Multiple Sclerosis Treatment & Management: Approach …

Disease-modifying therapies have shown beneficial effects in patients with relapsing MS, including reduced frequency and severity of clinical attacks. These agents appear to slow the progression of disability and the reduce accumulation of lesions within the brain and spinal cord. The disease-modifying agents for MS (DMAMS) currently approved for use by the US Food and Drug Administration (FDA) include the following:

Interferon beta-1a (Avonex, Rebif) [6]

Interferon beta-1b (Betaseron, Extavia) [7]

Peginterferon beta-1a (Plegridy) [8]

Glatiramer acetate (Copaxone) [9]

Natalizumab (Tysabri) [10, 11]

Fingolimod (Gilenya) [13]

Teriflunomide (Aubagio) [14]

Dimethyl fumarate (Tecfidera) [15, 16, 17, 18]

Alemtuzumab (Lemtrada) [19, 20, 21]

Daclizumab (Zinbryta) [22, 23]

Fingolimod, teriflunomide, and dimethyl fumarate are administered orally; natalizumab and mitoxantrone are administered by intravenous infusion; interferon beta-1a (Avonex) is administered intramuscularly; and interferon beta-1a (Rebif), interferon beta-1b, and glatiramer acetate are administered by subcutaneous injection.

Note that in January 2013, the FDA approved a single-use autoinjector (Rebidose, EMD Serono Inc./Pfizer Inc) for self-injection of interferon beta-1a (Rebif) in patients with relapsing forms of MS. [24] The ease of use, patient satisfaction and acceptability, and functional reliability of the Rebidose are supported by data from a 12-week open-label, single-group study in 109 patients. The autoinjector is available in a monthly pack in 22 and 44 g doses and in a titration pack. [24]

Patient lifestyle, patient tolerance, and adverse effects of injections should be considered in the choice of DMAMS. To a certain extent, health-care-provider preference and experience with the medications also play a role in determining which drug is appropriate in a particular situation.

Acase-control study from the MSBase longitudinal cohort found that MSpatients who are well controlled on injectable drugs but switch to oral therapies aren't at greater risk of early relapse.This is the first study to compare early relapse switch probability in the period immediately following switch to oral treatment in a population previously stable on injectable therapy.Results showedthere were no differences in the rate of first relapse or disability progression over the first 6 months. [86]

The first medication approved by the FDA for MS, in 1993, was interferon beta-1b (Betaseron, Extavia). It is indicated for the treatment of relapsing forms of MS to reduce the frequency of clinical exacerbations. It has shown efficacy in patients who have experienced a first clinical episode of MS and have MRI features consistent with MS. [7]

In a double-blind, placebo-controlled trial of 372 patients with relapsing-remitting MS, interferon beta-1b (8 million IU every other day) decreased the frequency of relapses by 34% after 2 years. In treated patients, the MRI T2 lesion burden increased 3.6% over 5 years, compared with 30.2% in the placebo group. At 5 year follow-up, the incidence of disease progression was lower in the interferon beta-1b group compared with the placebo group (35% versus 45%). [87]

Interferon beta-1b is administered every other day subcutaneously by self-injection. The most frequently reported adverse reactions include asthenia, depression, flu-like symptoms, hypertonia, increased liver enzymes, injection site reactions, leukopenia, and myasthenia. Interferon beta-1b can be coadministered with analgesics or antipyretics to help with the occurrence of flu-like symptoms. [7]

In a study of 301 patients with relapsing-remitting disease who were given weekly intramuscular injections (6 million U [30 g]) of interferon beta-1a (Avonex), the annual exacerbation rate decreased 29%. [88] Over 2 years, disease progression occurred in 21.9% of patients in the interferon beta-1a group and 34.9% of those in the placebo group. In addition, MRI data showed a decrease in the mean lesion volume and number of enhancing lesions in the interferon beta-1a group.

In Europe and Canada, higher doses of subcutaneous interferon beta-1a (Rebif) were studied in the Prevention of Relapse and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) Study. [89] The dose-comparison study of interferon beta-1a reported a 27% reduction in the relapse rate in patients receiving 66 g/wk and a 33% reduction in those receiving 132 g/wk. This study, of 560 patients with relapsing-remitting disease, also demonstrated a significant reduction in accrual of disability and MRI lesion burden with the higher dose. [89]

In 2002, the FDA approved interferon beta-1a (Rebif) in 22 g and 44 g formulations given 3 times per week.

