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Treating Relapsing Forms of Multiple Sclerosis: Injection and Oral Therapies

Le H. Hua

INTRODUCTION

There has been an overwhelming increase in available therapies for relapsing forms of MS since the first disease-modifying therapy (DMT) was approved in 1993. The DMTs have varying mechanisms, routes of administration, efficacy, and safety profiles. The decision of which therapy to use can be challenging, but also allows for improved tailoring of therapy specific to individuals based on disease characteristics and patient preferences. At present, there are more than 15 approved DMTs for MS, and this chapter focuses on the injectable and oral treatment options. Chapter 14 will focus on infusion therapies. Mechanism of action, trial results, start-up and monitoring, risk stratification, and typical patients will be covered, respectively, for interferons, glatiramer acetate (GA), daclizumab (DAC), fingolimod, teriflunomide, and dimethyl fumarate (DMF). Tables covering trial results and safety considerations for reference are provided, but are not intended for cross-trial comparisons (Tables 13.1 and 13.2).

INTERFERON BETA

Mechanism of Action

There are several formulations of interferon (IFN) beta which vary in dosing frequency: IFN beta-1b administered subcutaneously every other day (Betaseron and Extavia), IFN beta-1a administered intramuscularly once a week (Avonex) or subcutaneously three times per week (Rebif), and peginterferon beta-1a administered subcutaneously every 2 weeks (Plegridy). IFN beta-1b is developed in Escheria coli and not glycosylated, whereas IFN beta-1a is produced in the Chinese hamster ovarian cell lines and is glycosylated (16). The clinical importance of these differences is unknown in MS. Brand names will be subsequently used for IFN beta therapy when clarification of the specific formulation is necessary.

IFN beta was developed for use in MS, based on the recognition that there was lower endogenous IFN beta production in patients with MS. IFN beta is thought to have anti-inflammatory and immunodulatory effects by inhibiting T-cell activation and proliferation, inducing apoptosis of autoreactive T cells, cytokine modulation and enhancing anti-inflammatory responses, and inhibition of leukocyte migration across the blood–brain barrier (17).

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Trial Results

The pivotal trials leading to approval of IFN beta therapies demonstrated annualized relapse rate (ARR) reductions of 18% to 34%, when compared to placebo. Secondary MRI endpoints of relative reduction in new T2 lesions and gadolinium (Gd) enhancing lesions ranged from 34% to 83% and 22% to 67%, respectively (1–5). Disability endpoints were not significant for Betaseron (1). Disability outcomes were the primary endpoint for the Avonex trial, which demonstrated a 36% reduction in 6-month confirmed disability progression compared to placebo (3). Compared to placebo, Rebif showed 32% to 38% relative reduction in disability (4). Dose comparison trials of IFN beta treatments suggest higher efficacy with higher dose formulations (18,19).

A pegylated IFN beta-1a formulation was approved in 2014 based on the results of the ADVANCE trial (6). Compared to placebo, pegylated IFN beta-1a demonstrated an ARR reduction of 27%, relative reduction in T2 lesions of 67%, and Gd enhancing lesions by 86%. There was also a 38% relative reduction in 3-month confirmed disability progression. These results are comparable to the pivotal IFN beta trials.

Safety and adverse events were similar across all IFN beta trials. Common adverse events were influenza-like symptoms (fevers, chills, myalgias, malaise), depression, neutropenia, lymphopenia, elevated transaminases, and thyroid dysfunction. Some patients also report worsening of headaches with IFN beta use.

Start-Up, Monitoring, and Risk Stratification

Each IFN beta formulation has a dose titration schedule which allows for improved tolerability. The target dose of Avonex is 30 mcg intramuscular weekly. Titration starts with 7.5 mcg for the first week and increases by 7.5 mcg weekly to reach the full 30 mcg dose (20). Rebif is available at 22 and 44 mcg doses subcutaneous three times per week. Titrations schedule begins with 20% of the total dose for the first 2 weeks, then half the dose for 2 weeks, and reaching full dose at week 5 (21). The target dose of Betaseron and Extavia is 0.25 mg subcutaneous every other day. Titration starts at 0.625 mg every other day for 2 weeks, and increases by 0.625 mg every 2 weeks to reach the full 0.25 mg dose starting week 7 (22). Finally, Plegridy is dosed at 125 mcg subcutaneous every 2 weeks. Titrations start at 63 mcg on day 1, 94 mcg on day 15, and the full dose of 125 mcg on day 29 (23).

119Patients need to have baseline complete blood counts (CBCs), liver function testing (LFT), and thyroid function testing. CBC and LFT should be monitored while on medication at intervals of 1, 3, and 6 months after treatment start, and then periodically thereafter, for example, every 6 to 12 months. Thyroid function should be monitored as clinically indicated. In the past, the development of neutralizing antibodies (NAbs) to IFN beta led to concern regarding potential decreased efficacy. Higher doses were associated with higher rates of NAb formation (24). The necessity of measuring NAbs to IFN beta have decreased, particularly as there are many alternative DMTs available for patients who demonstrate disease activity while on IFN beta therapy. In Europe, however, the guidelines suggest checking for presence of NAbs at 12 and 24 months. Patients who are positive for NAbs should be retested 3 to 6 months later, and treatment discontinued with high titers of NAbs.

