Can We Treat Secondary Progressive Multiple Sclerosis Now?

Secondary progressive multiple sclerosis (SPMS) is characterized by progressive accumulation of disability without intermittent recovery. Treatment of these patients is challenging due to limited understanding of pathogenesis and fewer therapeutic options. This article summarizes difficulties in defining and conducting trials in SPMS, review major clinical trials on therapies approved and unapproved in SPMS and lastly, therapies in pipeline for use in SPMS.

INTRODUCTION

Multiple sclerosis (MS) is an autoimmune, chronic demyelinating disorder of the central nervous system. Most of the patients have a relapsing-remitting illness at onset which in a substantial proportion evolves into a slowly worsening stage leading to disability accumulation, termed as secondary progressive MS (SPMS). A recent systematic search including 92 articles, showed that around 25% patients with relapsing-remitting MS (RRMS) progress by 10 years, 50% by 20 years, and >75% by 30 years with most studies reporting a mean age of 40 years at conversion to SPMS.[1] Although the last decade has seen approval of various disease-modifying therapies for relapsing forms of MS, there exist limited options to treat progressive forms of MS. Hence, there has been a recent shift in focus of clinical trials to target these progressive forms of disease. This article primarily focuses on SPMS and we talk about difficulties in defining and conducting trials in SPMS, review major clinical trials on therapies approved and unapproved in SPMS, and finally, therapies in pipeline for use in SPMS.

HOW DO WE DEFINE AND WHAT ARE THE PROBLEMS IN DEFINING PROGRESSIVE MULTIPLE SCLEROSIS?

It was only in 1996, the consensus terminology of “chronic progressive MS” was modified to SPMS, PPMS, and progressive-relapsing MS (PRMS).[2] In 2014, there was a proposal to classify all these phenotypes as active and inactive (based on previous 12 months) and progressive forms as progressive and nonprogressive (based on previous 12 months). For assessment of activity, the group recommended annual clinical assessment; however, there was no consensus on frequency of imaging. Similarly, they suggested that progression should be determined annually by history or a more objective measure like Expanded Disability Status Scale (EDSS). Thus, a patient with SPMS who has progressed gradually and had Gd-enhancing lesions on imaging will be classified as SPMS – active and progressing.[3]

Lorscheider et al.[4] have proposed definition of SPMS as 1-point EDSS worsening with EDSS ≤5.5 or a 0.5-point EDSS worsening with EDSS ≥6.0 in the absence of a relapse, a minimum EDSS score of 4, pyramidal FS (Functional Score) score of ≥2 with confirmed worsening over ≥3 months, and confirmation of worsening within the same FS as worsening onset. It does not mention the minimal duration of progressive disability accumulation, which makes it difficult to distinguish it from a relapse.[4] Furthermore, it is difficult to know the exact time of onset of progression as patients are seen only at intervals and this further delays treatment initiation and diagnosis is mostly done in retrospective.

HOW DO PROGRESSIVE FORMS VARY FROM RELAPSING-REMITTING MULTIPLE SCLEROSIS?

The underlying mechanisms of progressive forms of MS are different and incompletely understood, thus having different therapeutic implications. The proposed mechanisms include mitochondrial injury, oxidative stress, microglial activation, increased demand of demyelinating axons, etc., precise role of which are not clearly known.[5] Recently, a potential role of kynurenine pathway has been suggested which leads to excitotoxic degeneration.[6] It has been observed that there is a shift from active to inactive plaques with progression along with progressive atrophy of gray and white matter, which can be evident on MRI. Imaging, therefore, may be a potential biomarker in this situation.[7]

WHAT ARE THE CHALLENGES IN CONDUCTING CLINICAL TRIALS AND ASSESSING OUTCOME MEASURES IN SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS?

