Treating Progressive Multiple Sclerosis


Treating Progressive Multiple Sclerosis

Carrie M. Hersh


         Primary progressive multiple sclerosis (PPMS) is defined by progressive accrual of disability in the absence of relapses.

         Secondary progressive multiple sclerosis (SPMS) is defined as an initial relapsing–remitting disease course followed by gradual clinical progression with or without relapses.

         Recent changes have been proposed to the classification of progressive MS that focus on presence (or absence) of disease activity and continued disability progression. These proposals will help identify patients for PPMS and SPMS clinical trials and treatment.

         Ocrelizumab is the first disease-modifying therapy approved for PPMS and suggests a role for B-cell therapy for both the inflammatory and perhaps neurodegenerative phases of progressive multiple sclerosis (MS).

         Numerous therapeutics for the treatment of PPMS and SPMS with unique mechanisms of action are currently in the investigatory phase, including siponimod, high-dose biotin, and ibudilast.

         Concerted efforts are currently in progress via the Progressive MS Alliance, Multiple Sclerosis Outcome Assessments Consortium, and the International Collaborative on Progressive MS to identify robust metrics for measuring MS-related disability in progressive MS and, as an extension, developing novel neurotherapeutics.

         Symptomatic therapies and neurorehabilitation are important management strategies to improve quality of life and function in progressive MS.


MS is a chronic, inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) that affects the white and gray matter of the brain and spinal cord. Approximately, 85% of patients present with a relapsing–remitting MS (RRMS) disease course at onset, defined as alternating episodes of new or worsening symptoms (relapses), followed by complete or partial recovery of symptoms (remission). About two-thirds of RRMS patients will transition to SPMS, a clinical form of MS that is characterized by gradual accumulation of disability independent of relapses over time. PPMS occurs in about 10% of patients, characterized as gradual worsening of neurologic disability from disease onset with absence of distinct relapses or remissions (1). The term “progressive MS” is a collective term for both SPMS and PPMS.


There are two important limitations in clinical practice for managing progressive MS, which can reflexively pose a challenge in developing an effective individualized therapeutic strategy:

1.    Identification of the distinct time of transition from a RRMS to SPMS disease course, typically defined as a period of 6 to 12 months of gradual disability progression proceeding the relapsing phase.

2.    Identification of PPMS at symptom onset as distinct from a relapsing–remitting disease course with slower or delayed onset of subsequent relapses.

The recognition of progressive MS can therefore be delayed past a point where irreversible or “fixed” disability 137has already incurred. There are no MRI or laboratory biomarkers yet available that effectively identify patients with progressive MS. Thus, practitioners are tasked with recognizing a progressive disease course based on careful clinical observation and scrutiny.

In SPMS there are several risk factors that shorten the transition time to clinical progression from a relapsing–remitting disease course: advanced age at the time of onset; initial presentation of posterior fossa or spinal cord syndromes; incomplete recovery of function following the initial relapse; higher number of relapses within the first 5 years of disease onset; and higher disability early in the disease course (2). A feature that distinguishes PPMS from the more common presentation of RRMS, besides a slower, insidious onset of symptoms, is an older age at presentation (40–50 years old). Most studies show that PPMS patients are typically about 10 years older than those presenting with RRMS (3,4). It should also be noted that relapses may still occur in patients with SPMS, and occasionally even in individuals with PPMS (5). Although the term “progressive relapsing” MS was previously generally accepted to define the latter phenotype, new criteria have since been proposed to simplify the classification.

An international panel of MS experts recently proposed changes to the classification of MS to more effectively characterize the clinical course of progressive MS (6). One of the changes included the categorization of progressive disease as either phenotypically manifesting active inflammation (“active”) or no active inflammation (“nonactive”) via new clinical relapses and/or new T2 and/or gadolinium-enhancing (GdE) MRI lesions within the past year. Another proposed change was the categorization of progressive disease on the presence or absence of continued gradual clinical decline (“with progression” or “without progression”) (see Figure 15.1). These proposed recommendations were built to allow clearer conceptualization of progressive MS and more efficient recruitment of progressive MS patients into clinical trials.

