Table of Contents  

Leutmezer: Upcoming therapeutic options for progressive multiple sclerosis

Introduction

Although 13 immunomodulatory therapies are currently available for the treatment of relapsing–remitting multiple sclerosis (RRMS), the therapeutic arena for progressive multiple sclerosis (PMS) remains a no man’s land. This difference is driven, at least in part, by the factors presented below:

  1. The mechanisms of PMS are less well understood than those of RRMS. The absence of a well-established experimental model for PMS, in contrast to the model of experimental autoimmune encephalomyelitis (EAE) for RRMS, might provide one explanation for this.

  2. PMS is less common than RRMS, making clinical trial recruitment a more challenging task.

  3. Although clinical relapse and new T2 lesion count are easy-to-measure outcome parameters in RRMS, definition and objective measurement of clinical and radiological progression are difficult tasks in PMS. Therefore, clinical trials in PMS need larger patient numbers and/or longer observation periods than RRMS trials to achieve significant results.

  4. The time of onset of a patient’s first clinical relapse is easy to define in RRMS, while, in PMS, the onset is less clear and often definable only retrospectively. As a result, early initiation of a particular therapy, which is a prerequisite for a favourable treatment response in RRMS, is hard to achieve in PMS.

In response to the challenges, more than 50 phase II or III clinical trials including patients with PMS have been completed in the last 30 years.1 The majority of treatment regimes studied during this period includes immunosuppressants, chemotherapeutics or immunomodulators. Despite the large number of clinical trials, only three disease-modifying drugs have been approved for use in PMS by the US Food and Drug Administration (FDA) [mitoxantrone for secondary PMS (SPMS) and ocrelizumab (Ocrevus®, Roche) for primary PMS (PPMS)] or the European Medicines Agency (EMA) [mitoxantrone and interferon (IFN)β-1b (Betaseron®/Betaferon®, Schering) for SPMS; approval for ocrelizumab in PPMS is expected in late 2017].

Interferon β-1b

Interferon β-1b has been tested in two clinical trials in SPMS. The European SPMS (EUSPMS) trial2 recruited 718 patients in a randomized double-blind placebo-controlled phase III trial. Treatment with IFN-β1b resulted in a 22% reduction in the number of patients with 3 months of confirmed disability progression that was independent of baseline Expanded Disability Status Scale (EDSS) score, pre-entry relapse rate and the occurrence of relapses during the study. There was a significant reduction in clinical and magnetic resonance imaging (MRI) activity, which was of the same magnitude observed in the pivotal clinical trial in RRMS. In contrast, a subsequent study3 performed in North America failed to confirm the effect of IFN-β1b on disability progression, even if the efficacy of clinical and MRI measures of disease activity was confirmed. A comparison of the two studies revealed a younger and more active population in the EUSPMS trial, characteristics that are in line with a better response to anti-inflammatory treatments in patients with more active disease. Moreover, it is probable that a higher relapse rate during the study may have driven the EDSS changes, as the annualized relapse rate of 0.64 observed in the placebo arm of the EUSPMS trial is a value not observed even in pure RRMS clinical trials today.4 A Cochrane Database Systematic Review5 concluded that IFNs do not reduce the risk of sustained 6-month EDSS progression in SPMS patients; however, there is a significant decrease in the risk of 3-month confirmed disability progression, reflecting relapse-related disability changes. Based on these results, the clinical use of IFNs in SPMS patients is restricted to the use of IFN-β1b in those with persisting attacks, and mostly to those with low levels of disability. The rationale for this is twofold: (1) these patients have some level of ongoing inflammatory activity that may respond to the drug and (2) IFNs increase spasticity, and the potential advantages of protection from new lesions are countered by adverse effects on the motor system.6

