Clinical trials in multiple sclerosis …

Jennifer Wiseman MD

Neuroimmunology

Updated 12.15.2025
Released 11.12.2002
Expires For CME 12.15.2028

Clinical trials in multiple sclerosis

Author: Jennifer Wiseman MD

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Editor: Anthony T Reder MD

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Clinical trials in multiple sclerosis

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Introduction

Overview

Prior to the introduction of interferon in 1993, there were no treatments approved for multiple sclerosis: the disease would inevitably progress, and patients would almost certainly become disabled, relying on a cane within 10 years and likely requiring a wheelchair within 20 years. Thanks to dedicated researchers and patients willing to participate in trials, there are now 20 FDA-approved disease-modifying therapies for multiple sclerosis. This article briefly discusses the basics of multiple sclerosis clinical trial design and the importance of standardized parameters and summarizes key information about FDA-approved treatment of acute relapses and long-term therapy for relapsing and progressive forms of multiple sclerosis.

Key points

	• There are 20 FDA-approved disease-modifying therapies for the treatment of relapsing forms of multiple sclerosis.
	• There will likely be a nomenclature shift from relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, and secondary progressive multiple sclerosis to relapsing and progressive forms of multiple sclerosis.
	• Ocrelizumab is currently the only FDA-approved therapy for primary progressive multiple sclerosis. There are no treatments specifically indicated for secondary progressive multiple sclerosis; rather, medications originally approved for primary progressive multiple sclerosis can be used for any relapsing form.
	• BTK inhibitors (phase III), anti-CD40L monoclonal antibodies (phase III), and CD19 chimeric antigen receptor (CAR)-T cell therapies (phase I) are currently being studied.

Clinical trials in multiple sclerosis

Although the first comprehensive description of multiple sclerosis was in 1868 by Jean-Martin Charcot, there would not be an FDA-approved disease-modifying therapy for another 125 years, when interferon beta-1b was approved in 1993. Since then, there has been extensive progress in the development of disease-modifying therapies for multiple sclerosis. There are currently 20 FDA-approved disease-modifying therapies approved for relapsing-remitting multiple sclerosis, one of which–ocrelizumab–is also approved for primary progressive multiple sclerosis. Effective treatment of progressive multiple sclerosis (be it primary or secondary progressive multiple sclerosis) remains elusive.

The two main perspectives of evaluating disability related to multiple sclerosis are relapse-associated worsening (RAW) and progression (of disability) independent of relapse. Relapses are acute-to-subacute onset of new or worsening neurologic dysfunction, typically lasting 2 to 6 weeks, and are associated with underlying inflammation. Relapses must be distinguished from a pseudorelapse, which is a situational, temporary worsening due to a stressor or illness. Progression can include clinically worsening function over time (disability progression), whereas disease progression refers to smoldering neurodegeneration and inflammation that could occur without exam changes (02). It is hypothesized that progressive disease is a separate disease process from relapsing disease. (See The future of multiple sclerosis treatment.)

MRI data are the best-described biomarkers for multiple sclerosis disease activity (28) and are typically a primary endpoint in phase II trials (which focus on safety and efficacy) and a secondary endpoint in phase III trials (which focus on confirming efficacy in a larger participant group for a longer period of time). Common trial endpoints are (1) new gadolinium-enhancing T1-weighted lesions, (2) new or enlarging T2-weighted lesions, (3) annualized relapse rates, and (4) confirmed disability progression for 6 months. Confirmed disability progression may be measured by different criteria: worsening Expanded Disability Status Scale (EDSS) score, slower timed 25-foot walk, and worse performance of the 9-Hole Peg Test (9HPT). The EDSS is the internationally utilized grading scale of multiple sclerosis–related disability based on deficits in the following categories: pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, and cerebral. The scores range from 0.0 to 10.0, with higher scores indicating more severe disability. EDSS scoring allows for a more uniform grading of disability but is not immune to inter-grader variability. The EDSS score is greatly impacted by a patient’s ambulatory status and may underrepresent other important deficits, such as hand dexterity. Confirmed disability progression on EDSS over 12 weeks is the standard metric used to evaluate disease-modifying therapies in secondary progressive multiple sclerosis and primary progressive multiple sclerosis. “No evidence of disease activity” (NEDA) is a composite endpoint in trials and clinically, whereby there is stability in several categories: absence of relapses and disability progression, and absence of gadolinium-enhancing T1 lesions and new/enlarging T2 lesions. As more trials are underway to study progressive forms of multiple sclerosis, the author anticipates more studies will highlight T25FW and 9HPT as primary endpoints, for example, ORATORIO-HAND (36).

For a detailed discussion on symptomatic therapy of multiple sclerosis, please consult the relevant MedLink article, Multiple sclerosis: treatment of its symptoms. This article will discuss major clinical trials for disease-modifying therapies in primary progressive multiple sclerosis, secondary progressive multiple sclerosis, and radiologically isolated syndrome after reviewing foundational studies on the treatment of relapses.

Treatment of acute relapses

Intravenous high-dose methylprednisolone 1000 mg/day for 3 to 5 days is the gold standard of management of moderate to severe relapses. Oral prednisone 1250 mg/day for 3 to 5 days, an equivalent dose, is considered noninferior, cheaper, and can be more easily used in the outpatient setting. However, it should be mentioned that this would require the patient to take twenty-five 50 mg tablets daily, and there is a significantly higher association with insomnia (62). In general, data do not support additional benefit from oral steroid tapers (85). However, some clinicians may choose to offer oral steroid tapers for those patients with severe attacks, larger lesions, or incomplete recovery.

For patients with disabling multiple sclerosis relapse symptoms not responding to treatment with adrenocorticotropic hormone or a course of intravenous or oral corticosteroids, plasma exchange should be considered (109; 60; 19).

A milestone in the treatment of relapses was a well-designed, controlled, double-blind, multicenter clinical trial reported in 1970 (arguably the first multicenter clinical trial in multiple sclerosis) (92). Patients were randomly assigned to either adrenocorticotropic hormone (ACTH) gel or placebo gel, both intramuscular injections. A total of 197 patients were enrolled from 10 centers throughout the United States. This study was also the first to utilize the Disability Status Scale (DSS), which later, and with minor modification, became what is known today as the Expanded Disability Status Scale (EDSS). In this study, a treatment regimen of 40 units of ACTH twice daily for 7 days, followed by 20 units twice daily for 4 days, and 20 units twice daily for 3 days, showed beneficial effects in DSS recovery, greatest in the first week. These data led to the broad acceptance of adrenocorticotropic hormone as a treatment for relapses and eventually to the FDA approval of ACTH in 1978.

Studies in the 1980s shifted focus to the use of intravenous methylprednisolone (IVMP) as the preferred treatment option for relapse, in part due to ease of access and lower cost. Several studies compared IVMP to ACTH (01; 06; 72; 102) and to placebo (25; 73). The dosages used in these studies differ from as low as IVMP 40 mg/day (72) to 500 mg/day (73), 15 mg/kg/day, and 1000 mg per day (25; 102). Lower dosages were found to be ineffective (72), and dosages from 500 to 1000 mg per day became widely accepted. The length of treatment also varied in these studies, and the consensus on how long the relapse should be treated transformed over the years. Although back in the 1960s to 1980s it was common practice to treat multiple sclerosis exacerbation for 4 weeks and even for up to 35 days (91; 92; 72), significantly shorter courses of 3 to 7 days were subsequently found to be sufficient (73; 102).

Practical recommendations. Accurate identification of multiple sclerosis relapses versus pseudorelapses is essential. Although mild relapses may not require treatment (90), there is a consensus that moderate to severe disabling relapses should be treated using systemic steroids (preferably corticosteroids). There is no consensus as to how early steroid treatment must be initiated to be effective, but it is generally thought that it should be started as early as possible from symptom onset. That said, it has been suggested that relapse treatment can be successfully initiated even as late as 1 to 2 months into a relapse (35).

Treatment for relapsing forms of multiple sclerosis

There are currently 20 FDA-approved disease-modifying therapies for relapsing multiple sclerosis, of which ocrelizumab is the only approved therapy for primary progressive multiple sclerosis.

There are no FDA-approved treatments specifically for secondary progressive multiple sclerosis. Ublituximab is the newest therapy and has been available since mid-2023 for the treatment of relapsing multiple sclerosis.

FDA-approved disease-modifying therapies for multiple sclerosis

Since 1993, 20 disease-modifying therapies have been approved by the FDA for the treatment of relapsing multiple sclerosis. Ocrelizumab remains the only therapy approved for primary progressive multiple sclerosis. Ublituximab i...

