Multiple sclerosis: A paradigm change with oral agents?

Key Points

Abstract

Multiple sclerosis (MS) is the most common disabling neurologic disease afflicting young adults in the United States. Since the majority of MS patients have normal or near-normal life expectancy, the clinical and economic burden is substantial, with disability typically worsening over time. Disease-modifying therapies (DMTs) have been shown to decrease and postpone long-term disability by lowering the relapse rate, extending the remission phase, and reducing the accumulation of new magnetic resonance imaging lesions and related neurologic deficits, but an estimated 43% of relapsing-remitting MS patients are not receiving DMTs. A contributing factor may be that until recently all available DMTs were injectables. The recent approval and availability of new oral medications for MS-fingolimod and dalfampridine-signal a paradigm change from parenteral to oral agents and offer hope that a greater number of MS patients will receive the treatment they need. This article reviews the evidence supporting use of existing therapies, critically appraises the newly approved oral agents, and examines their place in therapy relative to the established therapies. Novel treatments currently being developed for MS and pharmacoeconomic studies of fingolimod are also discussed. (Formulary. 2011;46:228–240.)

DISEASE CLASSIFICATION

MS presents in 4 clinical patterns: relapsing-remitting, secondary progressive, primary progressive, or progressive-relapsing. Approximately 85% of patients present with relapsing-remitting MS (RRMS), which is characterized by bouts of attacks with fully or partially reversible focal neurologic deficits. The stage of index attack followed by recovery is referred to as a clinically isolated syndrome (CIS) compatible with demyelination.² After 10 to 20 years, about half of RRMS patients accumulate irreversible neurologic deficits and transition to secondary progressive MS (SPMS). Approximately 10% of MS patients have primary progressive MS (PPMS), which is characterized by progressive disease from onset and does not show patterns of relapses and remissions. A minority of PPMS patients develops superimposed relapses and are therefore referred to as having progressive-relapsing MS (PRMS).^3,4

A diagnosis of MS is determined by neurologic examination that includes magnetic resonance imaging (MRI) measures, evoked potential tests, and spinal fluid analysis.^1,3 MS-related disability is measured by using the Expanded Disability Status Scale (EDSS) with a range from 0 (normal) to 10 (death). Individuals with a score <4 are considered to have mild disability, whereas those with a score >7 are considered to have severe disease.⁵

CURRENT TREATMENT OPTIONS

FIRST-LINE AGENTS

IFNb preparations. IFNb is believed to work by causing alteration of immune functions, which include inhibition of the activation and proliferation of T cells, leukocyte migration, and several inflammatory processes.^6,8,10,15 All 3 preparations of IFNb have shown clinical benefits and similar adverse effect profiles. Common adverse effects include flu-like symptoms, injection-site reactions, elevated hepatic enzymes, and formation of neutralizing antibodies (NABs). NABs decrease the clinical efficacy and MRI effects of IFNb by interacting with the drug, resulting in a decreased biological effect. The incidence of NABs is much higher with the subcutaneous (SC) route of administration compared with the intramuscular (IM) route, and the highest incidence is observed with IFNb-1b. Other rare but serious adverse effects include injection-site necrosis, depression, and suicidal ideation.¹⁵

IFNb-1b SC (Betaseron). IFNb-1b SC was approved in 1993 as the first DMT for RRMS.⁶ In a phase 3 trial, 372 patients with baseline EDSS scores of 0 to 5.5 and at least 2 relapses during the 2 years prior to enrollment were assigned to receive IFNb-1b 50 µg, IFNb-1b 250 µg, or placebo every other day for 2 years. At the end of the study period, a significant reduction in relapses, T2 active lesions, new T2 lesions, and disease burden was observed with both doses of IFNb-1b. Yet, the effect on disability progression was similar between treatment and placebo groups.¹⁵

IFNb-1a IM (Avonex). IFNb-1a IM was approved for RRMS treatment in 1996. In a randomized, double-blind, multicenter phase 3 study, 301 RRMS patients with at least 2 relapses during the 3 years prior to enrollment were assigned to receive IFNb-1a 30 µg IM or placebo once weekly for 2 years. The trial was stopped prematurely with only 57% of patients completing the entire course of therapy. IFNb-1a was associated with a 37% risk reduction for disability progression as well as an 18% and 32% reduction in relapse rate for the intent-to-treat population and for those that completed the 2-year trial, respectively. There was a significant reduction in the number and volume of gadolinium positive (Gd+) lesions with IFNb-1a IM treatment versus placebo.¹⁶