Mitoxantrone

Mitoxantrone is an antineoplastic anthracenedione derivative that inhibits DNA replication, DNA-dependent ribonucleic acid (RNA) synthesis and DNA repair, resulting in a marked reduction of B- and T-cell numbers. Mitoxantrone is a very small molecule and, therefore, is able to cross the blood–brain barrier (BBB) and interact with cells in the central nervous system (CNS).7,8 In the Mitoxantrone in MS (MIMS) trial,9 194 patients with worsening RRMS or SPMS (around half of the participants) were assigned placebo or mitoxantrone at a dose of 12 mg/m2 intravenously every 3 months for 24 months. At 24 months, mitoxantrone showed a significant benefit compared with the placebo group for disability progression confirmed at 3 and 6 months. However, the overall proportion of patients who progressed was low (19% in the placebo arm vs. 7% in the mitoxantrone arm) and a separate statistical analysis of the SPMS patients was not performed. Secondary outcome parameters (relapse rate and MRI parameters) also favoured mitoxantrone over placebo. However, the population included in the MIMS trial does not allow conclusions to be drawn on the efficacy of mitoxantrone in SPMS patients without attacks. Interestingly, an open-label study10 comparing the efficacy of mitoxantrone in RRMS and SPMS showed that the proportion of patients who experienced no disability progression was significantly higher in the RRMS group than in the SPMS group, in line with observations using IFNβ. The most important limitations of mitoxantrone are long-term safety concerns, specifically the risk of cardiotoxicity and acute leukaemia.11

Ocrelizumab

Ocrelizumab is a recombinant humanized antibody designed to selectively target cells that express the B-lymphocyte antigen CD20 on their surface. The CD20 molecule is an activated-glycosylated phosphoprotein expressed on a broad range of cells of the human B-cell lineage, with increasing concentrations from pre-B-cells through to naive and memory B-cells, whereas CD20 is not expressed on stem cells, pro-B-cells or differentiated plasma cells.12

Although T-cells and their role in the pathogenesis of MS have been extensively studied for decades, B-cells have attracted the attention of the MS medical community only recently. Two features that might be responsible for their pathogenic role in MS are (1) B-cells can produce proinflammatory cytokines and are potent antigen-presenting cells involved in the activation of proinflammatory T cells and (2) B-cells may differentiate into plasma cells that can produce autoantibodies directed against myelin and cause a complement-mediated attack on the myelin sheath.13 Studies of the pathology of MS have shown that ectopic lymphoid follicles resembling germinal centres containing B-cells and plasma cells are present in the meninges of patients with SPMS, indicating that B-cells migrate to the brain. Although reportedly restricted to late disease phases, the establishment of lymphoid-like structures in the brains of patients with MS suggests a pathophysiological role of B-cells in MS.14

Ocrelizumab was tested in a randomized double-blind placebo-controlled phase III trial – Ocrelizumab Versus Placebo in Primary Progressive Multiple Sclerosis (ORATORIO)15 – in which 732 patients with PPMS received intravenous ocrelizumab (600 mg) or placebo in a 2 : 1 ratio every 24 weeks for ≥ 120 weeks. The study met the primary end point with a significant reduction in 12-week confirmed disability progression. Secondary outcome parameters (24-week confirmed disability progression, performance on the 25-foot walk test and total brain volume loss) were also met. However, some discussion remains as to whether or not the study population truly reflects the whole population of PPMS patients. In particular, the clinical activity, with a median EDSS score of 4.5 after a median disease duration of 6 years, as well as the radiological activity, with 28% of patients with gadolinium-enhancing lesions, were quite high for a PPMS population. This is of particular interest because another PPMS phase III trial16 with a monoclonal CD20 antibody (rituximab) failed to show superiority when compared with placebo. In this study, the overall population showed less clinical and radiological activity. Moreover, a preplanned subgroup analysis suggested a significant effect in younger patients with gadolinium-enhancing lesions on brain MRI in terms of clinical and radiological activity.

In the ORATORIO trial,15 overall tolerability and safety were good, with infusion-related reactions, upper respiratory tract infections and oral herpes infections being the side-effects occurring more frequently with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo. Although the incidence of neoplasms was extraordinarily low in the placebo group and within the normal range in the ocrelizumab group, some vigilance is mandatory in this respect. There was no clinically significant difference between groups in the rates of serious adverse events and serious infections.15 Sporadic cases of progressive multifocal leucoencephalopathy with rituximab, and one additional case in a patient with ocrelizumab in the post-marketing phase, are also worth noting.17

Ocrelizumab was approved by the FDA for patients with PPMS in March 2017 and approval by the EMA is expected in late 2017. The therapy is applied as an infusion (2 × 300 mg separated by 2 weeks) twice a year.