Since the inauguration of disease-modifying therapies (DMTs) in 1993, there have been dramatic advances in the MS field. These breakthroughs have primarily centered on the development of agents targeting inflammation to modify the overall disease course in relapsing MS. However, up until recently, there has been a significant unmet need in developing effective neurotherapeutics for PPMS and SPMS, specifically for progressive disease that is inactive but progressive. This dearth of treatment for progressive MS stems from an incomplete understanding of the disease pathogenesis, lack of validated outcome measures, and mostly negative clinical trial experiences to date.


FIGURE 15.1    Proposed classification of the clinical course in progressive multiple sclerosis.

Source: Lublin FD, Reingold SC, Cohen JA, et al, Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014; 83:278-286 and


In RRMS, a predominant pathological feature is the breakdown of the blood–brain barrier with subsequent focal inflammatory demyelination. In progressive MS, inflammation is a less defining pathological hallmark. Instead, progressive MS is characterized by neurodegeneration of the white and gray matter resulting in brain and spinal cord atrophy on a background of mild–moderate inflammation (7). Predominant factors driving neurodegeneration include mitochondrial dysfunction due to defective oxidative phosphorylation and nitric oxide production, resulting in a chronic state of virtual hypoxia due to unmet energy demands (8), and age-dependent iron accumulation in myelin and oligodendrocytes leading to oxidative tissue damage (9).

Growing evidence supports a strong pathogenic role of B lymphocytes on MS disease activity and implicates a unique neurotherapeutic target, as suggested by the OLYMPUS trial (10). This notion is further substantiated by postmortem brain tissue from patients with SPMS that showed meningeal lymphoid follicles containing proliferating B cells (11). Diffuse T lymphocyte- and B lymphocyte-driven meningeal inflammation has also been demonstrated in PPMS, resulting in extensive demyelination and neurite loss in the cortical gray matter, leading to a more severe clinical disease course (12).

A fundamental question that remains is whether or not there are innate differences in the inflammatory response of relapsing versus progressive forms of MS, given the failure of most anti-inflammatory DMTs in progressive MS to date (8), including interferon beta (13–16), cladribine (17), glatiramer acetate (18), rituximab (10), and fingolimod (19) (see Table 15.1). Although mitoxantrone showed reduced progression of disability and clinical relapses in a population of patients with RRMS and SPMS (20), significant safety concerns restrict its use in clinical practice. In either case, the key neurodegenerative pathophysiologic mechanisms that underlie progressive MS, namely PPMS and SPMS that is inactive yet still progressive, warrant further understanding to identify targets beyond the inflammatory aspects of disease that will more effectively uncover robust neurotherapeutics.



Overall, an incomplete understanding of progressive MS pathogenesis has slowed the development of effective therapies and requires further inquiry. Nevertheless, the field recently made a substantial advancement in neurotherapeutics with the approval of the first DMT indicated for PPMS, ocrelizumab. This exciting breakthrough is encouraging for the future development of neuroprotective and neurorestorative agents, providing more complete control of a highly heterogeneous and complex disease.



Ocrelizumab is a humanized monoclonal antibody that targets CD20 on B lymphocytes. Ocrelizumab depletes B lymphocytes through various mechanisms including complement-dependent cytolysis, direct antibody–dependent cytolysis, and apoptosis (21). Driven by positive results in the subgroup analysis of the OLYMPUS trial investigating rituximab in PPMS, a phase III trial of ocrelizumab with similar study design was conducted in patients with PPMS against a placebo-controlled group (ORATORIO) (22). Key eligibility criteria included patients who were between 18 and 55 years of age, carried a diagnosis of PPMS (per 2005 revised McDonald Criteria), scored between 3.0 and 6.5 on the Expanded Disability Status Scale (EDSS), had duration of MS symptoms of less than 15 years if EDSS was > 5.0 at screening or less than 10 years if EDSS ≤5.0 at screening, and had a documented history of elevated immunoglobulin G (IgG) index or at least one IgG oligoclonal band on cerebrospinal fluid testing. Patients were randomly assigned in a 2:1 ratio to receive ocrelizumab 600 mg intravenous (IV) (initially divided into two 300 mg IV infusions 14 days apart) or matching placebo every 6 months. About 488 patients were assigned to receive ocrelizumab, and 244 patients were assigned to placebo. Among the total enrollees, 402 patients (82%) assigned to ocrelizumab and 174 (71%) assigned to placebo completed 120 weeks of the trial.