INJECTABLE DISEASE-MODIFYING THERAPIES

Interferon beta

It is not fully understood how interferon-beta improves multiple sclerosis outcomes. Generally, it has been shown to reduce the inflammation when given early in the disease, but it does not have much effect on neurodegeneration later in the disease process. In the context of multiple sclerosis, interferon-beta likely reduces relapse rates through several mechanisms: inhibiting T-cell proliferation, reducing MHC class II molecules on antigen-presenting cells, reducing T-cell migration into CNS, and shifting cytokines from pro-inflammatory to anti-inflammatory and promoting more balanced levels of cytokines. In the 1980s, intrathecal interferon-beta was reported to reduce relapse rates (51; 52). Subsequent trials for interferon-beta led to approval of subcutaneous and intramuscular formulations: interferon-beta 1b (every-other-day), interferon-beta 1a (weekly), interferon-beta 1a (weekly or twice-weekly).

Interferon-beta 1b. In 1993, the Interferon beta-1b Multiple Sclerosis Study Group trial was published (03; 83), which eventually led to FDA approval of interferon-beta 1b. This randomized, double-blind, placebo-controlled study included 372 patients with EDSS scores between 0 and 5.5 and at least two relapses in the preceding 2 years, randomized into three equal groups: 50 µg, 250 µg, or placebo subcutaneously every other day for 2 years. The primary endpoints were a reduction in exacerbation rate and proportion of patients who were exacerbation-free. Interferon-beta 1b 250 mcg significantly reduced relapse rates by 34% (relative reduction) and decreased the annual rate of active MRI lesions by 58%. Clinically and radiographically, there was a dose-response effect when compared to placebo 250 mcg (p=0.0001), 50 mcg (p=0.01), as well as to each other: 250 versus 50 mcg (p=0.0086). Due to gradual patient accrual and a long period for analysis and FDA submission, some patients in the pivotal trial of every-other-day 250 mcg interferon-beta 1b were followed for up to 4 to 5 years (04). The 30% relapse rate reduction observed in the pivotal trial was maintained through year 5, although significance was lost, likely because of the reduced sample size. With treatment, the median volume of T2 disease burden did not significantly change from baseline in each of the 5 years and was always significantly lower than that observed in placebo-treated patients.

Interferon-beta 1a. The Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis Study (PRISMS) was a multicenter controlled trial that led to the eventual approval of interferon-beta 1a. PRISMS-2 was the initial trial that followed patients for 2 years. In PRISMS-4, the PRISMS-2 placebo patients were re-randomized to either 22 or 44 mcg; the drug arm patients continued their original assignments for 2 more years. The primary outcome measure of the original 1998 study was relapse frequency during the 2 years. Five hundred and sixty patients with an EDSS score between 1.0 and 5.0 and at least two relapses in the preceding 2 years were randomized to 2-year treatment with placebo or interferon-beta 1a (22 or 44 mcg subcutaneously three times weekly) (PRISMS Study Group 1998a; 88; 65). Percent reduction in relapse rate compared to placebo was 33% for the 44-mcg group and 27% for the 22-mcg group. For both treatment groups, the time to EDSS progression was longer than for placebo. New MRI activity was lower than placebo (67% for 22 mcg, 78% for 44 mcg), with a statistically significant dose-response effect favoring 44 mcg over 22 mcg. In PRISMS-4, the patients who switched from a placebo to the drug showed reductions in relapse and MRI activity. This group, originally given a placebo, had an earlier time to EDSS progression than those originally assigned to the drug arm.

Clanet and colleagues compared intramuscular interferon-beta 1a at 30 or 60 mcg in 802 patients and found that the doses were equally effective clinically and radiographically (08). They concluded that there is a ceiling effect for weekly interferon: below a threshold dose, there might be a dose-response curve, but above this threshold, efficacy does not increase. An alternative explanation could be that this ceiling effect can be overcome if interferon beta is given with a multiple weekly administration per week protocol.

INCOMIN and EVIDENCE support the hypothesis that the dose and dosing schedule have a major impact on the clinical efficacy of beta interferon. They also corroborate pharmacological and preclinical data favoring more frequent administration of high-dose beta interferon.

INCOMIN directly compared the clinical and MRI efficacy of interferon-beta 1b 250 mcg subcutaneously every other day to interferon-beta 1a 30 mcg intramuscularly once a week (26). One hundred eighty-eight patients with an EDSS between 1 and 3.5 and at least two relapses in the preceding 2 years were randomized to treatment with either drug for 2 years. INCOMIN is the only multicenter trial examining interferon beta for treating multiple sclerosis, not sponsored by drug companies, with funding coming from institutional sources instead.

Every-other-day compared to weekly interferon-beta 1a over the 2 years showed that the interferon-beta 1b group had a statistically significant lower rate of annualized relapses (RR: 0.44), lower rate of new T2 lesions (RR: 0.6), lower proportion of patients with disability progression, and longer time to disability progression. The differences in efficacy were found to increase over time. However, there were limitations in matching: the interferon-beta 1a group had a greater number of total and enhancing lesions, was older by about 2 years, and had more male patients. Greater age at disease onset and male sex are associated with an adverse outcome according to a population-based study (110). This would suggest a poorer prognosis for patients treated with interferon-beta 1a and, therefore, bias the results in favor of interferon-beta 1b.

EVIDENCE compared the efficacies of interferon-beta 1a 44 mcg subcutaneously three times weekly (TIW) and interferon-beta 1a 30 mcg intramuscularly once weekly (QW), with a trial duration of under 1 year (82). The primary endpoints were the proportion of patients relapse-free at 24 weeks and the number of active lesions per patient per scan at 24 weeks. Significantly more patients were relapse-free with the 44-mcg subcutaneous TIW dosing schedule (75%) compared to 30-mcg intramuscular QW (63%). At 48 weeks, clinical and MRI effects still favored high-dose, three times weekly interferon-beta 1a, although the difference between the two groups became less pronounced.

According to the analysis of clinical outcomes of the original treatment groups 16 years after the pivotal interferon-beta 1b trial, there was a greater reduction in long-term disability and mortality rates among patients originally treated with interferon-beta 1b than in the original placebo group (18.3% for placebo vs. 8.3% for interferon-beta 1b 50 mcg and 5.4% for interferon-beta 1b 250 mcg) (27). Furthermore, a randomized cohort study 21 years after the start of the pivotal interferon-beta 1b trial reported that the hazard rate of death was reduced by 46.8% among patients treated with interferon-beta 1b 250 mcg compared with placebo (40).

Most of the side effects associated with interferon beta use are mild to moderate in intensity, most likely to occur during the first 3 to 6 months of treatment (eg, liver enzyme elevation), and likely to decline in frequency thereafter (107). The INCOMIN study showed that the frequency of some side effects was greater in the high-dose, high-frequency regimens. Local skin reactions to interferon beta tend to decline with improved injection technique (103).

During treatment, some patients develop antibodies against interferon beta. Neutralizing antibodies (NAbs) to interferon beta may affect its biological availability and the production of interferon-induced biological markers (93; 21; 18; 104; 07). Neutralizing antibodies may also impact interferon-beta clinical and MRI efficacy. However, the NAbs data remain somewhat controversial: whereas some studies find a detrimental effect of neutralizing antibodies on treatment response (05; 93; 97; 69; 34; 56), others did not (Anonymous 1998a; 26; 82). Long-term evaluations show that the impact of NAbs on clinical outcomes might be delayed for between 3 and 4 years (88). It is worth noting that neutralizing antibodies frequency is lower for intramuscular interferon beta 1a (which has been associated with the lowest frequency of NAbs, 2% to 6%) (50; 82) compared to subcutaneous interferon beta 1a (12% to 25%) (Anonymous 1998a; 82) and interferon beta 1b (22% to 38%) (05; 26; 97).

Strategies to reduce the occurrence of NAbs have been studied. The addition of 1 g methylprednisolone each month to interferon beta therapy was well tolerated and reduced the development of NAbs by over 50% (87). Another approach is to increase the interferon beta dose. The PRISMS study showed that NAbs frequency was significantly lower in patients treated with the higher dose (Anonymous 1998a; 34). The OPTimization of Interferon for MS (OPTIMS) study, a multicenter, prospective trial investigating outcomes with two interferon beta-1b doses, 250 or 375 mcg, administered subcutaneously every other day, showed that NAbs-positive patients treated with 375 mcg interferon beta-1b had a significantly greater probability of NAbs disappearance (24).

There is a lack of consensus on whether a single weekly administration of interferon beta is less effective than higher-dose, more frequent injections of either interferon beta-1a or beta-1b. Patient preference and resulting adherence to prescribed therapy are important to weigh against the presented evidence suggesting that interferon beta given by more frequent injections is more effective than once-weekly injections.