Siponimod

Siponimod (BAF312) is an oral modulator of sphingosine-1-phosphate receptor 1 (S1P1) that selectively acts on S1P1 and sphingosine-1-phosphate receptor 5 (S1P5), leading to a putative greater selectivity than the S1P1-5 agonist fingolimod (Gilenya®, Novartis).18 Siponimod inhibits egress of potentially autoaggressive lymphocytes into the circulatory system and consequently their infiltration of the CNS. Moreover, it may have direct CNS effects by modulating neurobiological processes via S1P1 and S1P5 on astrocytes and oligodendrocytes and has therefore been suggested to exert neuroprotective and regenerative actions in the CNS.19 A randomized double-blind placebo-controlled phase III trial of siponimod in patients with SPMS has recently been completed [Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND)]. Although not yet published, it has been revealed that siponimod reduced the risk of confirmed disability progression (the primary outcome) and met several other outcome parameters, but no change was observed in the 25-foot walk test.20

Adrenocorticotropic hormone

Adrenocorticotropic hormone (ACTH) has been used for decades in the treatment of MS relapses owing to its steroidogenic properties. Recent data suggest that it also has additional corticosteroid-independent mechanisms. For instance, it has been suggested that ACTH exerts anti-inflammatory effects [via modulation of regulatory T-cells, inhibition of activation of nuclear factor kappa B (NF-κB) and possibly the triggering of CNS-restricted release of noradrenaline and acetylcholine] and may have neuroprotective effects in spinal cord injury and ischaemic brain injury.21,22 These aspects provided the rationale for an ongoing phase II trial (NCT01950234)23 of ACTH in PMS.

Antiepileptic drugs

It has been shown in experimental animal models that loading of partially demyelinated axons with sodium ions results in an accumulation of calcium ions, which triggers a cascade of degradative enzyme activity and finally leads to axonal degeneration.24 Consequently, partial blockade of sodium channels might have neuroprotective effects.25 As such, sodium-blocking agents such as phenytoin, lamotrigine and carbamazepine have been suggested as potential therapeutic strategies in PMS. Proof of this concept is still pending, because lamotrigine failed to show beneficial effects in a phase II trial26 versus placebo in patients with SPMS. In contrast, lamotrigine treatment was unexpectedly found to be associated with greater annual cerebral volume loss in the first year than placebo. This effect was partially reversed after discontinuation of treatment. However, the rate of decline on the timed 25-foot walk test was significantly reduced in the treatment group.26 Interpretation of the results has been further complicated by a non-adherence rate of up to 50% in the lamotrigine group.

It is known that the use of steroids in the treatment of acute optic neuritis, a common manifestation of MS, has little or no impact on the eventual extent of recovery.27 Optical coherence tomography of the retinal nerve fibre layer and MRI of the optic nerve following optic neuritis have shown volume loss (neuroaxonal loss) in correlation with impaired visual function.28 In a phase II trial of phenytoin versus placebo in patients with acute optic neuritis, treatment with phenytoin within 2 weeks of symptom onset was accompanied by a 30% protective effect on retinal nerve fibre layer thickness and macular volume after 6 months of acute optic neuritis.29 A phase II trial (NCT02104661)30 of oxcarbazepine (Trileptal®, Novartis) in SPMS assessing the change in the content of neurofilament light chain in cerebrospinal fluid, a proposed surrogate marker of neurodegeneration, as well as clinical disability and imaging outcomes, is under way.31

Amiloride, fluoxetine and riluzole

Amiloride is a potassium-sparing diuretic capable of inhibiting acid-sensing ion channels, a property that has been linked to possible neuroprotective effects. It has been found to reduce functional neurological deficits in EAE studies.32 However, a clinical trial of amiloride in patients with optic neuritis33 showed no positive effect in terms of optical coherence tomography parameters and was prematurely stopped. Riluzole is an inhibitor of tetrodotoxin-sensitive voltage-gated sodium channels, has an antiglutamatergic profile and is the only established disease-modifying treatment for amyotrophic lateral sclerosis.34 Fluoxetine is a selective serotonin reuptake inhibitor that has been suggested to have neuroprotective properties by suppression of microglial activation, NF-κB (a family of transcription factors with an essential role in inflammation and innate immunity) activity and enhancement of the production of the brain-derived neurotrophic factor in animal models.35 A four-arm phase II trial – Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS SMART) (NCT01910259)36 – of amiloride, fluoxetine and riluzole compared with placebo in patients with SPMS is currently under way, using novel outcome parameters including neurofilament and modern MRI techniques.