The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. Disability progression was defined as an increase in the EDSS of at least 1.0 point from baseline that was sustained for at least 12 weeks if the baseline score was ≤5.5 or an increase of at least 0.5 points sustained over at least 12 weeks if the baseline score was ≤5.5. The investigation met its primary endpoint with 12-week confirmed disability progression of 32.9% in ocrelizumab versus 39.3% in the placebo group (hazard ratio: 0.76; 95% confidence interval [CI]: 0.59–0.98, p = 0.03) with a relative risk reduction of 24.0% and number needed to treat of 16 patients. In a secondary end point analysis, the percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio: 0.75; 95% CI: 0.58–0.98, p = 0.04) with a relative risk reduction of 25%. The results also favored ocrelizumab with respect to ambulation speed as measured by the Timed 25-Foot Walk (T25FW, p = 0.04), change in the total volume of T2-weighted brain MRI lesions (p < 0.001), and change in brain volume (p = 0.02). Details on the results of these secondary endpoints are highlighted in Table 15.2.

The results of a subgroup analysis of efficacy endpoints in patients with and without GdE lesions at baseline were directionally consistent with the findings in the overall trial population. The trial was not powered to detect between-group differences among these subgroups, but the results suggest that active inflammation at baseline might represent a possible treatment-effect-modifying factor. In other words, patients with earlier, more active disease (e.g., clinical relapses and/or new MRI disease activity) might have increased benefit from ocrelizumab compared to 140those who have more advanced, “purely” progressive MS. The ORATORIO trial enrollment criteria excluded PPMS patients older than 55 years of age. Therefore, experience from clinical practice and extension phase data are warranted to further clarify treatment effects in an older MS population.

In a safety analysis, infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo. The imbalance in observed neoplasms in ocrelizumab warrants continued evaluation in the context of what is expected in an aging MS population and other anti-CD20 therapies (23,24). In the postmarketing experience, one case of progressive multifocal leukoencephalopathy (PML) was reported in a German patient with relapsing MS who transitioned from natalizumab to ocrelizumab through a compassionate use program (26). These results affirm that long-term clinical experience is warranted to better identify future safety signals and thereby stratify potential risks.



Siponimod (BAF312) is an oral selective sphingosine-1 phosphate (S1P) modulator, specifically targeting S1P-1 and S1P-5 receptors, and demonstrating greater selectivity than fingolimod (31). Siponimod therefore results in fewer organ-specific side effects based on the narrower distribution of S1P receptors throughout the body. Siponimod reduces circulation and infiltration of autoreactive lymphocytes into the CNS. It might exert its CNS effects by modulating neurobiological processes via S1P-1 and S1P-5 receptors on astrocytes and oligodendrocytes. A recent phase II trial demonstrated a reduction in brain MRI lesions and relapses by up to 80% of patients treated with siponimod versus placebo (32).

EXPAND, the largest phase III, randomized, double-blind, placebo-controlled study in SPMS to date, included over 1,600 patients from 31 different countries. SPMS patients with or without relapses and aged 18–60 years with an EDSS score from 3.0 to 6.5 were enrolled. Siponimod (2 mg once daily oral pill) reduced the risk of 3-month confirmed disability progression by 21% compared with placebo (p = 0.013) (33). Other results from the EXPAND study showed improvements compared with placebo in 12- and 24-month annualized relapse rate, the percentage change in brain volume, and change from baseline in T2 lesion volume. Based on the results in the given population, the optimal patient for siponimod would presumably be younger with earlier, more active disease. However, even patients with secondary progressive disease for over 3 years and EDSS scores of 6.5 seemed to gain some benefit in the clinical trial. These data suggest a potential therapeutic role for patients with SPMS, possibly even impacting those with a less inflammatory disease course. Overall, siponimod was well tolerated with a relatively benign safety profile.