Glatiramer acetate

Randomized trials. The first large, controlled trial included 251 patients with an EDSS score between 0 and 5.5 and at least two relapses in the preceding 2 years, randomized to receive either placebo or 20 mg glatiramer acetate subcutaneous daily for up to 3 years (53). At 2 years, glatiramer acetate reduced relapse rate (-29%; p=0.007), the primary endpoint, and slowed unconfirmed 1.5-point EDSS progression (-28%; p=0.037), compared to placebo. No MRI outcome measures were assessed as part of this trial.

A second trial was undertaken to evaluate MRI measures (16). It involved 249 patients with EDSS scores between 0 and 5.0, at least one relapse in the previous 2 years, and one gadolinium-enhancing lesion on the screening MRI. Patients were randomized to receive either a placebo or 20 mg glatiramer acetate for 9 months, with monthly MRIs. Glatiramer acetate reduced the total number of enhancing lesions (the primary endpoint) (-35%; p=0.001), relapse rate (-33%; p=0.012), and the median change in T2 disease burden (-8.3%; p=0.0011). The effect on MRI-enhancing lesions was delayed until 6 months after starting treatment. The compound was subsequently approved.

Another multicenter randomized study evaluated the efficacy, safety, and tolerability of glatiramer acetate 40 mg daily versus the approved 20 mg formulation given for 9 months (13). The trial enrolled 229 patients with EDSS scores of 0 to 5.0, no previous use of glatiramer acetate, at least one relapse in the previous year, and 1 to 15 Gd+ lesions on a screening MRI. Of the 229 patients, 90 were randomly assigned 1:1 to glatiramer acetate 20 mg or 40 mg. The primary efficacy endpoint was the total number of enhancing lesions at months 7, 8, and 9, and it showed a trend favoring the 40 mg dose (38% relative reduction, p = 0.090). The clinical endpoints were statistically significant in favor of the 40 mg dose: relapse-free subjects (p=0.018) and time to first relapse (p=0.037). The results suggest a trend for higher efficacy of the 40 mg dose over the 20 mg dose in reducing MRI activity. The 40 mg dose was significantly more effective than the standard dose on clinical endpoints (clinical relapses, time to first relapse).

Although the 20 mg dose of glatiramer acetate appears to be sufficient to provide meaningful efficacy, there is hope that a higher dose (40 mg) at less frequent dosing intervals may be able to demonstrate even greater convenience. Based on several open-label, small-scale (30 to 68 subjects) studies (30 to 68 subjects) that demonstrated relatively comparable efficacy of the standard daily dosing glatiramer acetate to alternate days or twice weekly, a large-scale, multinational, multicenter double-blinded placebo-controlled trial of glatiramer acetate 40 mg three times a week versus placebo was designed. In the phase III, Glatiramer Acetate Low-Frequency Administration (GALA) study, there was a 34.4% reduction in annualized relapse rate (ARR) as compared to placebo (p< 0.0001). Additionally, there was a 34.4% reduction in the cumulative number of new and enlarging T2 lesions (p< 0.0001) and a 44.8% reduction in the cumulative number of gadolinium-enhancing lesions (p< 0.0001). At 12 months, there was no significant difference in the percent change of brain volume between glatiramer acetate and placebo. Discontinuation rates among the glatiramer acetate and placebo patient cohorts were comparable. The overall frequency of adverse events in the two arms was comparable; the most reported adverse events were injection-site reactions, headaches, and nasopharyngitis.

Glatiramer acetate is usually well-tolerated. Short-lived local skin reactions are common. Lipoatrophy can be very disfiguring and is thought to be permanent, which should be taken into consideration. Patients should be aware of the possibility of lipoatrophy, be able to identify it, and discontinue injecting in areas where it is identified. Glatiramer acetate 40 mg daily showed the same safety profile as the 20 mg formulation (13).

Persistence of glatiramer acetate efficacy over time, comparative trials, and treatment protocol. A report on the extended open-label use (approximately 5.8 years) of glatiramer acetate in 152 patients initially enrolled in the placebo-controlled study has been published (54). The authors reported a reduction in relapse rate of almost 70% and stabilization of the EDSS score during follow-up. However, the overall dropout rate was high (40%), possibly resulting in a self-selected cohort of patients who responded well to therapy. During this long-term open-label follow-up period, relapse rates were similar in those patients receiving active treatment from the beginning of the trial as well as in those initially randomized to placebo.

Another extended, open-label use, multicenter study (going back approximately 13.6 years) of glatiramer acetate in 100 patients initially enrolled in the placebo-controlled study has been published (31). For ongoing patients, annual relapse rates (ARRs) maintained a decline from 1.12 +/- 0.82 at baseline to 0.25 +/- 0.34 per year; 57% had stable or improved EDSS scores (change 0.5 or fewer points); 65% had not transitioned to secondary progressive multiple sclerosis; 38%, 18%, and 3% reached EDSS 4, 6, and 8. The authors also reported the results of a follow-up MRI scan from 135 patients remaining in the open-label follow-up, obtained after an average of 4 years of treatment (112). This enabled a comparison of Gd+ lesion frequency in a group of patients receiving glatiramer acetate for approximately 4 years with the group that had remained on active treatment since the trials began (about 6.7 years). In patients receiving active treatment for a shorter period, the risk of having enhancing lesions was 2.5 times higher, suggesting that the full benefit of glatiramer on this MRI finding occurs after many years of treatment. Of note, the T2 disease burden, an MRI parameter that better reflects accumulated disease activity, was similar in both groups. As previously discussed, open-label extension studies may have statistical bias and be difficult to interpret.

A Cochrane systematic review assessed the efficacy of glatiramer acetate by pooling together data from four published individual trials (76). The authors tried to get raw patient data from the original trials from the company producing glatiramer, but they did not receive any answer. The authors used intent-to-treat analysis and calculated the risk ratio with the fixed effect model for most outcomes (disability progression at 2 years, EDSS change at 2 years, and proportion of patients with relapses), using a random model only in case of outcomes with a significant heterogeneity (mean number of relapses at 1 and 2 years). Glatiramer acetate did not seem better than placebo either in preventing clinical progression or in reducing the number of relapse-free patients at 2 years. For the mean number of relapses, the weighted mean difference showed no significant decrease in relapse at 1 and 2 years.

Another systematic review, instead of analyzing the various studies individually, pooled raw patient data from the original trials provided by the company producing glatiramer (70). They claimed that glatiramer could reduce the relapse rate by 28% compared to placebo over a 2-year follow-up. Martinelli Boneschi and colleagues used data from only three of the four published studies on this topic and did not specify criteria for study selection. They used multivariate regression analysis and did not mention either intention-to-treat analysis or evaluation of data heterogeneity. Finally, they evaluated only continuous outcomes (annualized relapse rate and time to first relapse). It should be noted that a dichotomous outcome, such as the proportion of patients who were relapse-free (the outcome used in the analysis of Munari and colleagues) instead of relapse rate (used by Martinelli Boneschi and colleagues), is a more sensitive outcome measure (70; 76). A few patients with many relapses might, in fact, disproportionately affect the overall relapse rate, whereas they proportionally affect the number of relapse-free patients, always being counted as one patient with relapses, independent of the number of relapses. Martinelli Boneschi and colleagues did not assess the heterogeneity among studies; therefore, heterogeneity was not considered in their multivariate analysis (74).

Two head-to-head studies were conducted between glatiramer and interferon products: REGARD and BEYOND. REGARD was designed based on the preconceived expectation that interferon beta-1a 44 mcg three times a week is superior to daily glatiramer acetate 20 mg. In this direct head-to-head comparison trial, there did not appear to be meaningful differences between interferon beta-1a 44 mcg three times a week and glatiramer acetate 20 mg daily (71). Similarly, BEYOND (a trial that aimed to demonstrate superiority of double-dose interferon beta-1b over the standard dose of 250 mcg and over glatiramer acetate 20 mg daily) did not demonstrate meaningful differences between interferon beta-1b and glatiramer acetate in respect to the primary outcome of the study (relapse risk) (79); however, the rater-blinded, post hoc analysis on new MRI lesion evolution into permanent “black holes,” a marker of irreversible tissue damage, provided Class III evidence that interferon beta-1b is associated with a reduction in MRI permanent “black holes” formation and evolution compared with glatiramer acetate between years 1 and 2 of treatment (29).

Furthermore, it should be noted that based on the CombiRx study data, the arms of glatiramer acetate monotherapy and combined glatiramer acetate and IFN-beta-1a IM weekly did not show a statistically significant difference with respect to the primary outcome (annualized relapse rate). (CombiRx study was an NIH-funded clinical trial comparing several arms: (1) IFN-beta-1a intramuscular weekly monotherapy; (2) glatiramer acetate subcutaneous monotherapy; (3) combination therapy of IFN-beta-1a intramuscular weekly and glatiramer acetate subcutaneous daily.) This evidence indicates that adding IFN-beta-1A intramuscular weekly to glatiramer acetate did not provide any additional benefit (67).

