Mina Baghzouz, PharmD

In recent years, there have been major advancements in the development of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS), with promising new treatments soon. Despite this, there are still many unmet needs in the treatment of MS.

Existing treatments for MS may reduce relapse rates and slow disease progression, but responses to these treatments are often suboptimal, produce variable responses in patients, and, if successful, are only preventative and not restorative. Currently, there are no FDA-approved treatment options for progressive forms of MS.

This article will review MS treatments currently in phase 3 trials, and how they may address some of the unmet needs of patients.

Siponimod is an oral drug in the same class as the FDA-approved DMT fingolimod (Gilenya), a sphingosine-1-phosphate (S1P) modulator. Like fingolimod, siponimod binds S1P receptors on the surface of lymphocytes. These receptors play a key role in the immune system, and regulate the movement of lymphocytes from lymph tissue into circulation.

By binding to these receptors, S1P modulators ultimately cause receptor down-regulation, resulting in lymphocytes remaining in the lymph tissue.

As a second-generation S1P modulator, siponimod targets S1P receptors 1 and 5, while sparing receptors 2, 3, and 4.

The goal of this specificity is to improve upon the side effect profile of fingolimod (a first-generation S1P modulator).

The efficacy and safety of various siponimod doses was evaluated in patients with relapsing-remitting multiple sclerosis (RRMS) in the phase 2 BOLD trial. In this double-blind trial, patients were assigned to 1 of 2 cohorts.

In the first cohort, 188 patients were randomized (1:1:1:1) to receive once-daily siponimod 0.5-mg, 2-mg, 10-mg, or placebo for 6 months. In the second cohort, 109 patients were randomized (4:4:1) to receive once-daily siponimod 1.25-mg, 0.5-mg, or placebo for 3 months.

The primary endpoint was percent reduction in monthly number of combined active lesions, as determined by MRI at 3 months for the 5 different doses.

Despite limited sample size and duration in this trial, siponimod demonstrated dose-dependent reduction of combined active lesions ranging from 35% (0.25-mg) to 82% (10-mg).

The most common adverse events were headache, upper respiratory tract infection, nasopharyngitis, increase in liver transaminases, lymphopenia, and heart rate reduction. Currently there is an ongoing phase 3 trial of siponimod in patients with progressive MS.

Like siponimod, ponesimod is an oral investigational drug in the S1P modulator class. Ponesimod is a second-generation S1P modulator that targets S1P receptor 1 with some effect on receptors 3 and 5, but no effect on receptors 2 and 4.

In trials, ponesimod has been found to have less pharmacokinetic variability then fingolimod and a shorter half-life (approximately 32 hours compared with approximately 8 days with fingolimod). Ponesimod’s pharmacological effects are rapidly reversible, with lymphocyte counts returning to normal range within 96 hours.

In comparison, lymphocyte counts return to normal within 1 to 2 months after therapy with fingolimod. The results of a double-blind, placebo-controlled phase 2 trial evaluating the efficacy and safety of ponesimod in RRMS were published in early 2016. In that trial, 464 patients were randomized to receive once-daily ponesimod at a dose of 10-, 20-, or 40-mg or placebo (1:1:1:1) for 24 weeks.

The primary endpoint was the cumulative number of new lesions, as detected on MRI per patient recorded every month from weeks 12 to 24. Secondary endpoints were the annualized relapse rate (ARR) and the time to first confirmed relapse. The cumulative number of new lesions was significantly lowered in a dose-dependent manner in the ponesimod 10-mg (by 43%), 20-mg (by 83%), and 40-mg (by 77%) groups compared with placebo.

The ARR was reduced with ponesimod therapy compared to placebo (by 37% with 10-mg, 21% with 20-mg, and 52% with 40-mg), and the time to first relapse was also increased. Ponesimod was well tolerated at doses below 40-mg, with the most common adverse events including anxiety, dizziness, dyspnea, increased liver enzymes, influenza, insomnia, and peripheral edema.

Despite receptor selectivity, ponesimod was also associated with reduced heart rate after the first dose, as with other S1P modulators. In phase 1 trials, it was found that titrating up to the higher doses reduced this adverse event.

Currently, there is an ongoing phase 3 trial (OPTIMUM) comparing ponesimod to teriflunomide for RRMS that is expected to conclude in 2018.

 Further trials will be needed to confirm the efficacy and safety profile of ponesimod.

Like siponimod and ponesimod, ozanimod is another S1P receptor modulator that selectively targets S1P receptor subtypes 1 and 5.