High-Dose Biotin

Biotin (Vitamin H) is a ubiquitous water-soluble vitamin that acts as a coenzyme for various carboxylases involved in key steps of energy metabolism and fatty acid synthesis (26). A small case series recently described the treatment of “biotin responsive basal ganglia disease,” an orphan neurometabolic disease caused by mutations in the SLC19A3 gene coding for a thiamine transporter, with high doses of biotin (5–10 mg/kg/d) (27). Five patients with optic neuropathy and leukoencephalopathy also clinically responded to high-dose biotin, one of which was later found to have SPMS (28).

These findings prompted the development of a small pilot study investigating the effectiveness of high-dose biotin (100–300 mg/d) in both SPMS and PPMS (29). Evaluation criteria were variable across the 23 consecutive patients who were studied, including both quantitative and qualitative measurements. The preliminary data suggested that high doses of biotin might have a positive benefit in disability progression in progressive MS across visual and spinal cord pathways. The proposed mechanism of benefit likely stems from biotin’s role in targeting metabolic processes that provides energy production in a mismatched system of increased energy demand and a decreasing available reserve.

A French multicenter phase III double-blind, placebo-controlled trial investigating high-dose biotin (MD1003, 100 mg biotin tid) was conducted in progressive MS patients (either primary progressive or secondary progressive without recent relapses). The primary outcome of this study was the proportion of patients with disability reversal at 9 months, confirmed at 12 months, defined as a decrease in the EDSS score of ≥1 point (≥0.5 for EDSS 6.0–7.0) or a ≥20% decrease in the T25FW. 12.6% of the MD1003 group versus 0% of the placebo group met the primary endpoint (p < 0.005) (30). This trial showed that high-dose biotin reversed MS-related disability in some progressive MS patients, and importantly, demonstrated that this effect was sustained over 1 year.



Ibudilast (MN-166) is a nonselective phosphodiesterase (PDE-4 and PDE-10) inhibitor that also blocks the macrophage migration inhibitory factor. Earlier studies have shown that, together, these effects suppress the formation of pro-inflammatory cytokines and promote the production of brain growth factors (34). A phase II trial of ibudilast in patients with RRMS demonstrated no beneficial effect on the rate of newly active lesions and relapses but did show reduction in brain atrophy rates, suggesting a potential neuroprotective effect (35). 141A phase IIb study (SPRINT-MS) comparing ibudilast (50 mg twice daily oral pill) to placebo in either PPMS or SPMS is in progress in over 28 different centers across the United States. As of July 2016, half of the 255 enrolled patients completed the 96-week-long treatment schedule (NCT01982942) (36). For the primary endpoint of whole brain atrophy, ibudilast demonstrated a statistically significant 48% reduction in the rate of progression of whole brain atrophy compared to placebo (p = 0.04) in the modified ITT (intent-to-treat) population as measured by MRI analysis using brain parenchymal fraction (BPF). There were no significant outliers driving the results, and a modified sensitivity analysis was consistent with the primary analysis. Ibudilast also demonstrated a reduction in the progression of cortical atrophy compared to placebo as a secondary endpoint. Ibudilast had no effect on the progression of retinal nerve fiber layer thinning on optical coherence tomography.


Statins, hydroxymethylglutaryl-CoA reductase inhibitors, demonstrate immunomodulatory and neuroprotective effects in cerebrovascular disease (37). In this context, statins are potentially an attractive neurotherapeutic agent for progressive MS. Previous experimental allergic encephalomyelitis (EAE) models and open label trials showed decreased disease activity in patients with MS (38). A recent phase II trial (MS-STAT) showed a statistically significant reduction in the annualized rate of whole brain atrophy in patients treated with simvastatin 80 mg daily compared to placebo (−0.25% per year adjusted difference between the two groups; p = 0.003). In summary, patients treated with high-dose simvastatin showed a 43% reduction in the annualized rate of whole-brain atrophy versus placebo (39). It is important to note, however, that this metric has not been strongly linked to outcomes important to MS patients (e.g., cognition, symptoms, and overall function) and should be considered when designing future phase III clinical trials.