Ofatumumab

Ofatumumab is an anti-CD20 monoclonal antibody approved by the FDA in 2020. Unlike ocrelizumab and ublituximab, which are infusions, ofatumumab is a 20 mg, every-4-week subcutaneous injection that follows three weekly 20 mg loading doses. The identical phase III, randomized, double-blind trials ASCLEPIOS I and II were published in 2020 (44). Taken together, these studies enrolled 1882 patients with relapsing-remitting multiple sclerosis and compared ofatumumab to teriflunomide 14 mg daily. The primary outcome, annual relapse rate, was 0.11 and 0.10 in the ofatumumab groups in each study, respectively, with reductions of -0.11 (95% CI: -0.16 to -0.06, p< 0.001) and -0.15 (95% CI: -0.20 to -0.09). Confirmed disability progression at 12 weeks was reduced in the ofatumumab groups (HR: 0.66, p=0.002): 10.9% with ofatumumab versus 15% with teriflunomide. Injection reactions were seen in 20.2% of patients receiving ofatumumab (15% in the teriflunomide group with placebo injections); 2.5% of the ofatumumab groups had serious infections. An extension study to 3.5 years did not identify additional safety concerns (45).

ORAL DISEASE-MODIFYING THERAPIES

Sphingosine 1-phosphate receptor modulator (S1Ps)

Fingolimod. Fingolimod was approved by the FDA in 2010 for the treatment of relapsing forms of multiple sclerosis after the pivotal study demonstrating its efficacy in reducing the frequency of clinical exacerbations and delaying the accumulation of physical disability. Fingolimod is metabolized by sphingosine kinase to the active metabolite, fingolimod-phosphate. Fingolimod-phosphate is a sphingosine 1-phosphate receptor modulator and binds with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, substantially reducing the number of lymphocytes in peripheral blood. The efficacy of this drug was shown by two studies: the TRANSFORMS study (09) and the FREEDOMS study (59). After FDA approval, the FREEDOMS II trial confirmed the results of the FREEDOMS trial.

In the 12-month TRANSFORMS trial, 1292 patients with relapsing-remitting multiple sclerosis were randomly assigned in a double-dummy, double-blind design to fingolimod 1.25 mg oral daily, fingolimod 0.5 mg oral daily, or interferon beta-1a 30 mcg intramuscular weekly. A total of 1153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod--0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI: 0.12 to 0.21) in the 0.5-mg group--than in the interferon group (0.33, 95% CI: 0.26 to 0.42, p< 0.001 for both comparisons). MRI findings supported the primary outcome results. No significant differences were seen among the study groups with respect to progression of disability. Two fatal infections occurred in the group that received the 1.25 mg dose of fingolimod: disseminated primary varicella-zoster and herpes simplex encephalitis. Other adverse events among patients receiving fingolimod were nonfatal herpesvirus infections, bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver enzyme levels.

In the 24-month FREEDOMS study, 1272 patients with relapsing-remitting multiple sclerosis were randomly assigned in a double-blind design to one of three groups: fingolimod 1.25 mg oral daily, fingolimod 0.5 mg oral daily, or a matching placebo oral daily. A total of 1033 of the 1272 patients (81.2%) completed the study. The annualized relapse rate was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg of fingolimod, and 0.40 with placebo (p< 0.001 for either fingolimod dose vs. placebo). Fingolimod at doses of 0.5 mg and 1.25 mg significantly reduced the risk of disability progression over the 24-month period (hazard ratio, 0.70 and 0.68, respectively; p=0.02 vs. placebo, for both comparisons). The cumulative probability of disability progression (confirmed after 3 months) was 17.7% with 0.5 mg of fingolimod, 16.6% with 1.25 mg of fingolimod, and 24.1% with placebo. Both fingolimod doses were superior to placebo regarding MRI-related measures (number of new or enlarged lesions on T2-weighted images, Gd+ lesions, and brain-volume loss; p< 0.001 for all comparisons at 24 months). Causes of study discontinuation and adverse events related to fingolimod included bradycardia and atrioventricular conduction block at the time of fingolimod initiation, macular edema, elevated liver enzyme levels, and mild hypertension.

In 2012, FREEDOMS II randomized 1083 patients with relapsing-remitting multiple sclerosis to fingolimod 0.5 mg, 1.25 mg, or placebo in a 1:1:1 ratio. Participants were treated for 24 months. Three-fourths of the participants had undergone prior treatment with other disease-modifying treatments. Approximately 72% of patients enrolled in the trial completed this study. Fingolimod administered at a daily dose of 0.5 mg significantly reduced the annualized relapse rate by 48% compared with placebo (p< 0.001) and increased the percentage of patients free of multiple sclerosis relapse at the end of 24 months compared with placebo (71.5% vs. 52.7%, respectively). Brain atrophy was significantly reduced with daily treatment of 0.5 mg of fingolimod versus placebo at month 24: 33% reduction in brain volume versus placebo (p< 0.001). The effect on brain volume was seen as early as 6 months (39% reduction) and was consistent at 12 months (40% reduction) and 24 months.  Although numerically fewer patients treated with 0.5 mg of fingolimod experienced disability progression, as measured by change in Expanded Disability Status Scale (EDSS), this difference did not reach statistical significance. However, functional impairments, as measured by the Multiple Sclerosis Functional Composite (MSFC), were significantly less at month 24 in the group treated with a daily dose of 0.5 mg of fingolimod versus placebo (p=0.012). Fingolimod, administered at 0.5 mg, was superior to placebo on all MRI assessments of Gd+ lesions and new or newly enlarging T2 lesions.

The most common adverse events reported in the clinical trials were headache, influenza, diarrhea, back pain, liver transaminase elevations, and cough. The side-effect profiles seen in both phase III pivotal trials (FREEDOMS and TRANSFORMS) were similar.

Siponimod. Siponimod was approved by the FDA for relapsing multiple sclerosis. Like fingolimod, siponimod is a modulator of the sphingosine-1-phosphate receptor with specific affinity for S1PR types 1 and 5. The BOLD study tested two patient cohorts sequentially, separated by an interim analysis at 3 months. The primary endpoint was dose-response, assessed by the percentage reduction in the number of unique active lesions at 3 months for siponimod versus placebo. In cohort 1, 188 patients were allocated (1:1:1:1) to receive once-daily siponimod 10 mg, 2 mg, or 0.5 mg, or placebo for 6 months. In cohort 2, 109 patients were allocated (4:4:1) to siponimod 1.25 mg, siponimod 0.25 mg, or placebo once-daily for 3 months. The study showed a dose-response relation across the five doses of siponimod (p=0.0001), with reductions in unique active lesions at 3 months compared with placebo of 35% (95% CI: 17-57) for siponimod 0.25 mg (51 patients included in the primary endpoint analysis), 50% (29 to 69) for siponimod 0.5 mg (43 patients), 66% (48 to 80) for siponimod 1.25 mg (42 patients), 72% (57 to 84) for siponimod 2 mg (45 patients), and 82% (70 to 90) for siponimod 10 mg (44 patients). The highest incidence of adverse events was noted in patients receiving siponimod 10 and 2 mg daily. Cardiac adverse events, including bradycardia, bradyarrhythmia, and atrioventricular conduction delays, were noted when treatment was started without dose titration. Increases in liver transaminases were also observed in a dose-dependent manner. However, the incidence of infections was not related to dose (96). Siponimod use is dependent on the CYP2C9 genotype, and this must be tested prior to use as it impacts safety and titration schedules. Siponimod is contraindicated with the CYP2C9 * 3/* 3 genotype, whereas daily dosing is 1 mg in patients with CYP2C9 * 1/* 3 or * 2/* 3 genotypes (23).

An extension of the BOLD study was conducted and designed to assess the efficacy and safety of siponimod for up to 24 months. Patients taking siponimod continued at the originally assigned dose, and patients taking a placebo were rerandomized to the five siponimod doses. Of the 252 patients, 184 (73%) entered the extension; 159 (86.4%) completed the dose-blinded extension. The incidence of adverse events was similar across treatment groups (10 mg: 87.9%; 2 mg: 89.7%; 1.25 mg: 88.4%; 0.5 mg: 96.6%; and 0.25 mg: 84.0%). Reductions in mean (95% CI) gadolinium-enhancing T1 lesion counts from the last BOLD assessment were sustained in the 10 mg, 2 mg, 1.25 mg, and 0.5 mg dose groups. Similarly, both the annualized relapse rate and the number of new or newly enlarging T2 lesions were significantly lower in the three highest dose cohorts compared to the two lower dose cohorts up to 24 months (58).