At the annual American Academy of Neurology meeting in 2015, the phase 2 portion of the RADIANCE trial was presented.

The RADIANCE phase 2 trial was a 24-week, double-blind, randomized controlled trial in 258 patients who received once-daily ozanimod 0.5-mg, 1-mg, or placebo (1:1:1). The primary endpoint was cumulative number of lesions on monthly MRI, and secondary endpoints were ARR and number of new lesions. With both doses of ozanimod, the cumulative number of lesions from weeks 12 to 24 was found to be reduced by 86% compared with placebo.

The cumulative number of new lesions was reduced by 84% for the 0.5-mg group and 91% for the 1 mg group from weeks 12 to 24, while the ARR was reduced by 31% and 53%, respectively. The medication was well tolerated, with a high rate of trial completion (> 96%) across treatment groups.

The most common adverse events in the treatment groups versus the placebo group were nasopharyngitis, headache, and urinary tract infection. Effects on cardiac conduction with the first dose of ozanimod were negligible.

The phase 3 portion of the RADIANCE trial, which will evaluate ozanimod compared with interferon beta-1a in patients with progressive MS, is expected to conclude in 2017. Another phase 3 trial, SUNBEAM, will also compare ozanimod to interferon beta-1a in patients with relapsing MS. That trial will also conclude in 2017.

Laquinimod is a quinolone-3-carboxamide currently undergoing phase 3 trials for the treatment of MS. The mechanism of action of laquinimod is not fully understood, but is believed to help reduce the number of pro-inflammatory immune cells by interfering with the expression of pro-inflammatory genes.

In two phase 3 trials, laquinimod produced contradictory results. In the 24-month, double-blind, randomized, placebo-controlled ALLEGRO trial, laquinimod at a dose of 0.6-mg was found to modestly reduce annual ARR by 23% compared with placebo in patients with RRMS.

Laquinimod was also associated with a reduced mean cumulative number of lesions compared with placebo (P <0.001), as well as a reduction in disability progression. However, conflicting results were found in the 24-month, double-blind, randomized, placebo-controlled BRAVO trial comparing once-daily 0.6 mg laquinimod to placebo and to once-weekly 30 mcg Avonex.

There was not a significant difference found in the ARR between laquinimod and placebo, with ARR being reduced by only 18%. Laquinimod did produce positive results, however, with certain MRI parameters, including percent brain volume change (significantly reduced compared with placebo, P < 0.001). In both trials, laquinimod was well tolerated, with the most common adverse events including abdominal pain, back pain, cough, and elevated liver enzymes (reversible after discontinuation).

Despite the results from the BRAVO trial, laquinimod is still being studied in phase 2 and phase 3 trials. In the two phase 3 trials CONCERTO and ARPEGGIO, the higher dose treatment groups of laquinimod (1.2-mg and 1.5-mg) had to be discontinued due to cardiovascular events in 8 patients. Both trials will continue with the 0.6-mg treatment groups.

Further trials are required to establish the safety and efficacy of this drug.

Masitinib is a tyrosine kinase inhibitor (TKI), the first of its class to be evaluated in the use of MS. Masitinib blocks tyrosine kinase, an enzyme that plays a role in signaling the division, growth, and proliferation of immune cells. This blockade occurs by binding to epidermal growth factor receptor (EGFR), a receptor on the surface of most cells.

As a selective TKI, mast cells are the main target of this drug.

Oral masitinib was studied for the treatment of progressive forms of MS in a randomized, placebo-controlled phase 2 trial. Masitinib was dosed at 3- to 6-mg/kg/day for at least 12 months of therapy, with dose increases made if inadequate response and no toxicity.

The primary endpoint was a change in the multiple sclerosis functional composite (MSFC) score compared with baseline. Thirty-five patients were included in this trial, with 27 receiving masitinib and 8 receiving placebo. Although there was more improvement in the MSFC results in the masitinib treatment arm, it was not a significant improvement compared to the placebo treatment group, which had, overall, worsening MSFC scores.

This improvement was seen as early as 3 months, and was sustained through month 18. Masitinib was well-tolerated, with the most common adverse events including asthenia, rash, nausea, edema, and diarrhea. Those adverse events are consistent with other TKIs.

The frequency of adverse events was similar to placebo, but masitinib was associated with more severe adverse events.

Currently, a phase 3 trial is underway to further evaluate the efficacy and safety of masitinib in progressive forms of MS.

At this time, ocrelizumab is on the FDA fast track for approval for the treatment of RRMS and PPMS.

