selective S1P1 and S1P5 receptor modulator, exerts its anti-inflammatory action by inhibiting the egress of lymphocytes from lymph nodes, but it is thought to also have direct effects within the central nervous system since it crosses the blood–brain barrier. In fact, there is much more than inflammation. Many neuroprotective and repair-promoting treatments have been proposed in order to contain and reverse neurodegenerative processes. High doses of biotin (a vitamin acting as a cofactor for carboxylases involved in cellular metabolism) have been hypothesized to support myelin repair and to reduce axonal degeneration. On this basis, a phase III trial has been conducted, which demonstrated a 12.6% of progressive treated patients improving in disability measures versus none in the placebo group [15], with limits represented by the relatively short observation (12 months) and the unusual primary end point. On the other hand, after positive results of the phase II trial, the CUPID study of dronabinol (a cannabinoid with postulated neuroprotective action) in PP and SP MS was negative, probably due to low progression rate of the placebo group [16]. Many other exciting phase II and III trials involving neuroprotective compounds have been planned or are currently ongoing [3,17]. In particular, the following compounds are under investigation: simvastatin (planned phase III trial after a positive phase II study); phenytoin and oxcarbazepine (NCT02104661); amiloride, riluzole, and fluoxetine (MS-SMART trial, with an adaptive design, NCT01910259); ibudilast (NCT01982942); erythropoietin (NCT01144117); idebenone (NCT01854359); lipoic acid (NCT01188811) [18]; masitinib (NCT01433497); the green tea major constituent epigallocatechin-3-gallate (NCT00799890); and more recently MIS416 (NCT02228213). Repair strategies are more challenging. After promising premises, anti-LINGO-1 phase II trial in RR MS did not reach it primary end point [19]; its efficacy still needs to be assessed in progressive MS. Prolactin is known to promote myelin repair in experimental autoimmune encephalomyelitis models; according to its regulatory action on prolactin secretion, domperidone is currently being tested in progressive MS (NCT02308137). Cell-based therapies are of increasing interest; among them, an extremely fascinating trial based on mesenchymal stem cell transplantation (MESEMS, NCT01854957) is underway. Finally, interesting strategies in order to reduce microglial activation have been explored; in 2015, the results of a phase Ib trial of the recombinant human monoclonal antibody MOR103 to granulocyte–macrophage colony-stimulating factor have been published. Phase II and III trials are currently lacking in this field.

3. Clinical trial limitations

Despite great efforts and smart strategies, the difficulty to find a key therapy for progressive disease is evident. Investigators face a well-known series of limitations that characterize this field of research. The lack of animal models represents an obstacle for the preclinical phases of drug development. The choice of an adequate phase II surrogate end point, in order to rapidly assess not only safety but also efficacy of newly identified treatments, is still a matter of discussion. Several paraclinical measures have been purposed, such as whole brain atrophy, cortical or deep gray structure atrophy, spinal cord atrophy, evaluation of the retinal nerve fiber layer with optical coherence tomography, and cerebrospinal fluid biomarkers (e.g. light-chain neurofilaments). For phase III trials, the classical definition of confirmed disease progression has been enriched with composite scores (e.g. Multiple Sclerosis Functional Composite) and self-reported outcomes to overcome EDSS intrinsic limits such as inter-rater variability and low sensitivity for cognitive and upper arm dysfunctions. Moreover, a rigorous selection of patients with purely progressive disease is necessary, also considering the most recent disease classification [20]. Finally, a pretrial progression of at least 24 months and an adequate trial duration (3 years) have been proposed. These recommendations, derived from previous clinical trial experience, have been excellently summarized by Ontaneda and coauthors [17].

4. Expert opinion

Nowadays, the possibility of an effective treatment for progressive MS seems more realistic than ever, but it is still far from a definite confirmation. Optimism derives from the positive results of several recent trials, for example of high-dose biotin and especially of ocrelizumab. The latter, in particular, gave rise to enthusiasms in the scientific community, being the first answer to PP MS, a previously unmet medical need. Nevertheless, many aspects have to be clarified. First of all, even if efficacy data seem convincing, the ORATORIO trial enrolled mostly young patients and more than 25% of them had gadolinium-enhancing lesions at baseline [13]. This suggests that at least a part of the observed positive effect of ocrelizumab could be explained by its powerful and well-known anti-inflammatory action, clearly demonstrated in the OPERA I and OPERA II phase III studies for RR patients [21]. Therefore, efficacy in purely progressive patients needs further demonstration. In this perspective, it is crucial to reevaluate the impact of the drug on patients’ quality of life in a real-life setting and to take into account the cost-effectiveness, cost-utility, and cost-benefit of the widespread introduction of these new treatments. Second, also safety profile needs a confirmation, which will hopefully come from phase IV studies.

In conclusion, repair strategies are unquestionably the most exciting and promising options, but they require a deeper knowledge of pathophysiology of progression, still not completely clarified. Carefully designed clinical trials and adoption of reasonable end points – recognized by the regulatory agencies – are demanded to develop new medications. An effective acceleration to these processes is being guaranteed by the international efforts of the Progressive MS Alliance and the Multiple Sclerosis Outcome Assessments Consortium.

Declaration of interest

A. Sartori received travel and/or speaker honoraria from Almirall, Biogen, Genzyme, Merk, Novartis, and Teva. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.