Ozanimod. Ozanimod is an oral therapy that was approved by the FDA in 2020. Ozanimod is a sphingosine-1-phosphate receptor modulator with selective binding to receptor subtypes 1 and 5. Ozanimod was evaluated in the phase III SUNBEAM and RADIANCE trials (11; 17). SUNBEAM compared ozanimod with interferon beta-1a in patients with relapsing multiple sclerosis over 12 months. Patients had an EDSS of 5.0 or less, as well as either one relapse within 12 months or one relapse within 24 months and an enhancing lesion on MRI within 12 months. In this study, 1346 patients were enrolled, and treatment groups were ozanimod 1 mg daily, ozanimod 0.5 mg daily, or interferon beta-1a 30 μg weekly. The primary endpoint was an annualized relapse rate of 0.35 for interferon beta-1a, 0.24 for ozanimod 0.5 mg, and 0.18 for ozanimod 1 mg. When compared to interferon beta-1a, both ozanimod 0.5 mg (0.69) and ozanimod 1 mg (0.24) showed reduction based on rate ratio. No clinically significant arrhythmias or heart blocks were noted. RADIANCE made a similar comparison with a 24-month follow-up and found similar outcomes.

Ponesimod. Ponesimod is a sphingosine-1-phosphate receptor modulator that acts exclusively on receptor subtype 1 (S1P1R). The OPTIUUM trial evaluated the efficacy of ponesimod in comparison to teriflunomide 14 mg daily in patients with relapsing multiple sclerosis, an EDSS of 5.5 or less, and active disease evidenced by one or more relapses within 12 months, two or more relapses within 24 months, or one or more Gd+ lesions on MRI within 6 months (57). In this study, 1133 patients were enrolled and followed for 108 weeks; the primary outcome was an annualized relapse rate. The ponesimod group had an annualized relapse rate of 0.202 compared to 0.290 for the teriflunomide group, with a reduction in annualized relapse rate of 30.5%. Ponesimod reduced active lesions on MRI by 56%.

Fumarates

Dimethyl fumarate. Dimethyl fumarate was approved for relapsing-remitting multiple sclerosis in April 2013. The proposed mechanism of action is inhibition of the expression of proinflammatory adhesion molecules and cytokines, causing activation of Nrf2 pathways. Dimethyl fumarate’s efficacy has been studied in two pivotal phase III trials: DEFINE and CONFIRM (33; 39). Both DEFINE and CONFIRM were 2-year trials that enrolled more than 1200 subjects. In addition to the three arms of the DEFINE trial (dimethyl fumarate 240 mg twice daily; dimethyl fumarate 240 mg three times daily; placebo), CONFIRM included another comparator arm: daily subcutaneous glatiramer acetate. The incidence of serious infections was similar across treatment groups in both trials. The most common side effects of dimethyl fumarate are flushing and gastrointestinal symptoms, including abdominal cramps and diarrhea. In DEFINE, the annualized relapse rate was decreased by 53% (when compared to placebo) with 240 mg twice daily dosing (p< 0.001), with an 85% decrease in new or enlarging T2 lesions and a 90% decrease in Gd+ lesions. When comparing dimethyl fumarate 240 mg twice daily to placebo in CONFIRM, the annualized relapse rate was decreased by 44% (p< 0.001), with T2 MRI lesions and Gd+ reduced by 71% and 57%, respectively (p< 0.001).

Diroximel fumarate. Diroximel fumarate was approved by the FDA in 2019. Like dimethyl fumarate, it is a prodrug that is metabolized in the intestine to the active form, monomethyl fumarate. However, its different structure allows for a lower risk of gastrointestinal side effects (77). EVOLVE-MS-1 was a phase III open-label, single-arm, 2-year trial evaluating the long-term safety and efficacy of diroximel fumarate. The study enrolled 696 patients with relapsing-remitting multiple sclerosis aged 18 to 65 years (median of 42) with an EDSS below 6. The annualized relapse rate was 0.19 (after 1 year of treatment). At week 48, diroximel fumarate reduced Gd+ lesion reduction by 77% overall and by 96% in newly diagnosed patients. Absolute lymphocyte counts (ALC) declined by 28.4% in the first year, then stabilized. Diroximel fumarate was held for severe lymphopenia defined as ALC under 0.5 × 10⁹/L for 4 or more weeks, which occurred in six patients. Adverse events occurred in 84.6% of patients; the majority were mild (31.2%) or moderate (46.8%) in severity. Overall treatment discontinuation was 14.9%: 6.3% due to adverse events and less than 1% specifically due to gastrointestinal adverse events. Treatment-emergent adverse events occurred in 30.9%, of which 60% occurred during the first month of treatment; 0.4% of treatment-emergent adverse events were considered to be serious (inguinal hernia, peptic ulcer, abdominal pain).

Monomethyl fumarate. Monomethyl fumarate was approved by the FDA in April 2020. Monomethyl fumarate is the sole active metabolite of dimethyl fumarate and diroximel fumarate and was approved based on bioequivalence data.

Other oral disease-modifying therapies

Teriflunomide. Teriflunomide was approved by the FDA for the treatment of relapsing forms of multiple sclerosis in 2012. Teriflunomide, an immunomodulatory agent with anti-inflammatory properties, inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. Teriflunomide is the active metabolite of leflunomide, which was previously approved by the FDA for rheumatoid arthritis. The efficacy of teriflunomide was demonstrated in TEMSO, a double-blind, placebo-controlled study that evaluated once-daily doses of teriflunomide 7 mg and 14 mg in patients with relapsing forms of multiple sclerosis over 108 weeks (78). All patients had a definite diagnosis of multiple sclerosis, exhibiting a relapsing clinical course, with or without progression, and had experienced at least one relapse over the year preceding the trial or at least two relapses over the 2 years preceding the trial. Subjects had not received interferon beta for at least 4 months or any other preventive multiple sclerosis medications for at least 6 months before entering the study, nor were these medications permitted during the study. Neurologic evaluations were performed at screening every 12 weeks until week 108 and at unscheduled visits for suspected relapse. MRI was performed at screening at weeks 24, 48, 72, and 108. The primary endpoint was an annualized relapse rate.

In this study, 1088 patients were randomized 1:1:1 to receive 7 mg or 14 mg of teriflunomide or placebo (n=363). At entry, patients had an EDSS score of 5.5 or lower. The mean age of the study population was 37.9 years, the mean disease duration was 5.33 years, and the mean EDSS at baseline was 2.68. A total of 91.4% had relapsing-remitting multiple sclerosis, and 8.6% had a progressive form of multiple sclerosis with relapses. The mean time on placebo was 631 days, on teriflunomide 7 mg was 635 days, and on teriflunomide 14 mg was 627 days.

The annualized relapse rate was significantly reduced in patients treated with either 7 or 14 mg of teriflunomide compared to placebo. The time to disability progression sustained for 12 weeks was statistically significantly reduced only in the teriflunomide 14 mg group compared to placebo. The change in total lesion volume from baseline was significantly lower and had fewer Gd+ lesions in the 7 and 14 mg groups than in the placebo group. A consistent reduction of the annualized relapse rate was noted in subgroups defined by sex, age group, prior multiple sclerosis therapy, and baseline disease activity. The time to disability progression sustained for 12 weeks (as measured by at least a 1-point increase from baseline EDSS of 5.5 or less or a 0.5-point increase from baseline EDSS greater than 5.5) was statistically significantly reduced only in the teriflunomide 14 mg group compared to placebo. The effect of teriflunomide was assessed on several MRI variables, including the total lesion volume of T2 and hypointense T1 lesions. The change in total lesion volume from baseline was significantly lower in the 7 and 14 mg groups than in the placebo group. Patients in both teriflunomide groups had significantly fewer gadolinium-enhancing lesions per T1-weighted scan than those in the placebo group.

Although the FDA approval of teriflunomide was based on TEMSO, a second phase III, placebo-controlled trial of teriflunomide 7 mg and 14 mg has been reported (TOWER). The results of TOWER are consistent with those seen in TEMSO. In terms of annualized relapse rate, there was a 22.3% reduction (p=0.02) in the teriflunomide 7 mg arm and a 36.3% reduction (p< 0.0001) in the teriflunomide 14 mg arm, compared to placebo. In terms of 12-week sustained accumulation of physical disability, there was a statistically significant 31.5% (p=0.0442) reduction for teriflunomide 14 mg, but the reduction was not significant for teriflunomide 7 mg, as compared to placebo.