IFNb-1a SC (Rebif). IFNb-1a SC was approved in 2002 for the treatment of RRMS. In a phase 3 trial, 560 RRMS patients were assigned to receive IFNb-1a SC 22 µg, 44 µg, or placebo 3 times weekly for 2 years. A significant reduction in the relapse rate was observed for both doses of IFNb-1a versus placebo, specifically 27% and 33% with the 22- and 44-µg doses, respectively. MRI measures showed a decrease in disease burden and T2 active lesions with both doses of IFNb-1a, but the number of active T2 lesions was significantly lower with the higher dose of IFNb-1a SC.¹⁷ In addition, patients with more severe disease experienced greater benefit from the higher dose of IFNb-1a SC, and the lowest rate of disability progression was observed in patients who received the highest cumulative dose of IFNb-1a SC.^15,17

Glatiramer acetate (Copaxone). Glatiramer acetate (GA) is a synthetic amino acid polymer that is thought to modify immune processes by induction and activation of regulatory T cells in the periphery.¹⁵ This causes a release of anti-inflammatory cytokines and growth factors. Treatment with GA also results in the formation of neurotrophins that favor neuron repair and axonal protection.¹⁸

GA was approved in 1997 for treatment of RRMS and has a preferred adverse effect profile compared with IFNb formulations, without laboratory monitoring requirements. Adverse effects of GA include a self-limiting post-injection reaction that involves flushing, chest tightness, palpitations, anxiety, and dyspnea.¹⁵ Lipoatrophy can also occur with GA.¹⁸

In a randomized, double-blind phase 3 trial, 251 RRMS patients were assigned to receive either GA 20 mg SC or placebo daily for 2 years. The trial results showed a 29% reduction in relapse rate with GA versus placebo. However, GA did not have a significant effect on proportion of relapse-free patients, median time to first relapse, or disability progression versus placebo.¹⁹

Comparison of first-line agents. There are several factors to consider when analyzing first-line therapies for RRMS, such as efficacy concerning disability progression, relapse rate reduction, imaging measures, and cognitive function. In addition, safety and compliance issues should be weighed with regard to the medication's side effects and convenience of dosing regimen.

In phase 3 trials for RRMS, all first-line parenteral DMTs have shown an approximate 30% reduction in annual relapse rates.²⁰ However, it is difficult to directly compare the results between trials due to differences in study design, clinical and MRI outcomes, and patient populations.¹⁵ To resolve these issues, several head-to-head trials were completed.

The Evidence of Interferon Dose-Response–European North American Comparative Efficacy (EVIDENCE) trial compared IFNb-1a 44 µg SC 3 times weekly and IFNb-1a 30 µg IM once weekly in 677 RRMS patients over a 1-year period. The results showed a greater proportion of patients treated with IFNb-1a SC to remain relapse free compared with patients treated with IFNb-1a IM (74.9% vs 63.3%). Patients treated with IFNb-1a SC also developed fewer MRI lesions. Nevertheless, injection-site reactions, elevations in hepatic enzymes, white blood cell count abnormalities, and presence of NABs were all more frequent with IFNb-1a SC compared with IFNb-1a IM.²¹

The Independent Comparison of Interferon (INCOMIN) trial compared IFNb-1b 250 µg SC every other day to IFNb-1a 30 µg IM once weekly in 188 patients with RRMS. At 2 years, 51% of patients treated with IFNb-1b remained relapse free compared with 36% of patients treated with IFNb-1a. In addition, IFNb-1b was associated with a significantly greater reduction in patients experiencing disease progression than IFNb-1a. The frequency of adverse events was similar between treatment groups, but more patients experienced injection-site reactions and formation of NABs with IFNb-1b than with IFNb-1a.²²

The Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) trial compared GA 20 mg SC every day, IFNb-1b 500 µg SC every other day, and IFNb-1b 250 µg SC every other day in 2,244 treatment-naïve patients with RRMS for a range of 2 to 3.5 years. There was no significant difference in relapse risk or EDSS progression among the 3 treatment groups. Most MRI outcomes also showed no significant differences among the 3 groups with the exception of the cumulative number and relative increase in volume of T2 lesions, which was significantly higher with GA than with either dose of IFNb-1b. Both IFNb-1b and GA were well tolerated, but more patients experienced flu-like symptoms with IFNb-1b and injection-site reactions with GA.²³