In the Evidence of Interferon Dose-response: European North American Comparative Efficacy (EVIDENCE) trial, which compared 2 preparations of interferon beta-1a (Rebif and Avonex), relapse occurred less frequently with 44 g 3 times weekly (Rebif) than with 30 g once weekly (Avonex) (25% vs 37%). [90] In addition, the mean number of active unique MRI lesions per patient per scan was lower in the Rebif than in the Avonex group (0.17 vs 0.33). Patients on Rebif experienced fewer flulike symptoms, but more injection site reactions, hepatic function disorders, and white blood cell disorders. Rebif-treated patients had a higher incidence of neutralizing antibodies (Nabs). A reduced MRI effect was noted for Nab-positive patients on Rebif compared with Nab-negative patients on Rebif. However, Nab-positive Rebif patients had better clinical and comparable MRI results to Avonex patients. [90]

In a subsequent crossover phase of the EVIDENCE trial, patients who were originally randomized to low-dose weekly treatment were switched to the high-dose 3-times-weekly regimen for an additional 8 months. These patients demonstrated significant reductions in mean relapse rates compared with the last 6 months on Avonex (P< .001). [91]

In patients with uncontrolled depression, interferons should be used with caution. Glatiramer may be an appropriate choice in such cases.

Peginterferon beta-1a (Plegridy) was approved by the FDA in August 2014 for treatment of relapsing forms of MS. It is the first pegylated interferon approved for MS and can be self-administered by SC injection every 2 weeks. [8]

Approval was based on results from the ADVANCE trial of >1,500 patients with MS over a 2-year period. In the first year of the trial, peginterferon beta-1a dosed every 2 weeks significantly reduced annualized relapse rate (ARR) at 1 year by 36% compared with placebo (P = 0.0007). Risk of 12-week confirmed disability progression, as measured by the Expanded Disability Status Scale, was also reduced with peginterferon beta-1a by 38% (P = 0.0383) compared with placebo. Peginterferon beta-1a also significantly reduced the number of new gadolinium-enhanced [Gd+] lesions by 86% (P< 0.0001) and reduced new or newly enlarging T2-hyperintense lesions by 67% (P< 0.0001) compared with placebo. [8]

Glatiramer acetate (Copaxone) is a synthetic polypeptide approved for the reduction of the frequency of relapses in patients with relapsing-remitting MS, including patients who have experienced a first clinical episode and have MRI features consistent with MS. Glatiramer acetates mechanism of action is unknown, but this agent could theoretically modify some of the immune processes thought to be involved in the pathogenesis of MS. [9]

In a double-blind trial that included 251 patients with relapsing-remitting MS (RRMS), treatment with glatiramer acetate 20 mg SC once daily resulted in a 29% reduction in the relapse rate over 2 years; a positive effect on disability was suggested but this effect was not shown on predetermined disability measures in this trial. [92] For this reason, glatiramer acetate is not approved by the FDA for slowing disability progression in MS. A follow-up open-label study demonstrated continued efficacy of glatiramer over 6 years. [93]

In January 2014, a higher dose and lower-frequency dosage regimen of glatiramer was approved. The 20-mg/mL SC injection is specific for the original once-daily regimen, whereas the new 40-mg/mL SC injection is specific for the 3-times-per-week dosage regimen. Approval for the new regimen was based on the phase 3 Glatiramer Acetate Low-Frequency Administration (GALA) study. The GALA trial included 1,404 patients and showed that treatment with 40 mg SC 3 times/wk reduced mean annualized relapse rates by 34% compared with placebo (0.331 vs 0.505; P< .0001) at 12 months. [94]

Natalizumab (Tysabri) is a humanized monoclonal antibody that binds to the adhesion molecule alpha-4 integrin, inhibiting its adherence to its receptors. Natalizumab is indicated as monotherapy for the treatment of patients with relapsing forms of MS, to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. It is generally used in patients who have not responded to a first-line disease-modifying therapy or who have very active disease. [11]

In a placebo-controlled clinical trial, the use of natalizumab reduced the relapse rate (68%) and progression of disability (42%) over a period of 2 years. [95] Natalizumab is given as a 300 mg IV infusion over 1 hour every 4 weeks.

Natalizumab has been associated with progressive multifocal leukocephalopathy (PML), an opportunistic infection of the brain that can lead to death or severe disability. The risk of PML seems to increase with a history of previous immunosuppression, duration of exposure to natalizumab beyond 2 years, and JC virus antibody positivity.

Three cases of PML associated with natalizumab use prompted its temporary withdrawal from the market in 2005; however, it was reapproved in 2006 by the FDA for commercialization under a special restricted distribution program known as Tysabri Outreach Unified Commitment to Health (TOUCH). Use of natalizumab is limited to patients, physicians, and infusion centers that are registered with the TOUCH program.