A phase III, multinational, randomized parallel-group study (TENERE) was designed as a superiority trial to compare the effectiveness, defined as time to failure (first occurrence of confirmed relapse or permanent treatment discontinuation for any reason, whichever came first), and tolerability of oral teriflunomide 7 mg daily (n=109) or oral teriflunomide 14 mg daily (n=111) versus subcutaneous interferon beta-1a 44 mcg, three times weekly (n=104) (105). The results of this trial did not reveal any statistical differences in the primary composite endpoint: 48.6% for teriflunomide 7 mg, 42.3% for interferon beta-1a 44 mcg, and 37.8% for teriflunomide 14 mg. The adjusted annualized relapse rate over 96 weeks of treatment was 0.41 with teriflunomide 7 mg, 0.26 with teriflunomide 14 mg, and 0.22 with interferon beta-1a 44 mcg. There was no significant difference for teriflunomide 14 mg versus interferon beta-1a 44 mcg, but teriflunomide 7 mg was associated with a higher risk of relapse than interferon beta-1a 44 mcg (89.7%, p=0.03). Greater treatment satisfaction (p=0.02) and fewer discontinuations were observed with both doses of teriflunomide compared with interferon beta-1a 44 mcg. There was also a statistically significant lower adjusted mean change from baseline to week 48 in the fatigue impact scale score for the teriflunomide 7 mg arm as compared to the interferon beta-1a 44 mcg arm (p=0.03), but not for the teriflunomide 14 mg arm as compared to the interferon beta-1a 44 mcg arm (p=0.18).

The most common adverse events reported in the clinical trials were alanine aminotransferase increase, nasopharyngitis, alopecia, nausea, diarrhea, and paresthesia. Teriflunomide has a black box warning label of fetotoxicity; thus, it is contraindicated in pregnancy. In placebo-controlled studies, peripheral neuropathy, including both polyneuropathy and mononeuropathy (eg, carpal tunnel syndrome), was reported more frequently in patients taking teriflunomide than in patients taking a placebo.

Cladribine. Cladribine is a synthetic deoxyadenosine analogue approved by the FDA for relapsing multiple sclerosis based on the CLARITY study, which examined the efficacy of cladribine using the rate of relapse at 96 weeks as its primary endpoint (37). In the study, 1326 patients were randomly assigned in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine tablets (either 3.5 or 5.25 mg/kg) or matching placebo, given in two or four courses for the first 48 weeks, then in two courses starting at week 48 and week 52 (for a total of 8 to 20 days per year). Among patients who received cladribine tablets (either 3.5 or 5.25 mg/kg), there was a significantly lower annualized rate of relapse than in the placebo group (0.14 and 0.15, respectively, vs. 0.33; p< 0.001 for both comparisons), a higher relapse-free rate (79.7% and 78.9%, respectively, vs. 60.9%; p< 0.001 for both comparisons), a lower risk of 3-month sustained progression of disability (hazard ratio for the 3.5 mg/kg group: 0.67, p=0.02; hazard ratio for the 5.25 mg/kg group: 0.69, p=0.03), and significant reductions in the brain lesion count on MRI (p< 0.001 for all comparisons). Adverse events that were more frequent in the cladribine groups included lymphocytopenia (21.6% in the 3.5 mg/kg group and 31.5% in the 5.25 mg/kg group vs. 1.8%) and herpes zoster (8 and 12 patients, respectively, vs. no patients).

A post hoc and subgroup analysis of the CLARITY study showed that treatment with cladribine increased the proportion of patients showing NEDA-3 over a 96-week period. Freedom from disease activity is commonly defined using three clinical and radiographic parameters: absence of relapses, absence of new MRI lesions over a specified period, and absence of sustained change in EDSS over a 3-month period (38). Of the 1326 patients enrolled in the CLARITY study, 1192 were assessed for disease activity at 24, 48, and 96 weeks. These patients were analyzed based on treatment group as well as subgroups, including age, prior treatment status, disease duration, number of relapses in the previous 12 months, EDSS score, T1 Gd-enhancing lesions, T2 lesion volume, and patients with high disease activity. Over 24 weeks, 266 (67%) of 395 patients in the cladribine 3.5 mg/kg group and 283 (70%) of 406 in the cladribine 5.25 mg/kg group were free from disease activity versus 145 (39%) of 373 in the placebo group. Over 48 weeks, 208 (54%) of 384 patients in the cladribine 3.5 mg/kg group and 222 (56%) of 396 patients in the cladribine 5.25 mg/kg group were free from disease activity versus 86 (24%) of 360 patients in the placebo group. Over 96 weeks, 178 (44%) of 402 patients in the cladribine 3.5 mg/kg group and 189 (46%) of 411 patients in the cladribine 5.25 mg/kg group were free from disease activity versus 60 (16%) of 379 patients in the placebo group. The effects of cladribine tablets on freedom from disease activity were significant across all patient subgroups.

INFUSED DISEASE-MODIFYING THERAPIES

Natalizumab

Natalizumab was approved by the FDA in 2004 for treating relapsing forms of multiple sclerosis based on the demonstrated reduction of the frequency of clinical exacerbations and the delay in physical disability accumulation. Natalizumab is a recombinant humanized IgG4k monoclonal antibody. The efficacy of this drug was shown in two studies: AFFIRM (86) and SENTINEL (94). These were randomized, double-blind, placebo-controlled trials involving more than 2000 subjects who were enrolled if they had at least one relapse during the prior year and an EDSS score between 0 and 5.0. MRI scans were performed at baseline and after 1 year, analyzing T1-weighted enhancing lesions and T2-weighted hyperintense lesions.

In the AFFIRM study, 942 patients who had not received any treatment during the previous 6 months were randomized to receive either natalizumab (300 mg intravenously) or placebo every 4 weeks for 28 months. The median age was 37 years, with a median disease duration of 5 years. After 24 months of treatment, there was a significant reduction in the annualized relapse rate (-68%; p< 0.001) and in sustained disability progression risk (-42%; p< 0.001). There was also an increase of relapse-free patients (-21%; p< 0.001) in the natalizumab group compared with the placebo.

In the SENTINEL study, 1171 patients who had experienced one or more relapses during the prior year of treatment with interferon beta-1a once weekly (30 mcg intramuscularly) were randomized to receive natalizumab (300 mg intravenously) or placebo every 4 weeks for 28 months (while continuing interferon beta-1a 30 mcg once-weekly treatment). The median age was 39 years, and the median disease duration was 7 years. At 24 months, there was a significant decrease in relapse rate (54%; p< 0.001) and a significantly increased proportion of patients who remained relapse-free (54% vs. 32%; p< 0.001) in the natalizumab plus interferon beta-1a group compared to the placebo plus interferon beta-1a group.

The most frequent originally reported serious side effects, even if uncommon, were infections, hypersensitivity reactions (anaphylactic reactions, mostly during the first hours after the infusion), fever, low blood pressure, headache, and depression.

In 2005, natalizumab was voluntarily withdrawn from the market by the manufacturing company based on a report of two cases of progressive multifocal leukoencephalopathy, one of which was fatal (61). This opportunistic infection of the CNS is caused by the reactivation of clinically latent JC polyomavirus, which infects oligodendrocytes and leads to multifocal demyelination. This can lead to significant morbidity as well as mortality. In the past, progressive multifocal leukoencephalopathy typically occurred in the context of severe immunodepression, such as in patients with HIV/AIDS, hematological malignancy, or post-organ transplantation. After natalizumab was withdrawn from the market, a third case of progressive multifocal leukoencephalopathy was reported in a patient with Crohn disease who had also received other immunosuppressive drugs. A careful retrospective analysis of all the patients involved in the clinical studies did not find any new progressive multifocal leukoencephalopathy cases. After such analyses, the FDA approved a supplemental license application for reintroducing natalizumab as monotherapy treatment for relapsing forms of multiple sclerosis in 2006. However, the post-marketing experience was significant for more progressive multifocal leukoencephalopathy cases occurring in the setting of natalizumab monotherapy.

Three factors have been established as aids in risk stratification for patients with multiple sclerosis on natalizumab at risk for developing progressive multifocal leukoencephalopathy: (1) presence of antibodies to the JC virus (JCV Abs); (2) length of treatment with natalizumab (over 2 years); and (3) prior exposure to immunosuppressants. In late 2012, a second-generation enzyme-linked immunosorbent assay (ELISA), StatifyJCV, was made available to aid in determining prior exposure to the JC virus (108).