The Rebif vs. Glatiramer Acetate in Relapsing MS Disease (REGARD) trial was a randomized, parallel-group, open-label study that compared IFNb-1a 44 µg SC 3 times weekly to GA 20 mg SC once daily in 764 RRMS patients for 96 weeks. At the end of the trial, the 2 treatment groups were comparable in time to first relapse. In addition, MRI measures were analyzed in a subset of 460 patients, and no significant differences were found between the 2 treatment groups. However, a difference in the number of Gd+ lesions was observed-IFNb-1a was associated with significantly fewer lesions than was GA. The incidence and severity of adverse events between the 2 treatment groups were similar, but the type of events differed with more patients treated with IFNb-1a experiencing flu-like reactions and elevated hepatic enzymes compared to more frequent injection-site reactions and post-injection systemic reactions occurring with GA.²⁴

The Betaseron vs. Copaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3-Tesla MRI Endpoints (BECOME) trial compared MRI outcome measures between treatments with IFNb-1b 250 µg SC every other day or GA 20 mg SC once daily in 75 patients with RRMS or CIS. No significant differences were seen between the 2 treatment groups in the number of combined active lesions during the first year as well as in the number of new lesions and clinical exacerbations over 2 years.²⁵

SECOND-LINE AGENTS

Mitoxantrone (Novantrone). Mitoxantrone is the only DMT with an indication for multiple MS subtypes: RRMS, SPMS, and PRMS. Mitoxantrone works by intercalating with DNA and inhibiting topoisomerase II, which results in single and double strand DNA breaks and inhibition of DNA repair.²⁰ Mitoxantrone also exhibits immunomodulatory effects by decreasing the proliferation of B- and T-lymphocytes as well as reducing the release of gamma interferon, TNF alpha, and interleukin 2. Mitoxantrone is considered a second-line agent for RRMS due to its rare but serious side effects of cardiotoxicity and leukemia. The risk for cardiotoxicity is proportional to the lifetime cumulative dose and can involve a decrease in left ventricular ejection fraction or symptomatic congestive heart failure. Common adverse events associated with mitoxantrone treatment include nausea, vomiting, alopecia, and leukopenia.¹⁵

The Mitoxantrone in Multiple Sclerosis (MIMS) trial was a European phase 3 study that observed 194 patients with worsening RRMS or SPMS. Patients were assigned to treatment with placebo, mitoxantrone 5 mg/m², or mitoxantrone 12 mg/m² IV every 3 months for 2 years. After 2 years, mitoxantrone 12 mg/m² was associated with a reduction of disability progression, annual relapse rate, and corticosteroid-treated relapses as well as a decrease in Gd+ and T2-weighted lesions. In addition, no serious adverse events or clinically significant evidence of cardiac dysfunction was observed during the trial.²⁶

Natalizumab (Tysabri). Natalizumab is a humanized monoclonal antibody that acts as an integrin antagonist to inhibit lymphocyte invasion into target tissues. Natalizumab is also a second-line RRMS agent due to its association with progressive multifocal leukoencephalopathy (PML). The risk of PML increases with increased duration of treatment. More common adverse events of natalizumab include headache, fatigue, arthralgia, allergic reactions, urinary and respiratory tract infections, and gastroenteritis.¹⁵

Two key phase 3 trials, the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial and the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) trial, have shown natalizumab to reduce clinical relapse rate, progression of disability, and formation of new lesions on MRI.¹⁵

The AFFIRM trial compared natalizumab 300 mg given every 4 weeks to placebo in 942 RRMS patients over a 2-year period. Natalizumab was associated with a 68% reduction in relapse rate at 1 year and a 42% reduction in risk of disability progression at 2 years. In addition, natalizumab reduced Gd+ lesions by 92%, and mean number of new or enhancing T2-weighted lesions by 83%.²⁷

The SENTINEL trial compared natalizumab 300 mg every 4 weeks as add-on therapy to IFNb-1a IM versus placebo for 2 years in 1,171 patients with at least 1 relapse in the prior year while taking IFNb-1a IM. A lower annualized relapse rate as well as a reduction in new and enlarging T2-weighted lesions were seen with combination therapy versus IFNb-1a alone. In addition, combination therapy resulted in a 24% reduction in relative risk of sustained disability progression.²⁸