Anti-leucine-rich repeat and immunoglobulin-like domain-containing protein 1

Leucine-rich repeat and immunoglobin-like domain-containing protein 1 (LINGO-1) is a cell surface protein expressed in neural cells, and a negative modulator of axonal myelination via inhibition of the differentiation of oligodendrocyte precursor cells to mature oligodendrocytes.37 Blockage of LINGO-1 may therefore represent a potential strategy for remyelination and axonal preservation in MS. In an EAE study,38 anti-LINGO-1 antibodies improved axonal integrity and new myelin sheath formation, resulting in functional recovery.

In a recent randomized double-blind placebo-controlled phase II study – Safety and Efficacy of Opicinumab in Acute Optic Neuritis (RENEW)39 – participants with a first unilateral acute optic neuritis episode within 28 days of study baseline were assigned to receive either 100 mg/kg opicinumab intravenously or placebo once every 4 weeks (six doses) in addition to a standardized regimen of high-dose methylprednisolone. The primary end point was remyelination at 24 weeks, measured as the recovery of affected optic nerve conduction latency using full-field visual evoked potential (VEP) versus the unaffected fellow eye at baseline. Analysis was by intention to treat (ITT) and prespecified per protocol (PP) analyses were also conducted. Remyelination did not differ significantly between the opicinumab and placebo groups in the ITT population at week 24.39 However, results from the prespecified PP population suggest that enhancing remyelination in the human CNS with opicinumab might be possible and warrants further clinical investigation. In a post hoc analysis, a subgroup of patients identified by novel MRI techniques (diffusion tensor imaging and magnetization transfer imaging) had a more favourable outcome. These techniques are used as additional inclusion criteria in an ongoing trial – Efficacy and Safety of BIIB033 (Opicinumab) as an Add-On Therapy to Disease-Modifying Therapies (DMTs) in Relapsing Multiple Sclerosis (MS) (AFFINITY) (NCT03222973)40 – with opicinumab versus placebo as an add-on therapy to a standard immunomodulatory treatment in patients with RRMS.

Biotin

Biotin is a water-soluble vitamin belonging to the B complex family and an essential micronutrient that acts as a cofactor for decarboxylase enzymes. High doses of biotin have been found to prevent the course of biotin-responsive basal ganglia disease, an autosomal recessive subacute encephalopathy in childhood.41 In a case series of patients with relapsing episodes of ataxia and optic neuropathy, radiological findings suggested that leucodystrophies also responded to high doses of biotin.42 One of those patients was later diagnosed with SPMS. This was the rationale for an open-label pilot study of high-dose biotin (100–300 mg/day) in patients with SPMS and PPMS, which showed a positive impact on disease progression in patients with optic nerve and spinal cord involvement. A subsequent phase III trial43 of high-dose biotin (MD1003) in PMS showed an improvement in the EDSS in 13% of the treatment group compared with 0% in the placebo group. Similar improvement was achieved in the timed 25-foot walk test.43 Although the primary outcome parameter was achieved with statistical significance, some discussion remains about the magnitude of the observed effect (e.g. 0.2 points in the EDSS). Further trials are necessary to clarify whether or not high-dose biotin is a clinically meaningful option in PMS therapy.