The NOVA study compared the standard every-4-week dosing of natalizumab for relapsing-remitting multiple sclerosis and 6-week extended-interval dosing to evaluate efficacy. Due to the thought that extended-interval dosing may allow for increased immunosurveillance and reduced risk of progressive multifocal leukoencephalopathy, extended-interval dosing had been explored for safety purposes but had not been prospectively evaluated for efficacy. This was best evaluated by a retrospective cohort study utilizing the TOUCH safety database of patients positive for the JC virus, with a relative risk reduction of 94% (95). NOVA enrolled 499 patients with at least 12 months on natalizumab without relapse and no missed doses within 3 months. Patients were randomized 1:1 to natalizumab every 6 weeks or to the standard every-4-week dosing. The primary outcome was new or enlarging T2 lesions on MRI at week 72. Mean new or enlarging T2 lesions at week 72 were 0.20 in the every-6-weeks group and 0.05 in the every-4-weeks group, with a mean lesion ratio of 4.24. Two patients in the every-6-weeks group drove the mean lesion count with 25 or more new or enlarging lesions. There was one case of asymptomatic progressive multifocal leukoencephalopathy in the extended-interval dosing arm and no cases in the once every 4 weeks arm. The study was not powered to assess the risk of progressive multifocal leukoencephalopathy, and 21% of patients in the extended-interval dosing group and 19% of patients in the every-4-weeks group had JCV Abs in the serum (30). Taken together, extending natalizumab dosing from every 4 weeks to every 6 weeks is a reasonable option based on the available safety and efficacy data.

In August 2023, the FDA approved natalizumab-sztn, a biosimilar for natalizumab, based on the Antelope phase III randomized controlled trial (49). Biosimilars have previously been approved for rituximab, but this is the first biosimilar directly approved for treating relapsing multiple sclerosis.

Alemtuzumab

Alemtuzumab is a humanized monoclonal antibody that binds to CD52 found on T cells, B cells, and monocytes (14). Two pivotal phase III trials demonstrated the robust efficacy of alemtuzumab: CARE-MS I and CARE-MS II (10; 15). In both trials, intravenous alemtuzumab was infused daily for 5 days with no repeat dosing until the second year, when there were an additional 3 days of infusions. The comparator arm was subcutaneous interferon beta-1a 44 mcg three times weekly (with no placebo arm). CARE-MS I enrolled treatment-naive multiple sclerosis patients, whereas CARE-MS II enrolled treatment-experienced multiple sclerosis patients who had a history of at least one relapse after at least 6 months on one of their prior therapies. In both CARE-MS I and II, adverse events included thyroid disorders, immune thrombocytopenic purpura, other humoral autoimmune diseases, and infections (mostly respiratory). The annualized relapse ratio was 0.18 with alemtuzumab compared to 0.39 with interferon beta-1a in CARE-MS I (p< 0.001) and 0.26 compared to 0.50 in CARE-MS II (p< 0.001).

Ocrelizumab

Ocrelizumab is a humanized monoclonal anti-CD20 antibody that selectively depletes B cells. CD20 is a cell surface antigen found on some pre-B, all mature B and memory B, and some plasmablasts. Ocrelizumab was approved in 2017 for both relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis.

Ocrelizumab underwent several trials: parallel trials OPERA I and OPERA II (relapsing-remitting multiple sclerosis) and ORATORIO (primary progressive multiple sclerosis). In the OPERA I and II trials, 821 and 835 patients were respectively randomized to receive either intravenous ocrelizumab every 26 weeks or a subcutaneous interferon beta-1a injection three times a week for 96 weeks (43). In OPERA I and OPERA II, the annualized relapse rate was 46% and 47% lower, respectively, in the ocrelizumab group compared to the interferon beta-1a group. The disability progression measured by EDSS was lower in the ocrelizumab group than in the interferon beta-1a group at 12 weeks (9.1% vs. 13.6%) and at 24 weeks (6.9% vs. 10.5%). In OPERA I and OPERA II, the mean number of new Gd+ lesions was 94% and 95% lower, respectively, in the ocrelizumab group compared to the interferon beta-1a group.

Infections occurred in about 56.9% of patients on ocrelizumab and 54.3% of patients on interferon beta-1a in OPERA I. A similar trend was observed in OPERA II. Upper respiratory infections, nasopharyngitis, and urinary tract infections were the most common infectious manifestations in both groups. Urinary tract infections were more common in patients on ocrelizumab (15.2%) than in patients on interferon beta-1a therapy (10.5%). Herpes virus infections occurred more commonly in patients on ocrelizumab (5.9%) than in patients on interferon beta-1a (3.4%) across both trials. In both trials, one third of patients (34% to 37%) in the ocrelizumab arm developed infusion reactions, most of which were mild to moderate, and only one was a case of life-threatening bronchospasm, which resolved with symptomatic treatment. Over the course of both trials, four cases of malignancies (renal cell carcinoma, melanoma, and two invasive ductal breast cancers) occurred in the ocrelizumab groups and two (mantle cell lymphoma, squamous cell carcinoma in the chest) in the interferon beta-1a groups (43). More information about malignancy data in ocrelizumab for primary progressive multiple sclerosis is presented later in this article.

Ublituximab

FDA-approved in December 2022, ublituximab is a glycoengineered chimeric monoclonal antibody with a novel epitope on CD20, resulting in higher antibody-dependent cell-mediated cytotoxicity than ocrelizumab or ofatumumab. Similar to ocrelizumab, ublituximab is an intravenous infusion every 6 months but has a shorter infusion time of 60 minutes. Side effects from cytokine release may be reduced because the rate of B-cell killing is slower than with complement-mediated anti-CD20 killing.

The identical phase III, randomized, double-blind trials ULTIMATE I and II enrolled 1094 patients with relapsing-remitting multiple sclerosis who had two or more relapses in the prior 2 years, one relapse in the prior year, or one or more Gd+ lesions (98). Patients were randomized 1:1 to receive ublituximab or teriflunomide. ULTIMATE I and II found statistically significant lower annualized relapse rates (reduced by 59% and 49%, respectively) and fewer brain MRI lesions (reduced by 97% and 96%, respectively). However, the pooled analysis did not show significantly lower disability progression: 12-week worsening of disability was 5.2% in the ublituximab group compared to 5.9% in the teriflunomide group. Ublituximab was well tolerated; infusion reactions were predominantly mild and seen with the first infusion.

Treatment of primary progressive multiple sclerosis

Primary progressive multiple sclerosis is defined as progressive symptoms with disability progression over at least 12 months, without clinical relapse and having at least two of the following: one or more characteristic brain lesions, two or more characteristic spine lesions, or oligoclonal bands in the CSF (101). In the phase III ORATORIO trial, 732 patients with primary progressive multiple sclerosis were randomly assigned in a 2:1 ratio to receive ocrelizumab 600 mg or placebo every 24 weeks for at least 120 weeks until the primary endpoint was met: 544 completed the double-blind period, of which 527 entered the open-label extension (75). The primary endpoint was the percentage of patients with confirmed disability progression at 12 weeks. Secondary endpoints were 24-week confirmed disability progression; change in T25FW from baseline to week 120; change in total volume of T2-weighted brain lesions from baseline to week 120; and change in brain volume from week 24 to week 120. At 12 weeks, the percentage of patients with confirmed disability progression was 32.9% with ocrelizumab compared to 39.3% with placebo. At 24 weeks, confirmed disability progression was 29.6% with ocrelizumab and 35.7% with placebo. At 120 weeks, the performance of the T25FW worsened by 38.9% in those on ocrelizumab versus 55.1% on placebo. No opportunistic infections occurred during the duration of the trial.

Neoplasms were reported in 11 of 486 (2.3%) treatment patients [breast cancer (4), basal-cell carcinoma (3), endometrial adenocarcinoma (1), anaplastic large-cell lymphoma (1), malignant fibrous histiocytoma (1), pancreatic carcinoma (1)]. Two of the 239 placebo participants reported cancer: cervical adenocarcinoma in situ and basal-cell carcinoma. There is an FDA warning that there may be an increased risk of malignancy, including breast cancer, as no cases were reported in the placebo group. However, pooled 7-year safety data from 11 clinical trials found that of the 5680 patients who received ocrelizumab (18,218 patient-years of exposure), the rate of serious infections and malignancies (excluding nonmelanoma skin cancer) was consistent with epidemiologic data and did not suggest time- or dose-dependent exposure effect (46). Of the patients with breast cancer, most had a personal or family history and past or current tobacco use.

The open-label extension of ORATORIO found that patients originally randomized to the ocrelizumab arm demonstrated less disability progression compared to those who initially received placebo: EDSS 51.7% vs. 64.8%, 9HPT 30.6% vs. 43.1%, T25FW 63.2% vs. 70.7%, composite progression 73.2% vs. 83.3% (111). Percentage change from baseline was lower in the early ocrelizumab group versus placebo for lesion volume: T2 and T1 lesion volume (0.45% vs. 13% and 36.7% vs. 60.9%, respectively).