NEWLY APPROVED AGENTS

Fingolimod (Gilenya). Fingolimod is the first oral DMT approved by FDA in September 2010, at a dose of 0.5 mg once daily. It is indicated for reducing the frequency of clinical exacerbations and delaying accumulation of physical disability in RRMS.¹² Fingolimod acts by binding to sphingosine-1-phosphate receptors that are responsible for regulating the migration of lymphocytes from the lymphoid tissue. Once bound, it prevents lymphocytes from entering the CNS and causing damage, while decreasing serum lymphocyte counts. Additionally, fingolimod may have direct neuroprotective effects through its ability to cross the blood-brain barrier and bind to sphingosine-1-phosphate receptors in the brain.²⁹ There are 2 phase 3 trials highlighting the efficacy of fingolimod: the Fingolimod Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) trial and the Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). The FREEDOMS trial was a 24-month, double-blind, randomized study comparing fingolimod 0.5 mg or 1.25 mg daily to placebo in 1,272 RRMS patients.³⁰ The TRANSFORMS trial, on the other hand, took a different approach by comparing the efficacy of fingolimod 0.5 mg or 1.25 mg daily to a first-line DMT, IFNb-1a IM, over a period of 12 months in 1,292 RRMS patients.³¹ Both studies found that fingolimod significantly reduced the annualized relapse rates and increased the number of patients who were relapse-free compared to the groups receiving placebo or IFNb-1a IM. Patients on fingolimod also had significantly fewer new or enlarged lesions on T2-weighted images and lower mean brain volume loss. However, while the FREEDOMS trial observed a significantly lowered risk of disability progression (P=.02) with fingolimod compared to placebo, the TRANSFORMS trial did not show a difference in disability progression with fingolimod versus IFNb-1a IM. Interestingly, neither study observed a significant difference in efficacy between the 2 fingolimod doses.^30,31

Though the results of fingolimod's efficacy in RRMS patients are encouraging, serious side effects have been associated with its use. In the TRANSFORMS study, 2 fatal adverse events occurred during the trial and both were in patients receiving 1.25 mg of fingolimod. One of the events involved a case of herpes simplex encephalitis, and the other a varicella zoster infection. There was also a higher incidence of cancers in the fingolimod groups compared with the IFNb-1a IM group. Among the 10 localized skin cancers reported during the study, 8 occurred in the fingolimod groups versus 2 in the IFNb-1a IM group. For breast cancer, all 4 incidences occurred in patients receiving fingolimod; 1 case led to death after the study ended.³¹ Conversely, the FREEDOMS trial did not show a similar increase of neoplasms with fingolimod compared to placebo.³⁰ In terms of more common side effects, both studies had a higher rate of discontinuation due to adverse events with the 1.25-mg fingolimod dose than with the 0.5-mg dose.^30,31 Adverse effects that led to discontinuation included bradycardia and atrioventricular block at drug initiation, macular edema, elevated liver-enzyme levels, and hypertension.³⁰ Due to these findings, FDA is requiring physicians to monitor for cardiac changes for 6 hours after fingolimod initiation, and ophthalmologic evaluation is also recommended at baseline and 3 to 4 months after treatment initiation.¹²

Ongoing research with fingolimod includes the FREEDOMS II trial and the INFORMS trial. The FREEDOMS II trial is a 24-month study comparing fingolimod daily doses of 0.5 mg or 1.25 mg to placebo and is expected to be completed in March 2011. Notably, the INFORMS trial is a 36-month study comparing daily doses of fingolimod 1.25 mg to placebo in patients with PPMS. Treatment for this subset of MS patients is challenging and, to date, fingolimod has not been studied in this population. The expected completion date for this trial is December 2013.³²

Dalfampridine (Ampyra). Dalfampridine was approved by FDA in March 2010 for the symptomatic treatment of walking difficulty in MS patients. It is the only drug marketed for this indication. Dalfampridine is a potassium-channel blocker that is thought to work by improving conduction through demyelinated nerve fibers. However, dalfampridine is not a novel medication as it is actually an extended-release formulation of an old drug, 4-aminopyridine. 4-Aminopyridine was first developed as a bird poison and was used off-label for the treatment of MS symptoms for many years. Its use was limited due to questionable efficacy and an elevated seizure risk with a low therapeutic safety margin.³³ Currently, controlled trials looking at the FDA-approved dose of dalfampridine 10 mg twice daily have not observed an increase in seizures compared with placebo. Other adverse events associated with dalfampridine include headache, asthenia, dizziness, insomnia, back pain, balance disorder, and paresthesia.³⁴ Clinical trials have not shown a difference in prevalence of these side effects between the old and new formulation of dalfampridine.