Domperidone

Dopamine is a key player in the regulation of prolactin secretion, achieved mainly by inhibiting the anterior pituitary lactotrophs.44 Domperidone is a dopamine-2 receptor antagonist widely used in Canada and Europe as a prokinetic agent for gastroparesis, with the induction of lactation (via increasing prolactin secretion) as one possible side-effect. EAE studies suggest that prolactin can promote myelin repair45 and thereby may have a potential role as a remyelinating therapy in MS. This is in line with the observation of the beneficial effect of pregnancy in reducing disease activity in MS, an observation that may be, in part, related to higher prolactin levels. Consequently, a phase II trial (NCT02308137)46 of oral domperidone in patients with SPMS is currently in progress.

Erythropoietin

In animal models of several neurological diseases, erythropoietin (EPO) has been shown to have antioxidative, anti-inflammatory and neurotrophic effects.47 Accordingly, EPO has been shown to reduce clinical severity, axonal injury and demyelination, and diminish glial expression of major histocompatibility complex class II in the EAE model.48 A small open-label pilot study of EPO in patients with PMS showed both clinical and electrophysiological improvement of motor function with high-dose EPO.49 Similarly, EPO showed beneficial results on retinal nerve fibre layer thinning, a decrease in retrobulbar diameter of the optic nerve and VEP latencies in patients after optic neuritis in a phase II placebo-controlled trial.50 A phase II trial (NCT01144117)51 of EPO in PMS has recently been completed but results have not yet been released.

Haematopoietic stem cell therapy

Haematopoietic stem cell transplantation has been proposed as a second-line therapy for refractory MS. Although early clinical trials in PMS revealed only moderate efficacy on short-term clinical outcomes,52 long-term follow-up results of a single-centre trial suggested a more robust improvement in the disease progression-free survival rate, at least in those patients with active inflammation.53 In addition, several efforts to improve technical issues (optimization of the cell source and patient selection) and the safety and tolerability of the procedure have been made in recent years.54 In particular, the use of mesenchymal stem cells or autologous unfractionated bone marrow cells, without the need for preceding immunosuppression, has improved the tolerability of the procedure. This strategy was used in an open-label proof-of-concept trial in patients with SPMS with clinical evidence of optic nerve involvement.55 The study showed improved visual acuity and visual evoked response latency, and an increase in the optic nerve diameter, after infusion of autologous bone marrow-derived mesenchymal stem cells. A phase II trial (NCT01815632)56 of autologous bone marrow infusion in patients with SPMS or PPMS (ACTiMuS) is currently recruiting participants.

Ibudilast

Ibudilast is a non-selective phosphodiesterase inhibitor that has been suggested to have immunomodulatory and neuroprotective effects by inhibiting leukotrienes and nitric oxide synthesis, and reducing tumour necrosis factor-α from astrocytes and microglial cells.57 A phase II trial of ibudilast in patients with RRMS failed to show a positive effect on the number of new gadolinium-enhancing MRI lesions but showed some beneficial effect on brain atrophy, suggesting a potential neuroprotective mechanism of the compound.58 A phase II trial (NCT01982942)59 of ibudilast in PMS was completed in May 2017 and results are expected soon.

Idebenone

Idebenone is a synthetic analogue of coenzyme Q10, an endogenous antioxidant found in all cellular membranes and a constituent of the ATP-producing electron transport chain of mitochondria.60 In addition to antioxidant properties, idebenone has been shown to exert anti-inflammatory effects in vitro.61 Idebenone use in Friedreich’s ataxia and Leber’s hereditary optic neuropathy, both of which are thought to be mitochondrial disorders, has shown beneficial effects. In a recent animal study, idebenone was found to protect hippocampal HT22 cells from glutamate-induced cell death in vitro, although idebenone-treated EAE mice did not exhibit any clinical benefit with respect to reducing inflammation, demyelination and axonal injury.62 Given that mitochondrial dysfunction may play a key role in progressive axonal loss in MS, further investigations into a therapeutic option for PMS are rational. A phase II trial (NCT01854359)63 of idebenone in PPMS is currently under way.

Lipoic acid

Lipoic acid is a natural antioxidant with signal transduction modulatory pathways, and has been suggested as a potential therapeutic agent in diseases associated with oxidative stress such as diabetic neuropathy, Alzheimer’s disease and MS. Lipoic acid has been shown to suppress EAE by inhibiting the entry of T-cells into the CNS.64 In a recent small phase I study, lipoic acid was well tolerated in patients with MS and was associated with a reduction in matrix metalloproteinase-9 and soluble intercellular adhesion molecule-1.31,65 A phase II/III trial (NCT01188811)66 of lipoic acid in patients with SPMS has been completed and results are pending.

