Brief description: There has been a significant amount of new trial data released and some new product labeling changes over the past year related to the treatment of multiple sclerosis. This review discusses those changes and reviews the pipeline for disease modifying therapies used in the treatment of relapsing-remitting multiple sclerosis.

Multiple Sclerosis (MS) is chronic neurodegenerative disorder that involves Central Nervous System (CNS) inflammation. An autoimmune disease process results in damage to the myelin sheath of the neurons and thus the neurons themselves. The pathophysiology involves autoreactive T-cell proliferation and migration across the blood-brain barrier. Inflammatory mediators such as inflammatory cytokines are released and macrophages and microglial cells cause injury to the neurons, resulting in lesions in the CNS. B cells are also thought to play a role following the breakdown of the blood-brain barrier and also potentiate myelin degradation through the formation of myelin antibodies.

MS can result in significant morbidity. Fortunately, there are several disease modifying drugs (DMDs) recently approved or in the pipeline to slow the progression of the disease. Research has been aimed at blocking the inflammatory processes and thus hopefully slowing the progression of the disease. The American Academy of Neurology (AAN) meeting in 2012 had numerous posters and presentations related to clinical trials in MS. This will further complicate drug selection, as currently there are not evidence-based guidelines for the choice of which 1^st line agent to start with, when to switch, or what to switch to. More research is also being done on combination therapy, an area where evidence has been lacking.

Until recently, there were 4 therapies considered first line for the relapsing-remitting form of MS (RRMS): Interferon beta-1a intra-muscular injection (IM)(Avonex®), interferon beta-1a subcutaneous (SQ) (Rebif®), interferon beta-1b SQ (Betaseron®&Extavia®), and glatirameracetate IM (Copaxone®), referred to as ABC-R. None of these products are available generically. The ABC-R therapies were recently joined by fingolimod (Gilenya®). Prior to the approval of oral fingolimod, all of the available options were injectable therapies. However, the benefits of the oral route must now be weighed against some negative safety data, as will be discussed later.

Among the 4 injectable therapies, one medication does not stand out as the clear choice over the others, as they are generally considered to have similar efficacy. They do differ in specific side effect profiles; however, none are free from significant adverse effects. Smith and colleagues provide a very thorough review of the evidence; this review will briefly summarize the findings.¹ There have been five head to head trials comparing the interferons.^2–6 Avonex® was less effective than Betaseron® or Rebif® for relapse prevention, however there was no significant difference with regards to disability progression as measured by the Expanded Disability Status Scale(EDSS). One recent open label randomized controlled trial showed no statistical difference between the three interferons in either relapse rates or disability progression.⁷ Direct comparisons of glatiramer acetate to Rebif® and Betaseron® also resulted in no significant differences in relapse prevention or disease progression.^8–10 Overall, these medications are considered to have a greater effect on relapse outcomes than disability outcomes.

Although evidence is still not strong, there are some data to support that the formation of neutralizing antibodies associated with administration of beta interferons adversely affects relapse outcomes when patients are followed for longer periods (>2 years). Avonex® appears to have the lowest rate of development of these antibodies. The true clinical significance of these differences cannot be determined without further studies.¹

Overall, adverse event reporting was fairly weak across the clinical trials. No significant difference was seen in withdrawal rates due to adverse events. Elevations in alanine aminotransferase (ALT) occurred similarly with all the beta interferons, but most were transient and did not result in symptomatic problems. There is a little data to suggest that Rebif® may result in lower depression rates than the other beta interferons, with pooled relative frequencies of 14.4%, 19.7%, and 18.4% for Rebif®, Avonex®, and Betaseron® respectively.¹ Avonex® produces a lower incidence of injection site reactions, but a higher incidence of flu-like syndrome. Glatiramer produces higher rates of injection site reactions and post-injection responses, while having lower incidence of flu-like symptoms as compared to the beta interferons. Lipoatrophy is a side effect unique to glatiramer.