Multiple phase 3 studies have shown dalfampridine to significantly improve walking speed of MS patients compared to placebo as measured by the Timed 25-Foot Walk (T25FW). T25FW is a measure of how many seconds it takes a patient to walk 25 feet, and a normal result is approximately 6 seconds.³³

In 2 pivotal phase 3 trials involving 229 and 120 MS patients for 14 and 9 weeks, respectively, percentage of responders ranged from 35% to 43% of patients receiving dalfampridine compared to 8% to 9% in those given placebo. Responders were defined as those who improved their walking speed in most of the assessments during the treatment period. In both trials, the average improvement in T25FW with dalfampridine responders was only 0.51 ft/s above baseline, which translates to a difference of about 2 seconds.^34,35 Though the difference was statistically significant, this improvement has not been proven to have clinical relevance regarding quality of life.

PHARMACOECONOMIC STUDIES

Due to the substantial economic impact and burden associated with MS, it is important to assess the cost-effectiveness of the available treatment options. Several economic models have compared the first-line parenteral DMTs. Most of them used end points that included quality-adjusted life years (QALYs) and extrapolated 2-year study results to longer time horizons. For example, Bell et al conducted a lifetime cost-effectiveness analysis comparing the IFNb products and GA to symptom management alone.³⁶ The results were expressed in cost per QALY gained; GA was found to be the most cost-effective, followed by IFNb-1b, IFNb-1a IM, and finally IFNb-1a SC. The primary criticism of using QALYs as an end point is that it involves definitions and grading of health that are highly subjective. Hence, results may be biased based on the definitions used.

The study model also incorporated relapse and disease progression rates from previous clinical trials into prediction curves that estimated the long-term treatment effects of GA and the 3 IFN formulations.³⁶ Extrapolating study results can introduce greater uncertainty regarding real-life applicability of the study assumptions and findings. In contrast to previous pharmacoeconomic models, Goldberg et al used a 2-year time horizon based on 2-year RRMS pivotal clinical trials without extrapolation of the findings.³⁷ The model evaluated the cost-effectiveness of the first-line parenteral DMTs with the primary end point being cost per relapse avoided. Study assumptions included treatment persistence at 89.4% for all DMTs and number of relapses to be 2.55 for an untreated patient over a 2-year period. Based on these assumptions, IFNb-1a SC was the most cost-effective at $80,589 per relapse avoided, followed by IFNb-1b, GA, and IFNb-1a IM at $87,061, $88,310, and $141,721, respectively. Sensitivity analyses showed that these findings were robust to changes in key input parameters including number of relapses, the average cost of relapse, and the rate of treatment persistence.³⁷

Although no pharmacoeconomic analysis has been completed to evaluate the cost-effectiveness of the new DMT, fingolimod, it is important to note that fingolimod has only been compared to IFNb-1a IM in published clinical trials. It is highly desirable to have a clinical comparison between fingolimod and the other established, more clinically and cost-effective DMTs, such as IFNb-1a SC, IFNb-1b, or GA, before any pharmacoeconomic analysis could shed light on the debate over which DMTs are more cost-effective.

PLACE IN THERAPY

Fingolimod. Strong evidence supports fingolimod's efficacy in RRMS, with the TRANSFORMS trial showing fingolimod to be even more efficacious than a first-line agent, IFNb-1a IM, in reducing annualized relapse rates.³¹ The oral formulation of fingolimod also confers additional benefit in patients who are intolerant or unwilling to use other parenteral DMTs. Considering injection anxiety is a major barrier for adherence to current first-line DMTs, fingolimod represents a noteworthy development in MS treatment.³⁸ Another advantage of fingolimod lies in its mechanism of action. Since fingolimod sequesters lymphocytes but does not destroy them, its effects are reversible, with lymphocyte counts returning to baseline in 4 to 6 weeks after drug discontinuation.³⁹

Despite the various advantages of fingolimod, additional research is needed to evaluate the usefulness of fingolimod in other types of MS; hence the results of the ongoing INFORMS trial in PPMS are highly anticipated.³² Evidence of long-term safety with fingolimod is also lacking. MS patients are typically diagnosed as young adults who need lifelong therapy, and the acquisition of long-term safety data is essential. Based on the evidence currently available, the safety concerns regarding increased risk of fatal viral infections and cancer seen in the TRANSFORMS trial is not to be overlooked.³¹ In addition, it remains unclear how fingolimod would compare to other first-line agents in terms of clinical efficacy and cost effectiveness. At this point, fingolimod has only been compared to IFNb-1a IM in a head-to-head trial. As discussed earlier, the EVIDENCE and INCOMIN studies have shown IFNb-1a SC and IFNb-1b to be superior to IFNb-1a IM in efficacy.^21,22 Currently, as shown in Table 1, fingolimod also appears to be the most expensive first-line DMT at an annual cost of about $57,000, versus $37,000 to $50,000 for other first-line DMTs. Most importantly, the clinical significance of trial measures and outcomes needs to be examined. The primary goal for MS therapy is to improve patients' quality of life, which is mainly accomplished by delaying disability progression. Studies have found that MRI measures do not correlate with disease progression, and that other outcomes such as EDSS scores should be measured in order to accurately assess medication efficacy and disease severity in MS patients.²⁰ While the FREEDOMS trial found that fingolimod reduced the risk of disability progression compared to placebo, the TRANSFORMS trial did not find a difference in disability progression with fingolimod compared to IFNb-1a IM during the short observation period of 12 months.^30,31 A longer study comparing other DMTs would be more useful in assessing the relative efficacy and place of therapy of fingolimod.