Lithium

Lithium is one of the oldest antipsychotic drugs. Its therapeutic effects are mediated through inhibition of glycogen synthase kinase-3, a serine/threonine-protein kinase and major regulator of inflammation. Pretreatment with lithium has been shown to suppress disease activity onset in EAE in animals. Even when lithium was administered after the induction of EAE, it was able to reduce disease severity and facilitate symptom recovery.67 A pilot phase I/II trial (NCT01259388)68 of lithium in PMS has been completed and results are pending.

Masitinib

Masitinib is a selective tyrosine kinase inhibitor that modulates migration, survival and degranulation of mast cells.69 It has been restricted to use only in veterinary medicine and human mast cell tumours. Increasing evidence suggests that mast cells also play a role in pathogenesis of MS by releasing vasoactive mediators that sustain inflammatory cascade, disrupting the BBB and stimulating activated T-cells, among other mechanisms.70 In a phase IIa proof-of-concept trial,71 masitinib was well tolerated and found to have a positive but not statistically significant effect on clinical progression in patients with PMS. A phase IIb/III (NCT01433497)72 study of masitinib in patients with relapse-free SPMS or PPMS is in progress.

MIS416

MIS416 is a myeloid-directed microparticle immune response modifier (derived from Propionibacterium acnes), which was originally developed as a vaccine adjuvant.73 MIS416 has been suggested to modulate T-cell-mediated autoimmune responses in EAE by simultaneously activating innate toll-like receptor 9 and nucleotide-binding oligomerization domain-containing protein 2.73 The restricted uptake of MIS416 by phagocytic cells has been suggested to lead to targeted modulation of the innate immune system.74 MIS416 was initially used in patients with SPMS outside a formal clinical trial setting under compassionate use legislation in New Zealand. In a phase Ib/IIa clinical trial,74 MIS416 was shown to suppress the development of proinflammatory T-helper 1, 2 and 17 cells in EAE and to increase the serum levels of IFN-γ and IFN-γ-associated proteins in 19 patients with SPMS. A phase IIb trial75 showed good safety and tolerability of the compound, suggesting that further trials would be valuable to determine clinical efficacy.

Simvastatin

Statins (hydroxymethylglutaryl-CoA reductase inhibitors) are widely prescribed and well tolerated in the treatment of hypercholesterolaemia. However, they also exert immunomodulatory and neuroprotective properties and have been shown to improve cerebrovascular haemodynamics.76 These properties make statins an attractive candidate drug in patients in the later stages of MS when dysfunction of brain parenchymal cells and vascular endothelial cells occurs.77 Studies of statins in EAE and open-label trials in patients with MS have shown decreased disease activity.78 In a phase II trial of simvastatin versus placebo in patients with SPMS,79 simvastatin was found to significantly reduce the annualized rate of whole-brain atrophy compared with placebo by 43%. These results provide support for the advancement to a phase III trial of statins for PMS.31

Sunphenon epigallocatechin-3-gallate

Sunphenon® (Taiyo International) epigallocatechin-3-gallate (EGCg), a major constituent of green tea, has been suggested as a neuroprotective compound in several neurological disorders by mediating reactive oxygen species. In EAE studies, EGCg has been shown to have anti-inflammatory properties by influencing T-cell proliferation and inhibiting the activation of NF-κB, and neuroprotective properties by acting as a free radical scavenger.80 A phase II/III trial (NCT00799890)81 of oral Sunphenon EGCg in patients with PMS has been completed and results are pending.

Conclusion

The long list of therapeutic agents currently in development for the treatment of PMS, and the fact that the first agents for PMS showed significant efficacy in randomized placebo-controlled clinical trials, provides some reason for optimism in the therapeutic fields of PMS. Moreover, increased knowledge about the pathophysiological basis of PMS and the development of improved clinical trial design will further increase the chance that new therapeutic targets will eventually be identified and successfully pass clinical trial programmes in patients with PMS.

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