One major hindrance while making comparisons between trials is the incessant change in definitions of progressive MS with time, which makes patient selection less uniform. Recently, a large cohort of 17,536 patients was analyzed, incorporating various combinations of clinical, EDSS, and relapse criteria, which showed a diagnostic accuracy of 87% among physicians when using a three-strata progression magnitude in the absence of a relapse, confirmed after 3 months with EDSS step ≥4 and pyramidal score ≥2.[4] Yet another challenge in SPMS is a valid outcome assessment, EDSS being the most commonly used measure. However, it may not be specific enough to detect progression or sensitive enough to detect change.[8] Other outcome measures used progression-free disability, MS Functional Composite (MSFC), and recent trials have used more composite clinical end-points using EDSS, timed 25 feet walk test and 9-hole peg test.[9] Imaging to detect ongoing inflammation as well as neurodegeneration is increasingly being used as an end-point while work on cerebrospinal fluid biomarkers such as B-cell activating factor, CXCL13, neurofilament continues, as its implications are not yet clear.[10] Lately, there has also been a use of retinal nerve fiber layer thickness by optical coherence topography as a measure of remyelination and thus good clinical outcome,[11] mainly for research purposes.

WHAT DISEASE MODIFYING THERAPIES ARE AVAILABLE TO TREAT SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS?

Till date, there are 34 randomized trials in SPMS with 21 different molecules, with sample sizes ranging from 35 to 1949 participants, of which only 38% could achieve the primary end-point.[12] Most of the drugs tried were therapies approved in RRMS, with primary motive of targeting early relapses and preventing disability progression. Table 1 provides an overview of drugs used in SPMS till date.

Table 1

Drugs in secondary progressive multiple sclerosis

Drug	Year	Studies	Number of patients	MS type	RRR	Reduction in disease progression	Decrease in Gd+/new T2 lesions	Conclusion
Drugs used in RRMS
Beta IFN[13]	2012	5	1829: IFN beta 1293: Placebo	SPMS	0.91 (0.84–0.97)	0.88 (0.80–0.97) (NS)	No	May be used in early SPMS
Glatiramer acetate[14]	2010	6	1049	PMS	0.81 (0.5–1.29)	−0.45 (NS)	No	May be used in early SPMS
Immune suppressive drugs
Mitoxantrone[15]	2013	1	194	RRMS SPMS	−0.85 (–1.47–−0.23)	0.23 (0.09–0.59)	Yes(S)	Is approved in SPMS with ongoing inflammation
Azathioprine[16]	2007	5	698	RRMS SPMS	−0.26 (−0.43–−0.10)	0.42 (0.07–0.64)	No	Limited evidence
Cyclosporine[17]	1990	1	273: CSA 274: Placebo	PMS	0.765	0.17±0.39 (NS)	No	Limited evidence
MTX[18]	2004	1	31: MTX 29: Placebo	PMS	NA	11/31: MTX, 15/29: Placebo (NS)	No	May be used in financial constraints or those with other rheumatological disorders
CPP[1920]	2007	4	152	SPMS	NA	1.05 (0.79–1.41)	No	May be used
	2017	1	72: CPP 66: MPS	SPMS	NA	0.61 (0.31–1.22) (NS)	-	-
Linomide[21]	2000	1	715	SPMS	Terminated early due to ADR			No evidence
Cladiribine[22]	2000	1	Cladiribine: 105 Placebo: 54	SPMS	NA	24% versus 33% (NS)	Yes(S)	No clinical evidence
Monoclonal antibodies
NTZ[23]	2018	1	439: NTZ 449: Placebo	SPMS	NA	0.86 (0.66–0.13) (NS)	No	Limited evidence
RTX[24]	-	1	RTX: 292 Placebo: 147	PMS	NA	Mean change in EDSS 0.33 versus 0.45 (NS)	Yes(S)	Limited evidence
Alemtuzumab[25]	2017	1	15	SPMS	NA	−0.5	No	Limited evidence
IVIg[2627]	2004	1	159: IVIg 159: Placebo	SPMS	0.46	1.11 (0.80–1.53)	No	Limited evidence
-	2007	1	99: SPMS 98: Placebo	SPMS	0.50 versus 0.49 (NS)	48% versus 39% (NS)	-	-