Typical Patients

The IFN beta have established efficacy, favorable safety profiles, and are generally well tolerated. They are approved as first-line therapy for relapsing MS. Avonex, Betaseron, and Extavia are also approved for use in patients with a clinically isolated syndrome (CIS). Avonex and Plegridy offer less frequent dosing intervals than the other IFN beta. Overall, IFN beta is ideal for use in patients with mild disease, who are risk adverse, and are able to manage injections.

GLATIRAMER ACETATE

Mechanism of Action

GA is a complex polypeptide mixture of L-glutamic acid, L-lysine, L-alanine, and L-tyrosine, initially developed to induce demyelination in the experimental autoimmune encephalomyelitis (EAE) mouse. Surprisingly, this mixture was found to be protective, and thus further developed as a treatment for MS. The mechanism of action of GA accounting for its clinical benefit in MS is incompletely understood but is hypothesized to involve competition with myelin autoantigens at the major histocompatibility complex class II binding site on antigen presenting cells, induction of antigen-specific Th2 T cells leading to bystander suppression of inflammation, and stimulation of neurotrophic factor secretion by immune cells (25).

Trial Results

The phase 3 trial that lead to approval of GA showed relative reduction in ARR of 29% compared to placebo (7). There was a reduction in confirmed one-point disability progression of 12%; however, this was not significant. A separate, shorter, placebo-controlled trial was completed to evaluate MRI outcomes, and showed relative reduction in T2 lesions by 30% and Gd lesions by 29% (8). Years later, the Glatiramer Acetate Low-frequency Administration (GALA) study demonstrated that a 40 mg three times per week formulation was similarly efficacious, with a relative reducing in ARR by 34% compared to placebo, a 34.7% relative reduction in T2 lesions, and 44.8% relative reduction in Gd lesions (9). Disability outcomes were not evaluated. Safety and tolerability were comparable to GA 20 mg daily dosing.

Recently several generic formulations of GA 20 mg daily have been submitted for approval (Momenta/Sandoz, Mylan/NATCO, and Synthon/Pfizer). The U.S. Federal Drug Agency approved generic GA (Glatopa-Momenta/Sandoz) based on equivalent biophysiochemical properties and effects in the EAE model. Contrastingly, the European Medicines Agency advised Synthon to perform an equivalency trial for their generic GA product (26). This led to the GATE trial, a multicenter, randomized, double blind, active- and placebo-controlled phase 3 trial, using MRI as a primary outcome to compare generic versus brand formulations. Results from the GATE trial revealed equivalent efficacy, tolerability, and safety for the generic GA (Synthon) compared to brand GA (Teva) (27).

Common side effects for GA are injection site tenderness, induration, pruritis, and erythema. Immediate postinjection reactions can also infrequently occur consisting of flushing, palpitations, dyspnea, and anxiety occurring within minutes of injection and resolving up to 30 minutes later. With prolonged use, patients can develop lipoatrophy, with resultant scarring at site of injections.

Start-Up, Monitoring, and Risk Stratification

GA is administered subcutaneously and available as either 20 mg daily or 40 mg three times per week (28). There are no dose titration or laboratory monitoring requirements for GA. Unique among the MS DMTs, there were no adverse effects on embryo-fetal development, delivery or offspring growth, and development when GA was administered in animal studies and is generally considered safe in pregnancy.

120Typical Patients

Similar to IFN beta, GA also has established efficacy, favorable safety profiles, and is generally well tolerated. GA is approved for relapsing MS as well as CIS. It is also ideal for use in patients with mild disease, who are risk adverse, and are able to manage injections. As mentioned earlier, GA is considered safe in pregnancy and pregnant patients can remain on GA during the first trimester (29). As there are no effects on blood counts and liver function, GA can also be useful in patients where recurrent lymphopenia or transaminitis are concerns.

DACLIZUMAB (Withdrawn From Market in March 2018)

Mechanism of Action

DAC is a humanized anti-CD25 monoclonal antibody, which modulates interleukin-2 signaling, and leads to expansion of CD56^bright natural killer cells, inhibition of T-cell activation, and reduces development of lymphoid tissue inducer cells (30). It was initially developed to prevent rejection in renal transplant patients. Based on its immune effects, DAC was explored for use in MS. A high-yield process (HYP) was developed for long-term subcutaneous administration and less antibody-dependent cytotoxicity compared to the intravenous formulation.

Trial Results

The DECIDE study was the phase 3 trial that lead to the approval of DAC in MS (10). This was a double-blind, multicenter randomized controlled trial comparing DAC to intramuscular IFN beta-1a. Results from trial showed that DAC had a 45% relative risk reduction in ARR when compared to IFN beta-1a. There were no statistically significant differences in 3-month confirmed disability progression; however, 6-month confirmed disability progression was reduced by 27% compared to IFN beta-1a. For MRI endpoints, DAC had 54% relative reduction in T2 lesions and 60% relative reduction in Gd-enhancing lesions when compared to IFN beta-1a.