Although FDA approved fingolimod as first-line therapy for MS, considering all the pros and cons discussed above, the authors recommend fingolimod as a non-preferred first-line agent. Long-term safety of fingolimod has yet to be established and it is uncertain whether fingolimod would be more efficacious than first-line DMTs, other than IFNb-1a IM, for reducing relapse rates. In terms of disability progression, fingolimod was found to be equally efficacious compared to IFNb-1a IM and superior to placebo. However, fingolimod is associated with a risk of serious side effects like fatal viral infections, cardiac changes, macular edema, and cancer. Since the current first-line agents do not have such serious safety concerns, it is recommended that patients should complete an adequate trial of an established first-line DMT before being considered as candidates for fingolimod. Those patients who are intolerant or unwilling to receive the established first-line DMTs due to extreme injection anxiety may be considered as potential candidates for fingolimod. In addition, fingolimod should be restricted to RRMS patients with at least 1 documented relapse in the previous year or 2 relapses in the past 2 years as these patients have the highest benefit-to-risk ratio from fingolimod and reflect the population that was studied in the phase 3 trials. Those who do not demonstrate an improvement in relapses or disability progression after a full year of treatment should be re-evaluated and possibly switched to another medication.

Dalfampridine. Clinical trials have shown a statistically significant improvement in walking speed with dalfampridine, but this only translates to a minimal benefit for a select number of patients. This is evident in the 2 pivotal phase 3 trials where less than half of patients in the treatment group responded to dalfampridine.^34,35 One theory is that not all patients have demyelinated axons related to walking and therefore are not susceptible to treatment effects.³⁴ These trials have also observed an average improvement of only 2 seconds in the T25FW in patients who did respond. Taking into account both the cost of dalfampridine at roughly $15,400 per year and its limited benefit, dalfampridine would likely not be cost-effective.

EMERGING THERAPIES

There are presently 4 oral MS agents in phase 3 trials that will compete with fingolimod for market shares if approved by the FDA: laquinimod, teriflunomide, dimethyl fumarate, and cladribine.

Laquinimod is an immunomodulatory agent that causes interference of T cells' adherence to endothelial cells, which reduces the migration of lymphocytes into the CNS.⁴⁰ A 36-week, double-blind, placebo-controlled study found that laquinimod significantly reduced the mean cumulative Gd+ lesions by 40.4%. During the study, laquinimod was generally well tolerated with some reports of liver enzyme elevations.⁴¹ Three phase 3 trials involving laquinimod are expected to have results in 2011.³²

Teriflunomide is an active metabolite of leflunomide and decreases the proliferation of B and T cells by inhibiting an enzyme involved in pyrimidine synthesis.⁴² A phase 2 study involving 179 RRMS patients found that patients receiving teriflunomide had statistically significant reductions in brain lesions on MRI versus placebo. Serious adverse events were similar between treatment groups, and teriflunomide was generally well tolerated.⁴³ Two phase 3 trials are expected to have results soon-one is due to finish by late 2011 and another is due to be completed by 2013.³²

Dimethyl fumarate, or BG-12, activates the Nrf2 signaling pathway to inhibit microglia and astrocytes, which causes reduced CNS inflammation.⁴⁴ A 24-week, double-blind, placebo-controlled study found that BG-12 decreased mean number of new Gd+ lesions by 69%. Common side effects were abdominal pain and flushing. Incidence of serious adverse events was similar between treatment groups.⁴⁵ BG-12 is currently undergoing a phase 3 trial, which is expected to be completed in late 2011.³²

Cladribine is a purine analog that disrupts DNA synthesis and repair. A 96-week phase 3 study involving 1,326 RRMS patients found that cladribine significantly reduced relapse rates and risk of disability progression compared to placebo. However, patients receiving cladribine experienced more lymphocytopenia and herpes zoster infections. There were also 3 cases of severe neutropenia with cladribine that included severe thrombocytopenia and pancytopenia.⁴⁶ A new drug application for cladribine was filed in 2010, but in March 2011 FDA decided not to approve the medication for MS without more safety information.⁴⁷

Other novel medications currently in phase 3 trials for MS are progestin and estradiol, cyclophosphamide, daclizumab, rituximab, and alemtuzumab.^20,32 These therapies provide different mechanisms of action and, if approved, will serve as alternatives for patients who do not respond to current therapeutic options.