Gd=Gadolinium, MS=Multiple sclerosis, RRMS=Relapsing-remitting MS, SPMS=Secondary progressive MS, PMS=Progressive MS, MTX=Methotrexate, CPP=Cyclophosphamide, MPS=Methylprednisolone, S=Significant, NS=Nonsignificant, IVIg=Intravenous immune globulin, RTX=Rituximab, RRR=Relative risk reduction, IFN=Interferon, CSA=Cambridge Scientific Abstracts, ADR=Adverse drug reaction, NA=Not available, NTZ=Natalizumab, EDSS=Expanded Disability Status Scale

EVIDENCE-BASED THERAPIES IN SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS

Drugs used in relapsing-remitting multiple sclerosis

As per the American Academy of Neurology (AAN) 2018 recommendations, alternate-day Interferon (IFN) beta 1b and IFN beta-1a 60 mcg IM weekly have high and moderate confidence of greater efficacy respectively on the basis of a Class II study.[28] However, in our opinion, due to conflicting evidence from North American and European trails,[13] different pathophysiology of SPMS and otherwise moderate benefit of IFN in RRMS per se, we would not recommend its use in all patients of SPMS. They may be considered in patients transitioning into early SPMS, with either no prior treatment history, where a decision for switching from another agent is being made and where preference is for a safer option with understanding that the likely benefit is limited and uncertain. The patient should agree on close follow-up to assess for deterioration.[29] Glatiramer acetate as per Cochrane review may be given in patients with RRMS transitioning early into SPMS, however, there is no compelling evidence to support its use.[14]

Immune suppressive drugs in secondary progressive multiple sclerosis

Mitoxantrone is the only approved drug by the US Food and Drug Administration (FDA) for SPMS, PRMS, and worsening RRMS. There is moderate evidence to suggest its efficacy in reducing disability progression and it remains one of the mainstay treatment in SPMS. An Indian study showed efficacy of mitoxantrone in patients with MS, without enumeration of subtypes, making it difficult to extrapolate the results for SPMS alone.[30] However, there are a few drawbacks of choosing this medication. Patients on mitoxantrone require regular cardiac monitoring and an individual can receive a total maximum dose of no more than 140 mg (which covers about 2 years of disease period). Other adverse effects to be especially considered in young men and women are hair loss, amenorrhea, risk of infertility along with long-term risk of developing malignancy.[31] Finally, the choice of further immune suppression after the patient has received the maximum dose of mitoxantrone is a difficult decision to make, as options available are further limited or absent. We recommend that all these pros and cons should be discussed in detail before initiation of mitoxantrone in patients with SPMS.

Limited data exist on use of azathioprine (AZA) in patients with SPMS. Clinical evidence of reduction in disease progression has not been seen with AZA in clinical studies. However, keeping in mind its benefit in relapsing forms of MS and AZA being an immune suppressive agent, it may be of benefit in SPMS and needs further evidence to support its use. Similarly, routine use of cyclosporine in patients with SPMS is not recommended as there is limited data with high risk of adverse effects.

Methotrexate is an effective immune suppressive agent used in various rheumatological disorders with limited side effect profile and cheaper cost. It has shown a trend to be beneficial in reduction of disability in two trials[1832] and it may be considered as a therapeutic option in patients with concomitant rheumatological disorders, or those who have financial constraints and are not willing for a more aggressive agent like mitoxantrone.

Cyclophosphamide (CPP) has been tested in several randomized clinical trials (RCT’s) which did not show any significant change in disability progression[19] and was recently studied in PROMESS study,[20] where its use was compared to intravenous methylprednisolone and was found to be effective, but with a low tolerability profile. We think that CPP may be used as a cheap alternative immune suppressive agent as it has a convenient dosing schedule, but its poor side effect profile in form of renal toxicity (which is more common when used in higher doses for treatment of malignancies), infertility limits its use in young men and women, and finally, there remains a long-term risk of malignancies.