Amiloride, Riluzole, and Fluoxetine

The MS-SMART study is a four-arm phase II clinical trial investigating amiloride, riluzole, and fluoxetine compared with placebo (NCT01910259). Amiloride, a potassium-sparing diuretic, has been found to reduce functional neurologic deficits in previous EAE studies (40). Riluzole, an established disease therapy for amyotrophic lateral sclerosis, is an inhibitor of tetradotoxin-sensitive voltage-gated sodium channels with antiglutamatergic effects (41). Fluoxetine, a selective serotonin reuptake inhibitor, presumably has neuroprotective properties through suppression of microglia activation and enhancement of brain-derived neurotrophic factor in animal models (42,43). The mechanism of studying multiple therapeutics simultaneously is to minimize exposure to placebo while hastening the identification of an effective treatment strategy.

Restorative Therapies

Several potential restorative therapies are currently in the early phases of investigation in progressive MS.


Leucine-rich repeat and immunoglobulin-like domain containing neurite outgrowth inhibitor receptor-interacting protein-1 (LINGO-1) is a cell surface protein expressed in neural cells. It is a negative modulator of axonal myelination via inhibition of the differentiation of oligodendrocyte precursor cells to mature oligodendrocytes (44). In this context, blockage of LINGO-1 may represent a potential strategy for remyelination and preservation of axonal integrity in MS. A randomized, double-blind phase II trial (SYNERGY) of a novel anti-LINGO-1 monoclonal antibody (opicinumab, BIIB033) investigated the impact on disease progression in patients with RRMS and SPMS (45). Patients with either RRMS or relapsing SPMS were randomized either to one of four doses of IV opicinumab (3, 10, 30, or 100 mg/kg) in addition to IM interferon beta-1a or placebo. Out of 418 patients, 334 completed the 72-week study.

The primary endpoint of the study was the percentage of participants with 3-month confirmed improvement of neurophysical and/or cognitive function, using a multicomponent endpoint comprising the EDSS, T25FW, 9-Hole Peg Test, and 3-Second Paced Auditory Serial Addition Test. In summary, the investigators did not appreciate a linear dose response. Participants receiving the middle doses (10 and 30 mg/kg) achieved the strongest benefit with no detectable effects in the lowest and highest doses. Analyses also showed that opicinumab was more effective in younger patients and those with shorter disease duration and less severe whole brain volume loss at baseline. Although this U-shaped dose relationship failed to meet its primary endpoint, investigators plan to utilize what has been learned in the phase IIb trial by further investigating the middle dose that appears to have the strongest benefit (10 mg/kg) and recruiting patients most likely to be responders (younger individuals with early active disease) into future clinical trials.


Stem cell transplantation has been proposed as a second-line treatment strategy for refractory MS. The mechanism behind its role in MS is presumably through the eradication of autoreactive cells, thereby resetting the aberrant immune response to self-antigens, possibly promoting CNS regeneration (46). In an open label proof-of-concept clinical trial in patients with SPMS with clinical evidence of optic nerve involvement, infusion of autologous bone marrow–derived mesenchymal stem cells improved visual acuity and visual evoked response latency (47). A phase II trial of autologous bone marrow infusion in patients with SPMS or PPMS is in progress (NCT01815632).

Table 15.2 summarizes various clinical trials to date in progressive MS.





Progressive MS, like RRMS, is associated with a heterogeneous array of symptoms and functional deficits that result in a wide range of disability. Symptoms that contribute to the loss of independence and restriction in social activities critically impose upon quality of life and raise healthcare costs and utilization of resources. Individualized treatment of physical symptoms such as motor weakness, pain, mobility dysfunction, spasticity, and bladder and bowel disturbances; in addition to “invisible” symptoms such as fatigue, depression/anxiety, and cognitive and affective disorders is paramount.

Although pharmacotherapy can be beneficial and recommended when appropriate, nonpharmacological approaches can be equally, if not more, effective in progressive MS. An integral aspect of symptomatic treatment is physical and occupational therapy to help patients compensate for existing limitations and prevent disability-related injury. A regular strengthening, stretching, balance training, 145and fall prevention regimen instructed by an experienced therapist can be highly effective. Utilization of health psychology/counseling and social work resources to help patients manage life complications and stress that accompany progressive disability are key. Some institutions have access to a comprehensive rehabilitation team, which is particularly resourceful in managing MS-related spasticity, including Botox therapy and in some cases baclofen pump management for severe and/or intractable spasticity. In summary, a multidisciplinary approach is a highly effective strategy for treating the chronic symptoms of progressive MS.