If approved, ocrelizumab will be the first treatment approved for PPMS. Ocrelizumab is a monoclonal antibody specific for CD20 B cells, which play an important role in pro-inflammatory processes and the creation of autoantibodies.

Ocrelizumab was studied in three phase 3 trials: OPERA I, OPERA II, and ORATORIO. OPERA I and II were 2 identical randomized, double-blind, 96-week-long, parallel phase 3 trials evaluating the safety and efficacy of ocrelizumab compared with interferon-beta-1a in patients with relapsing forms of MS.

Patients were randomized (1:1) to receive intravenously infused ocrelizumab 600-mg monthly or subcutaneous interferon-beta-1a 44 mcg three times per week. The primary endpoint was number of patients achieving no evidence of disease activity (NEDA), defined as no relapses, disability progression, or new or enlarging lesions.

At 96 weeks, 47.9% ocrelizumab patients achieved NEDA versus 29.2% interferon patients in OPERA I (P < 0.0001). In OPERA II, 47.5% of ocrelizumab patients achieved NEDA vs. 25.1% of interferon patients (P< 0.001).20 In the double-blind, placebo-controlled, randomized ORATORIO trial, ocrelizumab was assessed in 732 patients with PPMS.

Patients were randomized (2:1) to receive ocrelizumab 600-mg (two doses of 300-mg two weeks apart) every 24 weeks or placebo for 120 weeks. The primary endpoint was the time to onset of confirmed disability progression (CDP) sustained for 12 weeks, as determined by an increase in the Expanded Disability Status Scale.

Ocrelizumab was found to significantly reduce the relative risk of 12-week CDP compared with placebo. Relative risk was reduced by 24% (P = 0.0321). In addition, ocrelizumab reduced the 24-week CDP by 25%, and the timed 25-foot walk test progression rate by 29% compared with placebo. Adverse events were similar in both groups.

The most common adverse events associated with ocrelizumab were infusion-related reactions and infections, most of which were mild to moderate.

With these results, ocrelizumab is the only late-stage pipeline medication with strong evidence of efficacy in primary progressive MS. The approval of ocrelizumab is highly anticipated, and the medication is expected to do well in the market.

There are several compounds in the late-stage pipeline for MS with promising clinical trial data, many of them in the S1P modulator class. Additionally, there are dozens of drugs in preclinical stages with a variety of targeted pathways. In the coming years, providers will likely have more medication options for the treatment of RRMS, as well as a much-needed treatment option for PPMS. It is important for providers and specialty pharmacists to be informed about pipeline medications, in order to provide accurate and up-to-date information to patients with MS.&ensp;

		Goodin DS, Frohman EM, Garmany GP Jr., et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. 

		Pan S, et al. Discovery of BAF312 (siponimod), a potent and selective S1P receptor modulator. 

		Selmaj K, Li DK, Hartung HP, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. 

		Brossard P, Derendorf H, Xu J, et al. Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptormodulator, in the first-in-human study. 

		Olsson T, Boster A, Fernández Ó, et al. Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial. 

		Oral ponesimod versus teriflunomide in relapsing multiple sclerosis (OPTIMUM). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02425644?term=ponesimod&rank=4. Published.  Published April 21, 2015. Accessed November 16, 2016.

		Multiple sclerosis drug candidate shows new promise. Science Daily. www.sciencedaily.com/releases/2014/09/140919092755.htm. Published September 19, 2014. Accessed November 16, 2016.

		Cohen JA, Arnold DL, Comi G, et al. Phase 2 results of the RADIANCE trial: a randomized, double-blind, placebo-controlled trial of oral RPC1063 in relapsing multiple sclerosis (LB1.1) 

		Moore C. Celgene to acquire Receptos, advancing leadership in immune&shy;inflammatory diseases such as MS and IBD. 

. http://multiplesclerosisnewstoday.com/2015/07/17/celgene-acquire-receptos-advancing-leadership-immune-inflammatory-diseases-ms-ibd/. Published July 17, 2015.  Accessed November 25, 2016.

		Efficacy and safety study of RPC1063 in relapsing multiple sclerosis (Radiance Study). ClinicalTrials.gov www.clinicaltrials.gov/ct2/show/NCT02047734?no_unk=Y&cond=multiple+sclerosis&phase=2&lup_s=12%2F01%2F2014&lup_e=09%2F29%2F2015&rank=55. Published April 14, 2015.  Accessed November 25, 2016.

		Kieseier, Bernd C. Defining a Role for Laquinimod in Multiple Sclerosis. 

Articles

Current stage 3 trials for multiple sclerosis medications may address several unmet needs in the patient population.