Cladribine has been compared in two doses against placebo in a recent trial, but did not show any clinical evidence of improvement, while there was a significant reduction in imaging parameters which are suggestive of disease progression. In view of no evidence of benefit in clinical end-point and nonavailability of oral formulation in India, we await results of more trials before adding it in routine practice.[22]

Monoclonal antibodies

ASCEND trial[23] assessed the efficacy of natalizumab (NTZ) in slowing disease progression in patients with SPMS. This was a two-part study with part 2 as an optional 2-year open-label extension study which was terminated by the funding authorities after seeing the results of Part 1. The results of this trial also show better improvement in upper limb disability as compared to lower limb. Whether this effect is due to the effect of NTZ on disease activity or neurodegeneration is unclear. However, this trial does not resolve the question of initiating NTZ in patients with SPMS without ongoing inflammatory activity. No cases of PML were reported at the end of part 2 of the study. However, one might consider it as an option in patients with SPMS with ongoing disease activity with due consideration for the cost and safety profile.

Rituximab (RTX) was tested in two trials, one of which was terminated early as the trial did not reach its primary end-point, the other trial failed to show any effect in clinical outcome.[2433] However, recent approval of ocrelizumab, anti-CD-20 antibody, in PPMS probably suggests that RTX, antibody with a similar mechanism of action, may be useful in halting disease progression and could be offered to selected patients with disease activity after careful communication about the uncertainty of its effect and safety concerns on long-term.

Cambridge cohort study comprising of 15 patients which showed some benefit of alemtuzumab in improving T25W test.[25] Thus, it remains an effective treatment option in patients with aggressive RRMS who have ongoing inflammatory activity, but there is no robust data to support its use in limiting disability progression.

Till date, two RCT's are available to study the effect of intravenous immunoglobulin (IVIg) in progressive MS,[2627] both of which showed that there was nonsignificant trend of time to confirmed progression with no improvement in neurological function in either group. IVIg is not recommended in patients with SPMS.

OTHER SPECIFIC AGENTS STUDIED FOR SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS

Siponimod is a sphingosine-1 phosphate receptor modulator and has been tested in the largest Phase III RCT in SPMS.[34] The trial randomized 1651 patients with SPMS (903 = siponimod and 424 placebo) across 31 countries to receive either 2 mg daily siponimod after dose titration or placebo. The drug reduced risk of progression by 26% and 32% at 3-month interval in siponimod and placebo group, respectively (hazard ratio 0.79, relative risk reduction 21%), in addition to reduction in ARR, brain volume, and volume of brain lesions. Serious adverse events were noted in 18% and 15%, respectively, with lymphopenia, transaminitis, macular edema, bradycardia, varicella zoster activation, and seizures being more common in siponimod group as compared to placebo.

Simvastatin was compared in a single trial, Multiple Sclerosis- Simvastatin Trial (MS-STAT), which randomized 140 participants to simvastatin 80 mg versus placebo and showed mean annualized atrophy rate was significantly lower in simvastatin group with adjusted difference in two groups being 0.254% per year.[10] A planned MS-STAT2 trial is underway and will soon begin enrollment.

Lamotrigine is found to have neuroprotective actions through its anti-glutaminergic effects and sodium channel blockade. Its use, in a single trial, failed to show any benefit in SPMS.[35]

Masatinib is an oral tyrosine kinase inhibitor and was found to be effective in a small proof of concept trial in 35 patients with PPMS and relapse-free SPMS which showed reduction in MSFC score and stable EDSS in either group. A larger phase III clinical trial is underway and its results are awaited.[3637]

WHAT ARE THE EMERGING THERAPIES IN SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS?

Table 2 provided a brief overview of upcoming agents in SPMS and awaiting results from larger trials.

Table 2

Emerging therapies in secondary progressive multiple sclerosis

Drug	Mechanism of action	Number of patients	Type of MS	Outcome	Comment
Biotin[3839]	Activation of acetyl coA carboxylase: Myelin synthesis	n=154 (100 mg)	SPMS and PPMS	Positive	Larger trial SPI2 (NCT02936037) awaited
Lipoic acid[40]	Anti-inflammatory	n=51 (1200 mg)	SPMS	Positive	Larger trial (NCT03161028) awaited
Ibudilast (phase2) (NCT01982942)	Macrophage migration inhibitor	255	SPMS and PPMS	Positive	formal results awaited
GbNAC1 (phase 2) (NCT02882858, NCT03239860)	Recombinant monoclonal antibody - envelope of MS associated enterovirus	-	RRMS	Negative	Upcoming trial in SPMS to be announced
Opinicumab[41]	Anti-LINGO1 antibody	-	SPMS and RRMS	Positive (optic neuritis)	Formal results awaited
Clemastine fumarate[42]	Anti-histaminic	50	Chronic optic neuropathy	Positive	Upcoming trial in MS to be announced