Fingolimod was approved by the FDA as a possible first line agent. Studies have demonstrated efficacy in RRMS with lower annualized relapse rates but no difference in disease progression compared to Avonex® in a head to head trial.¹¹ In May of 2012, new contraindications and monitoring requirements were added to the labeling following an investigation of cardiovascular post-marketing events and 11 deaths. In December of 2011, a death within 24hrs of the first dose of fingolimod was reported, despite doing fine in the 6hr post-dose monitoring period. Although no deaths could definitively be linked to fingolimod, concerns still exist with the cardiovascular safety of the medication. It has been known that bradycardia and AV block are potential side effects, but the risk is thought to potentially be higher than suspected. Fingolimod is now contraindicated in patients with high cardiovascular risk, including patients with a history or presence of cardiac conditions, such as myocardial infarction, heart failure or stroke in the previous 6 months, second- and third-degree atrioventricular block, prolonged QT interval 500 ms, or in patients treated with certain antiarrhythmic drugs. Monitoring recommendations have also changed. All patients should be monitored with hourly pulse and blood pressure for six hours after the first dose, with electrocardiogram (ECG) done before treatment and at the end of the observation period. The six hour period should be extended in certain patients at risk for bradycardia, such as concomitant administration of medications that could cause bradycardia or prolong the QT interval. Additional safety concerns exist for fingolimod related macular edema and viral infections. Fingolimod also had its first reported case of Progressive Multifocal Leukoencephalopathy (PML) reported this spring. However, the patient also had been on natalizumab previously and was positive for JVC virus antibodies, which are both risk factors for PML.

Natalizumab and mitoxantrone are not recommended as first line agents due to safety issues. They are recommended only for patients who have failed or cannot tolerate any of the first line agents. Natalizumab, although effective, has had a growing number of cases of PML since it was released. This year, updates were made to the product labeling to include additional risk factors for developing PML. These three factors are prior immunosuppressive therapy, treatment duration beyond 2 years, and being JVC antibody positive. If all three factors are present, the estimated risk of PML is 11 per 1000 users.¹² Nothing has changed with mitoxantrone; there is a cumulative dose risk of cardiovascular toxicity limiting its use in MS treatment.

There are numerous medications that have either completed or are currently being studied in phase 3 trials in RRMS. The most notable of these are teriflunomide, BG-12, alemtuzumab, laquinimod, daclizumab, and ocrelizumab. Oral teriflunomide has been submitted to the FDA for review following positive results in clinical trials. It works by inhibiting dihydroorotate dehydrogenase, which reduces T-cell and B-cell proliferation that results from autoantigen presentation, but preserves function of memory T-cells. In the TEMSO study, the drug reduced relapse rates, disability progression and disease activity on imaging tests compared to placebo.¹³ At doses of 7 mg and 14 mg, the relative risk for relapse was reduced by approximately 30%, which is comparable to other first line DMDs. Fewer patients had documented disability progression: teriflunomide 7 mg 21.7% (p = 0.08), teriflunomide 14 mg 20.2% (p=0.03), placebo 27.3%. Both teriflunomide groups had significantly fewer lesions on MRI than the placebo group. Significant dose related adverse events were diarrhea, nausea, hair thinning, and elevated ALT. Infection rates were similar among the three groups. A phase 3 non-inferiority trial (TENERE) was completed comparing the same two doses of teriflunomide to Rebif®.¹⁴ The results, which are not yet published in full, showed no difference between the groups on a primary composite outcome of risk for treatment failure. The 14 mg dose group also had a similar annual relapse rate compared with Rebif®. More patients in the Rebif® group withdrew due to adverse events (21.8% vs. 10.9% and 8.2% in the 14 mg and 7 mg groups respectively). Side effects were similar to what was seen in the first trial. A third trial (TOWER) was also recently completed but not yet published or fully analyzed.¹⁵ It was a placebo-controlled trial with an open label extension. The 14 mg dose showed a 36.3% reduction in ARR (p< 0.0001) and a 31.5% reduction in the risk for 12-week sustained accumulation of disability as measured by EDSS (p=0.0442). The only concern was one death due to sepsis in the teriflunomide group; this will be evaluated further.

BG-12 (dimethyl fumarate) is another promising oral agent in the pipeline for MS. It is thought that BG-12 has both anti-inflammatory and neuroprotective activity through activation of the Nrf2 pathway. Two unpublished phase 3 trials have been completed.¹⁶¹⁷ The DEFINE and CONFIRM trial data were used in the submission of a NDA earlier this year. Overall, the studies included more than 2,600 patients and looked at relapses, disability progression, and lesion burden. In the DEFINE trial, BG-12 reduced the risk of relapse at 2 years by 49% compared to placebo (p<0.0001) and reduced the risk of disability progression by 38% (p=0.0050). MRI results revealed a reduction in the number of new or enlarging T2 hyperintense lesions, Gd+ lesions, and T1 hypointense lesions by 85%, 90%, and 72%, respectively (p<0.0001). The CONFIRM study included glatiramer as an active comparator. BG-12 reduced the percent of patients who relapsed at 2 years by 34% compared to placebo (p<0.003), while glatiramer reduced this proportion by 29% compared to placebo (p<0.01). BG-12 outperformed glatiramer in reducing lesions, although not compared statistically due to study design. BG-12 reduced confirmed disability progression by 21% compared to placebo and glatiramer reduced the same measure by 7%. Results were not statistically significant, possibly due to low progression in the placebo group. With regards to safety and tolerability, the major side effects appear to be flushing (niacin-like effect) and GI symptoms. Another limitation is that, although the medication can be administered orally, it needs to be dosed twice daily.