A retrospective review of 906 patients from 5 clinical trials by Cadavid et al found that after treatment with natalizumab, disabled patients with relapsing-remitting MS were more likely to complete a timed 25-foot walk significantly faster; responders took an average of 2444% less time to walk 25 ft than nonresponders. Natalizumab also appeared to have some efficacy in disabled patients with SPMS. [96]

Fingolimod (Gilenya) is the first oral disease modifying treatment for relapsing forms of MS approved by the FDA. Like other disease-modifying agents for MS, fingolimod can reduce the frequency of clinical exacerbations and delay the accumulation of physical disability. The recommended dosage for fingolimod is 0.5 mg once a day. [13]

Fingolimod is a novel compound produced by chemical modification of a fungal precursor. Its active metabolite, formed by in vivo phosphorylation, modulates sphingosine 1-phosphate receptors, which are a subset of a larger family of cell-surface, G proteincoupled receptors that mediate the effects of bioactive lipids known as lysophospholipids. Lysophospholipids are membrane-derived bioactive lipid mediators that can affect fundamental cellular functions, which include proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis.

The mechanism of action of fingolimod is incompletely understood but appears to be fundamentally different from other MS medications. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. Fingolimod promotes sequestration of lymphocytes within the lymph nodes, which may reduce lymphocyte migration into the central nervous system. [97]

Fingolimod can be associated with macular edema, pulmonary dysfunction, and cardiac adverse effects.

In 2012, the FDA determined that new label changes are required for fingolimod. Within an hour of administering fingolimod, heart rate decreases are noted. The nadir in heart rate typically occurs at 6 hours, but it can be observed up to 24 hours after the first dose in some patients. Because of its cardiac adverse effects, the first dose of fingolimod should be administered in a setting in which resources are available to appropriately manage symptomatic bradycardia. Therefore, all patients started on fingolimod must be monitored for at least 6 hours following the first dose. Additionally, an ECG should be performed prior to dosing fingolimod, blood pressure and pulse should be monitored hourly, and an ECG should be performed at the end of the observation period.

Additional observation beyond 6 hours should be instituted if bradycardia occurs and until the finding has resolved in the following situations: the heart rate 6 hours post dose is less than 45 beats per minute, the heart rate 6 hours post dose is the lowest value observed post dose, or the ECG 6 hours post dose shows new-onset second-degree or higher (atrioventricular) AV block.

Should a patient require pharmacologic intervention for symptomatic bradycardia, continuous overnight ECG monitoring in a medical facility should be instituted, and the first dose monitoring strategy (described above) should be repeated after the second dose of fingolimod.

Fingolimod is now contraindicated in patients with recent myocardial infarction, unstable angina, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or class III/IV heart failure; history or presence of Mobitz type II second- or third-degree AV block or sick-sinus syndrome, unless the patient has a functioning pacemaker; baseline QTc interval greater than or equal to 500 ms; or treatment with class Ia or class III antiarrhythmic drugs.

The following are recommendations for the use of fingolimod in patients with preexisting cardiovascular conditions:

Patients with some preexisting conditions (eg, ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, history of symptomatic bradycardia, history of recurrent syncope, severe untreated sleep apnea, AV block, and sinoatrial heart block) may poorly tolerate the fingolimod-induced bradycardia or may experience serious rhythm disturbances after the first dose of fingolimod.

Prior to treatment, these patients should have a cardiac evaluation by a physician appropriately trained to conduct such an evaluation, and, if treated with fingolimod, should be monitored overnight with continuous ECG in a medical facility after the first dose.

Since initiation of fingolimod treatment results in decreased heart rate and may prolong the QT interval, overnight continuous ECG monitoring is recommended in patients who have prolonged QTc interval before or during the 6-hour observation (>450 ms males, >470 ms females), are at higher risk for QT prolongation (eg, hypokalemia, hypomagnesemia, congenital long-QT syndrome), are on concurrent therapy with drugs that prolong the QT interval, and have a known risk of torsades de pointes. The list of drugs associated with risk of torsades de pointes can be found at AzCERT (CredibleMeds).

The following are recommendations for the use of fingolimod with concomitant medications that slow the heart rate or AV conduction:

Experience is limited when coadministered with drugs that slow the heart rate or AV conduction (eg, beta-blockers, heart ratelowering calcium channel blockers such as diltiazem, verapamil, or digoxin).