MS=Multiple sclerosis, SPMS=Secondary progressive MS, PPMS=Primary progressive MS, RRMS=Relapsing-remitting MS

Stem cell therapy

Stem cell therapy is a restorative therapy that has shown substantial benefit in patients with RRMS. A Phase 2a study using intravenous administration of mesenchymal stem cells (MSC’s) has shown benefit in visual acuity and evoked potentials in ten patients with SPMS.[43] Intrathecal administration of MSC's has shown clinical improvement in 4 out of 6 patients with progressive MS.[44] Yet another trial (ACTiMUS) is enrolling patients exclusively of progressive MS and is underway (NCT01815632). Casanova et al. compared efficacy of autologous hematopoietic stem cell transplant (AHSCT) in RRMS and SPMS. They found 6 patients with RRMS (27.2%) and 4 in SPMS (44.4%) had a relapse after AHSCT. Seven patients (22.6%) in SPMS group had disability progression while none in RRMS had progression after follow-up of 5.4 years.[45] A recent meta-analysis,[46] including 15 studies with most comprising of patients with SPMS (10 out of 15) and average median proportion of patients with SPMS being 56% showed average rate of progression of 17% which is superior to other trials in SPMS. However, separate subgroup analysis would add more to our knowledge regarding benefit of AHSCT in SPMS.

HOW DO WE APPROACH A PATIENT WITH SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS?

As mentioned earlier, it is essentially important to detect progression in RRMS as early as possible. This can be achieved with regular patient visits, documentation of disability at the time of each visit with regular radiologic assessment of disease activity. Once it is acknowledged that a patient with RRMS on a given platform therapy is converting to early SPMS and imaging shows evidence of ongoing inflammation, two options potentially exist. In the first, he or she could be offered a lateral switch and monitored closely for further progression. In the second where the clinician feels that disease progression is affecting quality of life, where disability-progression is rapid or patients who already have a high EDSS at presentation with MRI evidence of ongoing inflammation, it may be prudent to switch them to second-line therapy after assessing the risk, benefit and appropriate counseling of the patient. Finally, there still remains a subgroup of patients with a burnt-out disease who have a high EDSS, with a prolonged course of illness and imaging showing only atrophy with no evidence of ongoing inflammation. In these patients, there exists little evidence for immune suppression and it may be advisable to treat them symptomatically and stop ongoing DMTs, as also recommended by the recent AAN 2018 practice guidelines for treatment of MS. Emerging therapies in the form of AHSCT may be considered as a therapeutic option in selective cases, although it is still under the purview of controlled studies. Other emerging agents could be tried within the limits of clinical trials. With the advent of FDA approval of ocrelizumab in PPMS, and many ongoing trials, there remains a hope for specific agents among these patients in the future.

CONCLUSION

Currently, there is a lack of defined treatment options in SPMS. However, in SPMS, unlike PPMS, there is a window of opportunity as the relapse phase with ongoing inflammation can be targeted by adequate therapy. A close follow-up and utilization of clinical and radiological measures of disease activity could help a clinician decide to switch therapy timely to prevent a stage of progressively cumulative worsening and transition to established advanced SPMS. It is prudent to recognize the deterioration early, as escalation therapies used for aggressive MS may have a potential role to play in such patients, considering, cost, risk, and benefit while deciding. Furthermore, as we evolve to understand the exact pathogenesis of disease progression and identify appropriate outcome measures, targeting therapy would be more specific. Treating SPMS continues to remain a challenge as it aims at targeting not only active inflammation but also associated neurodegeneration and demyelination. After many years, we have a clearer understanding of disease process, importance of adequate outcome measures and advances in drug therapies. At this point, we have to use our best reasoning and individualize therapy and likely extrapolate the evidence from trials of both RRMS and SPMS to manage a patient, although we are hopeful and optimistic about targeted therapies for SPMS in future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.