Alemtuzumab is also expected to be up for review by the FDA soon, after completing two recent phase 3 trials, CARE-MS 1 and CARE-MS 2.¹⁸¹⁹ Alemtuzumab has some unique features; it is given intravenously for five days, then a year later for three days. It is a humanized monoclonal antibody already approved for treatment of certain types of cancer. Alemtuzumab is thought to essentially “reset” the immune system by depleting T-cells and B-cells and allowing for lymphocyte repopulation. The two trials compared alemtuzumab to standard therapy with Rebif®. The first included patients with no previous DMD therapy, while the second trial included patients who relapsed while on another DMD. Results of CARE-MS I showed that a higher percentage of patients treated with alemtuzumab were relapse free for two years compared to those treated with Rebif®, 78% vs. 59% (p<0.0001). The percent of patients experiencing a worsening of disability was similar between the two groups, 8% for alemtuzumab vs. 11% for Rebif® (p=0.22). Alemtuzumab also showed potential advantages in physical and cognitive function as measured by the Multiple Sclerosis Functional Composite (MSFC), as well as in some imaging outcomes. CARE-MS II confirmed these benefits by meeting endpoints in both relapse rate reduction and reduction in disability progression. Patients on alemtuzumab actually showed improvement in their EDSS measure. A five year open label follow up of a previous controlled trial against Rebif® upheld the sustained superior activity in relapse and disability prevention. Along with the high efficacy, comes high risk for serious adverse events. Some intense monitoring is likely to be required with this therapy. Autoimmune thyroid-related events, immune thrombocytopenia, and infection are of high concern with this medication.

The status of laquinimod, another once daily oral agent, is somewhat up in the air. It had promising results in the first phase 3 trial, but failed to meet its primary endpoint of relapse rate reduction in a second study comparing it to Avonex®.²⁰²¹ After adjustment for some baseline disease severity, a difference was detected. Although laquinimod's effect on reducing relapses appears to be modest, it has a disproportionately greater effect on reduction of disability progression and reduction of brain atrophy. The safety profile looks favorable so far and the company plans on pursuing further studies. More research is being pursued in the area of humanized monoclonal antibodies. Once monthly intravenous daclizumab and cycles of intravenous ocrelizumab have had favorable efficacy results in phase 2 trials.²²²³ Ocrelizumab depletes B-cells and was not pursued in rheumatoid arthritis due to safety concerns after increased incidence of severe infections in phase 2 trials. Daclizumab inhibits T-cell activation. It was previously marketed for kidney transplantation, but withdrawn for commercial reasons. As with the other immunologic agents, safety concerns will likely exist, but there will likely be more news to come in the future with the use of monoclonal antibodies in the treatment of MS.

Given the different mechanisms of action of the DMDs, logic would suggest additive or synergistic activity with combination therapy. Results have been conflicting and have not been as positive as expected. A recent clinical trial looking at the combination of glatiramer and Avonex (CombiRx) demonstrated no benefit in clinical outcomes over the individual agents alone, but did have a positive effect on new lesion development.²⁴ Combinations using natalizumab with first line agents had good efficacy results, but resulted in increased risk of PML. The most promising combination therapy right now is the addition of teriflunomide to first line therapy with interferons or glatiramer. Twin studies have been completed with a duration of 6 months and an extension to one year.²⁵²⁶ Although the trials were designed for safety, patients taking interferon beta plus a daily dose of teriflunomide7mg had a RRR of 86% in the number of T1-Gd lesions at the one year mark compared to adjunctive placebo (p=0.0005). There were no major safety concerns and adverse effects were comparable between groups. Cost of all of the DMDs is high and this may limit the feasibility of using combination therapy.

As investigational agents get approved and safety concerns are raised, it will be a difficult task to develop recommendations and decide on formulary inclusion. The pricing of these agents will likely play a big role in the decision making process. It will need to be determined if the differences in efficacy and ease of administration justify the risks and costs. Patient specific decisions, as is recommended now, will continue to be the standard.