Because the initiation of fingolimod treatment is also associated with slowing of the heart rate, coadministration of other drugs that cause bradycardia may be associated with severe bradycardia or heart block.

The possibility to switch to drugs that do not slow the heart rate or AV conduction should be evaluated by the prescribing physician before initiating fingolimod. In patients who cannot switch, overnight continuous ECG monitoring is recommended after the first dose.

The reduction of peripheral lymphocyte count by fingolimod can possibly lead to an increased risk of infection. Reversible, asymptomatic elevations of liver enzymes may also occur. Other adverse reactions that have been commonly reported include headache, diarrhea, ALT/AST elevations and back pain.

If an MS patient is being switched from natalizumab to fingolimod oral therapy, a washout period of 8 weeks or less is advisable. In an observational cohort study involving 350 such patients, those with a washout time longer than 2 months had a higher risk of relapse; in a second study involving 142 patients, shorter washout periods of 8 or 12 weeks were associated with fewer active lesions and less disease recurrence than was a washout period of 16 weeks. [98, 99, 100]

Teriflunomide (Aubagio) was approved by the FDA in September 2012 for the treatment of patients with relapsing forms of MS (approved tablet forms are 7 mg and 14 mg). The prescribing information contains a black box warning for the risks of hepatotoxicity and teratogenicity (pregnancy category X). It is an oral pyrimidine synthesis inhibitor for treatment of relapsing forms of MS. Approval was based on a randomized trial (TEMSO) of 1088 patients with a minimum of 1 relapse in the previous year or 2 relapses in the last 2 years. Teriflunomide was shown to significantly reduce annualized relapse rates (31% relative risk reduction compared with placebo [P< .001]). It was also shown in the TEMSO trial to reduce disability progression at doses of 14 mg/day. [101] However, the FDA has not approved the use of teriflunomide to slow disability progression.

Phase III of the TEMSO studyfound that teriflunomide significantly slowed brain volume loss compared with placebo over 2 years in patients with relapsing MS. Data obtained from MRI were used to assess patients treated with 14 mgor 7 mg of the drug, or placebo. By month 12, median percent reduction from baseline in brain volume was 0.39, 0.40, and 0.61 for teriflunomide 14 mg, 7 mg, and placebo, respectively. [102]

The most common adverse reactions of teriflunomide are headache, alopecia, diarrhea, nausea, increased ALT, influenza, and paresthesias.

Teriflunomide can predispose to infections (due to a decrease in the white blood cell count that remains throughout treatment) and increases in blood pressure. To assess safety, it is recommended to obtain transaminase levels, bilirubin levels, and a CBC count within 6 months before initiation; screen for latent tuberculosis infection with a tuberculin skin test; and check the blood pressure before the first dose and periodically thereafter.

Teriflunomide is contraindicated in patients with severe hepatic impairment, patients who are pregnant or women of childbearing potential not using reliable contraception, or patients on current treatment with leflunomide. If liver injury occurs, teriflunomide should be immediately discontinued and an accelerated elimination procedure using either activated charcoal or cholestyramine should be initiated. Monitor liver tests weekly until normalized.

Upon discontinuing teriflunomide and based on the teratogenicity risk, it is recommended that all women of child-bearing potential undergo the accelerated elimination procedure, which includes verification of teriflunomide plasma concentrations less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02 mcg/mL) are expected to pose minimal risk. Without an accelerated elimination procedure, it takes teriflunomide on average of 8 months (and up to 2 y) to reach plasma concentrations less than 0.02 mg/L.

Teriflunomide or its parent compound, leflunomide, can also be associated with peripheral neuropathy and acute renal failure, hyperkalemia, hypophosphatemia, serious skin reactions, and interstitial lung disease.

Other trials for teriflunomide (TOWER) are completed (not yet published) or ongoing. Results from the TENERE study (n= 324) observed similar efficacy and safety between teriflunomide and interferon beta-1a for relapsing forms of MS. [103] Another study of teriflunomide added to beta interferon therapy is currently ongoing. [104]

Dimethyl fumarate (DMF) is an oral Nrf2 pathway activator indicated for relapsing forms of MS. The active metabolite, monomethyl fumarate (MMF), activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, a transcription factor encoded by the NFE2L2 gene.

FDA approval for DMF in adults with relapsing forms of multiple sclerosis [15, 16] was based on data from 2 phase 3 studies, the DEFINE [17] and CONFIRM [18] studies, that involved more than 2600 patients. An ongoing extension study (ENDORSE) includes some patients that have been followed for longer than 4 years.