CONCLUSION

Multiple sclerosis is a complex disorder that results in significant clinical and economic burden. The primary goal of treatment is to delay the progression of disability through use of DMTs. Until recently, the only available DMTs were injectables. The arrival of dalfampridine and fingolimod represents a paradigm shift from parenteral to oral agents. So far, dalfampridine has shown only limited clinical benefit for the symptomatic treatment of MS patients. Fingolimod, on the other hand, has demonstrated its clinical efficacy as a DMT. The parenteral DMTs all confer reductions in relapse rate and disability progression, but are differentiated mainly by their safety profile. The authors propose that fingolimod be considered a non-preferred first-line agent due to the lack of long-term safety data and the potential serious adverse effects. The introduction of an oral DMT for MS is an exciting development, but safety is paramount because most patients will require lifelong therapy from a young age. Until fingolimod has more long-term safety data, the established first-line parenteral DMTs should continue to be considered first. For patients who are intolerant or unwilling to receive the established first-line DMTs due to extreme injection anxiety, fingolimod is a viable option.

Dr Tam is managed care pharmacy practice resident, Health Plan of San Joaquin; Ms Lopez is a PharmD candidate at University of the Pacific. Dr Shek is associate professor of pharmacy practice, University of the Pacific, Stockton, Calif., and director of pharmacy, Health Plan of San Joaquin. Dr Yeh is clinical pharmacist and care management manager, Health Plan of San Joaquin, French Camp, Calif.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.

REFERENCES

1. National Multiple Sclerosis Society. About MS: Who Gets MS? http://nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/who-gets-ms/index.aspx. Accessed January 31, 2011.

2. Rejdak K, Jackson S, Giovannoni G. Multiple sclerosis: a practical overview for clinicians. Br Med Bull. 2010;95:79–104.

3. Kobelt G, Berg J, Atherly D, Hadjimichael O. Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States. Neurology. 2006;66:1696–1702.

4. Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain. 2006;129:606–616.

5. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444–1452.

6. Spain RI, Cameron MH, Bourdette D. Recent developments in multiple sclerosis therapeutics. BMC Med. 2009;7:74.

7. National Clinical Advisory Board of the National Multiple Sclerosis Society. Disease Management Consensus Statement. http://www.nationalmssociety.org/download.aspx?id=8. Accessed January 31, 2011.

8. Avonex [package insert]. Cambridge, MA: Biogen Idec, Inc.; 2008.

9. Rebif [package insert]. Rockland, ME: EMD Serono, Inc.; New York, NY: Pfizer, Inc.; 2009.

10. Betaseron [package insert]. Montville, NJ: Bayer HealthCare Pharmaceuticals; 2010.

11. Copaxone [package insert]. Kansas City, MO: Teva Neuroscience, Inc.; 2009.

12. Gilenya [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2010.

13. Ampyra [package insert]. Hawthorne, NY: Acorda Therapeuticals, Inc.; 2010.

14. 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. AHRQ, National Guideline Clearinghouse, NGC-3144. http://www.guideline.gov/content.aspx?id=4099&search=multiple+sclerosis/. Accessed August 10, 2010.

15. Vosoughi R, Freedman MS. Therapy of MS. Clin Neurol Neurosurg. 2010;112:365–385.

16. Jacobs LD, Cookfair DL, Rudick RA, et al; and the Multiple Sclerosis Collaborative Research Group (MSCRG). Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol. 1996;39:285–294.

17. PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon -1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352:1498–1504.

18. Johnson KP. Risks vs benefits of glatiramer acetate: a changing perspective as new therapies emerge for multiple sclerosis. Ther Clin Risk Manag. 2010;6:153–172.

19. Johnson KP, Brooks BR, Cohen JA, et al; and the Copolymer 1 Multiple Sclerosis Study Group. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology. 1995;45:1268–1276.

20. Gawronski KM, Rainka MM, Patel MJ, Gengo FM. Treatment options for multiple sclerosis: current and emerging therapies. Pharmacotherapy. 2010;30:916–927.