DAC was relatively well tolerated with 14% discontinuing treatment due to adverse events during the trial. Side effects include skin reactions (rash, dermatitis, eczema), transaminitis, infections, and depression. Severe risks include other immune-mediated disorders (skin reactions, lymphadenopathy, noninfectious colitis) and liver toxicity including autoimmune hepatitis.

Start-Up, Monitoring, and Risk Stratification

DAC-HYP is a 150 mg subcutaneous injection given monthly (31). Patients who receive treatment with DAC are required to enroll in a Risk Evaluation and Mitigation Strategy (REMS) program due to autoimmunity and liver failure risks. Baseline testing for liver function, tuberculosis exposure, and hepatitis B and C virus are required. Monthly LFT is required while on treatment and for an additional 6 months after discontinuing therapy.

Typical Patients

DAC is a high-efficacy treatment, with significant reductions in ARR and MRI endpoints against an active comparator. However, due to its safety profile, would be reserved as a second- or third-line agent. Its subcutaneous mechanism may be favorable compared to intravenous options for those with limited access to an infusion center or poor venous access. Patients would need to be able to comply with REMS requirement of monthly liver testing. DAC has not been associated with progressive multifocal leukoencephalopathy (PML) in renal transplant usage or trials with MS; however, longer follow-up is needed to further assess risk of PML.

FINGOLIMOD

Mechanism of Action

Fingolimod was developed during the search for novel drug compounds from analysis of fungal metabolites believed to have medicinal effects in folk medicine. This novel compound, originally named FTY720, appeared to have benefits in organ transplantation through nonimmunosuppressant mechanisms. Further studies led to the discovery that fingolimod binds to and modulates the sphingosine 1 phosphate (S1P) receptor (32). By binding to the S1P receptors, fingolimod is thought to sequester lymphocytes in lymph nodes, thus decreasing the inflammatory response in MS, although other mechanisms may underlie fingolimod’s potential for neuroprotection, as fingolimod crosses the blood–brain barrier, and S1P and S1P receptors are found in the central nervous system (CNS). S1P receptor interaction also accounts for the cardiovascular (bradycardia, slowed atrioventricular conduction, increased blood pressure), pulmonary, and macular edema side effects for fingolimod (33).

Trial Results

Fingolimod was the first oral therapy to be approved for relapsing MS. The two pivotal phase 3 studies were the FREEDOMS trial (24-month double blind, randomized trial of oral fingolimod compared to placebo) and the TRANSFORMS trial (12-month double blind, double 121dummy randomized trial of oral fingolimod compared to intramuscular IFN beta-1a) (11,12). Two doses of fingolimod, 0.5 and 1.25 mg, were studied in the trials; however, only the 0.5 mg dose was approved as there was comparable efficacy to the higher dose, with a more favorable safety profile. In FREEDOMS, fingolimod 0.5 mg showed a relative reduction in ARR by 54%, and a 27% relative risk reduction in 3-month confirmed disability progression at 24 months compared to placebo. There was also a significant relative reduction in 6-month confirmed disability progression of 34%. New T2 lesions and Gd-enhancing lesions showed relative reductions of 75% and 82%, respectively. In TRANSFORMS, ARR was relatively reduced by 52% compared to IFN beta-1a. MRI endpoints of new T2 lesions and Gd-enhancing lesions were relatively reduced by 35% and 55%, respectively. Disability progression was similar among treatment groups during the 1-year study.

Fingolimod is very well tolerated, with only 5% to 7.5% discontinuing the 0.5 mg dose formulation due to adverse events. Common side effects include bradycardia, headache, transaminitis, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, and extremity pain. Rare safety concerns include atrioventricular block, macular edema, PML, posterior reversible encephalopathy syndrome, herpes viral infections and cryptococcal infections, and basal cell carcinoma. A handful of PML cases have been reported in the postmarketing surveillance period.

Start-Up, Monitoring, and Risk Stratification

Fingolimod is a once daily pill. Prior to starting this medication, baseline testing requirements include CBC, LFT, varicella zoster virus (VZV) immunity, baseline electrocardiogram, and testing for macular edema. Patients in whom testing for VZV antibody is negative should undergo vaccination and treatment delayed for 1 month to allow for full vaccination effects. Testing for macular edema should occur after 3 to 4 months on treatment and periodically thereafter on treatment as indicated. A first-dose observation period of 6 hours, in which heart rate and blood pressure are monitored hourly, is required at initiation and again if drug is discontinued for more than 14 days. Heart rate should start to recover by the end of the 6 hours; otherwise, observation needs to continue until resolved. High-risk patients (those at risk of symptomatic bradycardia, heart block, prolonged QTc interval, and/or those taking other drugs with risk of torsades de pointes), should be monitored overnight. Recent myocardial infarction, unstable angina, stroke, transient ischemic attack, and heart failure are contraindications. Fingolimod should also be avoided in patients with Mobitz type II second-degree or third-degree atrioventricular (AV) block, sick sinus syndrome, or baseline QTc interval ≥ 500 milliseconds (34).

 

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