In ORATORIO, the risk reduction of hand disability [an exploratory endpoint of 20% increase in time to complete the 9-Hole Peg Test (9HPT)] was double the risk reduction for overall EDSS progression. This inspired the ORATORIO-HAND trial. At the ECTRIMS 2025 conference, late-breaking data from the phase IIIb ORATORIO-HAND trial was shared (36). ORATORIO-HAND included patients who are older (65 and under) and with more disability (EDSS 8.0 and below) than in the pivotal trial. In other words, it included people who would ordinarily be excluded from clinical trials. This trial demonstrated a 30% relative risk reduction (RRR) in the 12-week composite endpoint of disease progression (p=0.0007). When separated into overall EDSS and 9HPT, there was a 33% risk reduction in EDSS worsening and 41% risk reduction in CDP-9HPT (p=0.0002). The 24-week RRR for 9HPT was 44%. There was no significant increase in risk of cancer when compared to placebo.

Treatment of secondary progressive multiple sclerosis

Similar to the treatment of primary progressive multiple sclerosis, the treatment of progression in secondary progressive multiple sclerosis has been challenging. Although disease-modifying therapies approved for relapsing-remitting multiple sclerosis may continue to limit relapses, patients with secondary progressive multiple sclerosis also have a slow worsening of disability and can experience this decline without clinical relapses (68).

Siponimod was approved for relapsing-remitting multiple sclerosis in 2019 and underwent further evaluation in a dedicated study of secondary progressive multiple sclerosis; it was approved for all active forms of relapsing multiple sclerosis (clinically isolated syndrome, relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis). In the phase III EXPAND trial, 1651 patients were randomly assigned in a 2:1 ratio to siponimod or placebo (55). At baseline, the mean time since the first multiple sclerosis symptom was 16.8 years, and the mean time since conversion to secondary progressive multiple sclerosis was 3.8 years (SD 3.5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. Two hundred eighty-eight (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month confirmed disability progression (21%, p=0.013). Siponimod-associated adverse events included lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular edema, varicella zoster reactivation, hypertension, and convulsions. Initial dose titration mitigated cardiac first-dose side effects. The frequency of infection, malignancy, and death did not significantly differ between the two groups.

Given data from primary progressive multiple sclerosis studies demonstrating the impact on progressive pathophysiology, many neurologists will also use ocrelizumab (or other anti-CD20 DMTs) for secondary progressive multiple sclerosis.

The future of multiple sclerosis treatment

With the increasingly popular early adoption of high-efficacy treatments, most newly diagnosed patients will be prevented from having new relapses and MRI lesions. The comparison of outcomes of early high-efficacy therapy versus escalating therapy is being studied in the ongoing phase 4 TREAT-MS and DELIVER-MS.

What about the patients who already have lesions, especially in the spinal cord? These patients may still progress despite being on high-efficacy therapy. ENSEMBLE supported that early (first-line) treatment of relapsing-remitting multiple sclerosis with ocrelizumab maintained NEDA over 4 years of treatment (66.4%): clinical relapses (90.9%), new MRI activity (85%), confirmed disability progression (86.5%), composite confirmed disability progression at 24 weeks (69.2%) (42). In other words, 30.8% of patients had increased composite confirmed disability progression or worsening of their EDSS despite their first treatment being ocrelizumab. This suggests that although relapses were largely prevented, these patients had underlying progression, and there is a need for another class of medications to tackle progressive disease.

It is hypothesized that progressive disease is a separate disease process from relapsing disease: innate immune system-mediated inflammation (cytokines, activation of microglia, macrophages, etc) behind the blood-brain barrier, which is inaccessible to large molecules, such as anti-CD20s. Several Bruton tyrosine kinase (BTK) inhibitors are in phase III clinical trials for nonrelapsing secondary progressive multiple sclerosis, eg, tolebrutinib and remibrutinib. They have different profiles for CNS penetration, number of kinases inhibited, and side effects. GEMINI 1 and 2 phase III trials showed that tolebrutinib was not superior to teriflunomide in reducing relapses, but there was a reduction in 6-month confirmed disability progression, although this was not formally tested (80). HERCULES phase III specifically studied secondary progressive multiple sclerosis in a double-blind, placebo-controlled, event-driven trial randomizing 1131 participants 2:1 to receive tolebrutinib 60 mg or placebo (32). HERCULES found that the risk of confirmed disability progression sustained for 6 months was lower in the tolebrutinib group compared to placebo (22.6% vs. 30.7%; p=0.003); 4% compared to 1.6% of participants had increases in alanine aminotransferase up to more than three times the upper limit of normal.

CD40 ligand inhibitors are also in phase III trials for progressive multiple sclerosis, eg, frexalimab: FREXALT (compared to teriflunomide) and FREVIVA (compared to placebo). The anti-CD40L monoclonal antibody frexalimab is second-generation, with its Fc component engineered to reduce the thromboembolic risk that was found in similar first-generation antibodies. The phase II frexalimab study randomized 166 participants with relapsing forms of multiple sclerosis in a 4:4:1:1 ratio of infusion versus subcutaneous drugs versus placebo, with open-label after 12 weeks (106). This trial excluded patients older than 55, those with EDSS scores above 5.5, and those with nonrelapsing forms of disease. The intravenous dose was an 1800 mg load followed by a 1200 mg monthly infusion. The subcutaneous dose was a 600 mg load followed by 300 mg subcutaneous dose every 2 weeks. The primary endpoint was new gadolinium-enhancing T1 lesions at week 12 compared to week 8. Frexalimab significantly reduced the number of Gad+ lesions (relative reduction 89% intravenous and 79% subcutaneous) at week 12. Of note, the pooled placebo group was younger and had a higher number of T1-weighted lesions (mean 1.6 in placebo vs. 0.8–0.9 in drug groups). The exploratory endpoints found a decrease from baseline levels of inflammatory markers CXCL12 (21% reduction in the 1200 mg group, 30% reduction in 300 mg group) and NFL (24% reduction in the 1200 mg group; 18% reduction in the 300 mg group) and an increase in CXCL13 and NFL levels in the placebo groups.

Although rituximab, an anti-CD20, is not FDA-approved for the treatment of multiple sclerosis, it is commonly used off-label and continues to be studied. Rituximab went through phase II HERMES and OLYMPUS studies (48; 47). RIFUND-MS was a trial, rater-blinded, active-comparator, phase III, randomized controlled trial in Sweden that randomized 200 patients with early relapsing-remitting multiple sclerosis to be treated with rituximab (1000 mg once, followed by 500 mg every 6 months) or dimethyl fumarate (100). The study found that relapses were reduced over a 24-month period (3% vs. 16%, respectively). RIDOSE-MS found that 12-month dosing was noninferior to 6-month dosing (99).

Chimeric antigen receptor T-cell therapy is in early studies (84; 66; 89).

Treatments approved for pediatric multiple sclerosis are very limited, but trials are underway studying ocrelizumab (OPERETTA I and OPERETTA II), ofatumumab, and siponimod (NEOS). For more information on pediatric multiple sclerosis, please refer to the MedLink article Multiple sclerosis: biological differences in children and adults.

There are ongoing efforts to study remyelination, eg, clemastine (41; 20) and mesenchymal stem cells (12).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Jennifer Wiseman MD

Dr. Wiseman of the University of Chicago has no relevant financial relationships to disclose.
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Editor

Anthony T Reder MD

Dr. Reder of the University of Chicago received honorariums from Genentech, Genzyme, and TG Therapeutics for service on advisory boards and as a consultant and stock options from NKMax America for advisory work and an unrestricted lab research grant from BMS.
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Former Authors

Luca Durelli MD
Chiara Rivoiro MD PhD
Elisabetta Versino MD
Giulia Contessa MD
Marinella Clerico MD
Regina Berkovich MD PhD
Daniel Kantor MD
Elena Grebenciucova MD
Anna Shah MD
Andrew Wolf MD

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Clinical trials in multiple sclerosis

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Clinical Categories

Neuroimmunology

Clinical trials in multiple sclerosis

Cite this article

Introduction

Overview

Key points

Clinical trials in multiple sclerosis

Treatment of acute relapses

Treatment for relapsing forms of multiple sclerosis

INJECTABLE DISEASE-MODIFYING THERAPIES

Interferon beta

Glatiramer acetate

Ofatumumab

ORAL DISEASE-MODIFYING THERAPIES

Sphingosine 1-phosphate receptor modulator (S1Ps)

Fumarates

Other oral disease-modifying therapies

INFUSED DISEASE-MODIFYING THERAPIES

Natalizumab

Alemtuzumab

Ocrelizumab

Ublituximab

Treatment of primary progressive multiple sclerosis

Treatment of secondary progressive multiple sclerosis

Treatment of radiologically isolated syndrome

The future of multiple sclerosis treatment

Conclusions

Media

References

Contributors

Author

Editor

Former Authors

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