In the DEFINE trial, dimethyl fumarate significantly reduced [17] : (1) the proportion of patients who relapsed by 49%, (2) the annualized relapse rate by 53%, and (3) the 12-week confirmed disability progression, as measured by the Expanded Disability Status Scale (EDSS), by 38% relative to placebo at 2 years. In the CONFIRM study, dimethyl fumarate significantly reduced the annualized relapse rate by 44% and the proportion of patients who relapsed by 34% compared with placebo at 2 years. [18] Although not statistically significant, dimethyl fumarate also showed a 21% reduction in the CONFIRM trial's 12-week confirmed disability progression. [18] Both studies also showed that dimethyl fumarate significantly reduced lesions in the brain relative to placebo, as measured by magnetic resonance imaging. [17, 18]

Alemtuzumab (Lemtrada) was approved by the FDA in November 2014 for relapsing forms of multiple sclerosis. Because of the risk for severe autoimmune adverse effects, it is reserved for use in patients who have an inadequate response to 2 or more other drugs for MS. Alemtuzumab is a recombinant monoclonal antibody against CD52 (lymphocyte antigen). This action promotes antibody-dependent cell lysis.

Approval was based on 2 randomized Phase III open-label rater-blinded studies comparing treatment with alemtuzumab to high-dose subcutaneous interferon beta-1a (Rebif) in patients with relapsing remitting MS who were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II). In CARE-MS I, alemtuzumab was significantly more effective than interferon beta-1a at reducing annualized relapse rates; the difference observed in slowing disability progression did not reach statistical significance. [19] In CARE-MS II, alemtuzumab was significantly more effective than interferon beta-1a at reducing annualized relapse rates, and accumulation of disability was also significantly slowed. [20] The clinical development program for alemtuzumab use in MS involved nearly 1,500 patients with more than 6,400 patient-years of safety follow-up. [21]

In a single-arm, open-label study in 45 patients with MS that was refractory to treatment with interferon, alemtuzumab effectively reduced relapse rates and improved clinical scores. [105]

In subsequent subgroup analysis of 101 MS patients with multiple recent relapses and MRI-detected gadolinium-enhancing lesions, researchers found alemtuzumab to be more effective than interferon. [106] The study showed that after 2 years, almost a quarter of patients had achieved a disease activityfree state, whereas none of those treated with interferon and reached such a state.

In this study, disease activityfree was defined as no relapse, no sustained accumulation of disability (SAD) as measured by the Expanded Disability Status Scale (EDSS), and no new gadolinium-enhancing lesions or new or enlarging T2-hyperintense lesions. [106] Relapses occurred in 35.8% of the alemtuzumab group and 60.0% of the interferon group. Respective percentages for SAD were 7.4% and 17.5%; for gadolinium-enhancing lesion activity, 22.1% and 52.5%; and for T2 lesion activity, 60.0% and 92.5%.

Daclizumab (Zinbryta) was approved by the FDA in May 2016 for relapsing forms of MS. It is a humanized monoclonal antibody that binds to the high-affinity interleukin-2 (IL-2) receptor subunit (CD25). These subunits are expressed at high levels on T-cells that become abnormally activated in multiple sclerosis. Approval was based on results from 2 trials, DECIDE and SELECT, in which daclizumab 150 mg was administered SC every 4 wk in people with relapsing-remitting MS. In the DECIDE trial, daclizumab was compared with interferon beta-1a (30 mcg/wk IM). The annualized relapse rate was lower with daclizumab than with interferon beta-1a (0.22 vs. 0.39; 45% lower rate with daclizumab; P< 0.001). [22] The SELECT trial showed that the annualized relapse rate was lower for patients given daclizumab compared with placebo (54% reduction, 95% CI 33-68%; p< 00001). [23]

Ocrelizumab (Ocrevus) was approved in March 2017 for adults with relapsing or primary progressive forms of multiple sclerosis. Approval for RRMS was based on the OPERA 1 and 2 phase 3 trials that included about 800 patients with RMS who received intravenous ocrelizumab or subcutaneous interferon-beta1a. Results showed the annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P< 0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P< 0.001). The percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; P< 0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted MRI was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P< 0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P< 0.001). [84]

Further analysis of participants from the OPERA studies in October 2017 showed that ocrelizumab may improve visual outcomes in adult patients with RMS. Patients who received the drug intravenously had significantly greater improvement on low-contrast letter acuity (LCLA) tests compared with those who received subcutaneous interferon -1a. Within the visually impaired subgroup, significantly more patients receivingocrelizumab showed at least a 7-letter improvement at 12 weeks compared to the interferon group. [107]

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