Specifics on symptomatic therapy fall outside the scope of this chapter and are further discussed in Chapters 17–32 of this book.


The landscape for the development of effective treatment strategies for progressive MS is one of substantial need and significant promise. Currently, progressive MS lends many challenges to different disciplines: the scientist in understanding the pathogenesis of the disorder, the clinical researcher in identifying robust markers for measuring effective therapeutics in clinical trials, the healthcare provider in managing a chronic condition in clinical practice with few available, robust treatment strategies, and the patient for living day to day with a chronic, disabling illness.

Consider the concept of failed trials as opposed to failed therapeutics, whereby limitations in study design, specifically the absence of an effective therapeutic target, has led to delays in robust treatment strategies for progressive MS (48), notably PPMS and SPMS without active disease and continued progression. An example is the failure of fingolimod to show beneficial effects in PPMS in the INFORMS trial, in which greater than 40% of patients were greater than 50 years of age and greater than 85% of patients had no GdE lesions on baseline brain MRI (19). In summary, the trial population included an older, more advanced and predominantly neurodegenerative PPMS group, thereby selecting out patients with more inflammatory disease who would likely be better responders.

The incomplete understanding of the pathogenesis of progressive MS has made the identification of potential therapeutic targets difficult. Although targeting acute inflammation is a viable metric for relapsing MS, predicting clinical efficacy in phase II and phase III trials for progressive MS requires a more refined and focused assessment tool. One consideration for the failure of prior clinical trials investigating existing DMTs in progressive MS is lack of a sensitive, robust metric. Currently used clinical markers of disability such as the EDSS (49) and Multiple Sclerosis Functional Composite (MSFC) (50) have their own inherent limitations. EDSS is subject to high inter-rater variability (51), relies heavily on lower extremity function (52), does not include a meaningful cognitive component (53), and is overall insensitive to longitudinal change (54). The MSFC is limited in that it only assesses a restricted amount of neurologic function including arm, leg, visual, and cognitive features; and is not routinely measured in clinical practice. The challenge remains in identifying a metric that is easy to capture, sensitive to longitudinal change, quantitative, and strongly correlates with patient-reported function.

Concerted efforts are currently in progress to better identify new clinical outcome assessment tools that will enhance the development of effective therapeutics in progressive MS. The International Progressive MS Alliance is an expanding global coalition of MS organizations that aims to expedite the development of therapies for effective modification and symptom management of progressive MS (55). The Multiple Sclerosis Outcome Assessments Consortium (MSOAC), a conglomerate of industry, academic, regulatory, and patient representatives, strives to develop and support the adoption of new clinical outcome assessment tools for use in future MS clinical trials. The International Collaborative on Progressive MS has identified key priority areas for research that will leverage resources across disciplines and accelerate development of effective therapies in PMS (56) (see Table 15.3).

Clinical trials are now adopting unique metrics to more efficiently measure clinical efficacy outcomes in progressive MS (57) that capture the predominantly neurodegenerative aspect of the disease. Although this continues to remain a priority area of research, brain atrophy overall is the preferred method of monitoring the neurodegenerative process in progressive MS (58) and is a plausible surrogate measure of disability. This is a promising outcome metric, for sensitive and reproducible methods enable small amounts of brain atrophy to be detected over 1 year or less. Further, sample sizes for proof-of-concept trials that use brain atrophy as a primary outcome measure may be less than those required for clinical disability endpoints (59). However, whole-brain atrophy alone may not sufficiently correlate with patient-related function and should be considered when designing clinical trials and interpreting what this means from a phenotypic perspective. Other possible metrics include cerebrospinal fluid (CSF) biomarkers such as neurofilament chains, glial fibrillary acidic protein, tau, and S100b protein (60,61). Metabolomics profiling methods have also gained attention (62). Optimistically, the adoption of new study designs with novel outcome measures will pave the way for innovative, emerging therapeutics for progressive MS.

TABLE 15.3    International Collaborative on Progressive MS Key Priority Areas

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