21. Panitch H, Goodin DS, Francis G, et al, for the EVIDENCE Study Group and the University of British Columbia MS/MRI Research Group. Randomized, comparative study of interferon -1a treatment regimens in MS: the EVIDENCE Trial. Neurology. 2002;59:1496–1506.

22. Durelli L, Verdun E, Barbero P, et al, and the Independent Comparison of Interferon (INCOMIN) Trial Study Group. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002;359:1453–1460.

23. O'Connor P, Filippi M, Arnason B, et al, for the BEYOND Study Group. 250 µg or 500 µg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol. 2009;8:889–897.

24. Mikol DD, Barkhof F, Chang P, et al, on behalf of the REGARD study group. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008;7:903–914.

25. Cadavid D, Wolansky LJ, Skurnick J, et al. Efficacy of treatment of MS with IFN -1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology. 2009;72:1976–1983.

26. Hartung H, Gonsette R, König N, et al, and the Mitoxantrone in Multiple Sclerosis Study Group (MIMS). Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002;360:2018–2025.

27. Polman CH, O'Connor PW, Havrdova E, et al, for the AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899–910.

28. Rudick RA, Stuart WH, Calabresi PA, et al, for the SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354:911–923.

29. Dev KK, Mullershausen F, Mattes H, et al. Brain sphingosine-1-phosphate receptors: implication for FTY720 in the treatment of multiple sclerosis. Pharmacol Ther. 2008;117:77–93.

30. Kappos L, Radue EW, O'Connor P, et al, for the FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387–401.

31. Cohen JA, Barkhof F, Comi G, et al, for the TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–415.

32. http://www.clinicaltrials.gov/. Accessed March 2, 2011.

33. Hauser SL, Johnston SC. 4-Aminopyridine: new life for an old drug. Ann Neurol. 2010;68:A8-A9.

34. Goodman AD, Brown TR, Edwards KR, et al, on behalf of the MSF204 Investigators. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol. 2010;68:494–502.

35. Goodman AD, Brown TR, Krupp LB, et al, on behalf of the Fampridine MS-F203 Investigators. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet. 2009;373:732–738.

36. Bell C, Graham J, Earnshaw S, Oleen-Burkey M, Castelli-Haley J, Johnson K. Cost-effectiveness of four immunomodulatory therapies for relapsing-remitting multiple sclerosis: a Markov model based on long-term clinical data. J Manag Care Pharm. 2007;13:245–261.

37. Goldberg LD, Edwards NC, Fincher C, Doan QU, Al-Sabbagh A, Meletiche DM. Comparing the cost-effectiveness of disease-modifying drugs for the first-line treatment of relapsing-remitting multiple sclerosis. J Manag Care Pharm. 2009;15:543–555.

38. Fox EJ. Emerging oral agents for multiple sclerosis. Am J Manag Care. 2010;16:S219–S226.

39. Conway D, Cohen JA. Emerging oral therapies in multiple sclerosis. Curr Neurol Neurosci Rep. 2010;10:381–388.

40. Wegner C, Stadelmann C, Pförtner R, et al. Laquinimod interferes with migratory capacity of T cells and reduces IL-17 levels, inflammatory demyelination and acute axonal damage in mice with experimental autoimmune encephalomyelitis. J Neuroimmunol. 2010;227:133–143.

41. Comi G, Pulizzi A, Rovaris M, et al, for the LAQ/5062 Study Group. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;371:2085–2092.

42. Warnke C, Meyer Zu Hörste G, Hartung HP, Stüve O, Kieseier BC. Review of teriflunomide and its potential in the treatment of multiple sclerosis. Neuropsychiatr Dis Treat. 2009;5:333–340.

43. O'Connor PW, Li D, Freedman MS, et al, on behalf of the Teriflunomide Multiple Sclerosis Trial Group and the University of British Columbia MS/MRI Research Group. A phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology. 2006;66:894–900.

44. Bista P, Ryan S, Hahm K, et al. Dimethyl fumarate (BG00012) inhibits astrocyte and microglial activation. Multiple Sclerosis. 2009;15:S132.

45. Kappos L, Gold R, Miller DH, et al, for the BG-12 Phase IIb Study Investigators. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;372:1463–1472.

46. Giovannoni G, Comi G, Cook S, et al, for the CLARITY Study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362:416–426.

47. Gandey A. Medscape website. http://www.medscape.com/viewarticle/738239/. Updated March 2, 2011. Accessed March 2, 2011.