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Reduction of Multiple Sclerosis Exacerbations and Disability

For more than a decade and a half, there has been intensive study of several drugs and their potential value in reducing the risk of exacerbations in MS. As a corollary to this outcome, there has been increasing emphasis on their potential impact on reducing the risk of disability due to this disease. At press time, there are ten FDA- approved disease-modifying therapies for relapsing MS (see Table 2.4).

The first drug to be approved (1993) to reduce the frequency of MS exacerbations of (33% reduction) was IFN-p-1b (Betaseron®) [186, 187]. The drug also had a remarkable effect, significantly reducing the burden of disease as measured by brain MRI T2 lesion volumes [187]. Unfortunately, use of IFN-p-1b is consistently associated with flu-like symptoms and local inflammatory reaction at the injection site.

The drug IFN-p-1a is produced using mammalian cell lines and the authentic human genetic sequence, unlike IFN-p-1b that has two genetic alterations and which is made using coliform bacteria. IFN-p-1a is rapidly absorbed from the injection site and local reactions as well as neutralizing antibody formation are less. Avonex® brand of IFN-p-1a was approved in 1996 as a result of a study using 30 micrograms intramuscularly once weekly [188]. Risk of sustained disability for 24 weeks, the primary outcome measure, was reduced for drug recipients to 21.9 vs. 39.7% for placebo recipients in the study. Relapse risk was also reduced, 0.61 vs.

0.90 for those who completed the 104 weeks of the trial. However, data analysis employing “intent-to-treat analysis” showed a reduction in the risk of relapses with active drug treatment of 0.61 vs. 0.82 for placebo. The latter results reflect the fact that 40% of the patients did not complete the study because study drug was not available. Subsequently, the benefits on disability prevention were shown to be sustained [189].

A large three-arm pivotal (PRISMS) trial was reported in 2002, showing results resembling those reported for IFN-p-1b [190]. Subsequently, after additional

Table 2.4 Commonly used disease-modifying therapies in RRMS

Name of medication

Year of approval

Dosing

regimen

Proposed

mechanism of action

Important side effects

Injectables

IFN-B-1a

Avonex®

1996

Once a week; intramuscular injection; 30 mcg

Modulates T-cell and B-cell function, decreases expression of matrix

metalloproteinases, interferes with blood-brain barrier disruption, alters expression of cytokines [121]

Flu-like symptoms, depression, anemia, elevated LFTs, allergic reactions

IFN-B-la

Rebif®

1996

Three times a week;

subcutaneous injection; 44 mcg

As above

Flu-like symptoms, injection site reactions, blood dyscrasias, depression, elevated LFTs, allergic reactions

Pegylated

IFN-B-1a

Plegridy™

2014

Every 14 days; subcutaneous injection; 125 mcg

As above

Flu-like symptoms, injection site reactions, depression, anemia, elevated LFTs, allergic reactions, cardiac abnormalities

IFN-B-1P

Betaseron®

1993

Every other day;

subcutaneous injection; 250 mcg

As above

Flu-like symptoms, injection site reactions, allergic reactions, depression, elevated LFTs, leukopenia

IFN-B-1P

Extavia®

1993

Every other day;

subcutaneous injection; 0.25 mg

As above

As above

Glatiramer

acetate

Copaxone®

1997

Every day;

subcutaneous

injection;

20 mg OR three times a week;

subcutaneous

injection;

40 mg

Stimulates regulatory T cells, neuroprotective and repair mechanisms [121]

Injection site reactions; idiosyncratic reaction including anxiety, chest pain, palpitations, SOB, flushing; vasodilation

(continued)

Table 2.4 (continued)

Name of medication

Year of approval

Dosing

regimen

Proposed

mechanism of action

Important side effects

Oral drugs

Fingolimod

Gilenya®

2010

Every day; capsule taken orally; 0.5 mg

Sphingosine-1- phosphate receptor modulator that inhibits the migration of T cells from lymphoid tissue into the CNS [123]

Headache, flu, diarrhea, back pain, elevated LFTs, cough, prolonged QT interval/bradycardia following first dose, infections, macular edema

Teriflunomide

Aubagio®

2012

Every day; pill taken orally;

7 mg or 14 mg

Interferes with de novo synthesis of pyrimidines by inhibition of dihydroorotate dehydrogenase, leads to blocking cell replication in rapidly dividing cells

Hair thinning, diarrhea, flu, nausea, abnormal LFTs, paresthesia, leukopenia, hypertension, hepatic injury

Dimethyl

fumarate

Tecfidera®

2013

Twice a day; capsule taken orally; 120 mg for 1 week and 240 mg thereafter

Unknown; possibly via action on nuclear factor erythroid2- related factor 2, which upregulates antioxidative pathways; inhibition of the translocation of nuclear factor-KB and therefore inhibits cascade of inflammatory cytokines, chemokines, and adhesion molecules [124]

Flushing,

gastrointestinal effects, rash, proteinuria, elevated LFTs, blood dyscrasias

Infusions

Natalizumab

Tysabri®

2003

Every 4 weeks by IV; 300 mg.

Binds a4-integrin and blocks interaction with leukocytes with vascular cell adhesion molecules, resulting in inhibited migrations of leukocytes from the blood into the CNS [122]

PML, allergic, or hypersensitivity reactions within 2 h of infusion, headache, fatigue, urinary tract infections, depression, respiratory tract infections, joint pain, gastrointestinal effects, vaginitis

2 Multiple Sclerosis: Clinical Features, Immunopathogenesis, and Treatment

Table 2.4 (continued)

Name of medication

Year of approval

Dosing

regimen

Proposed

mechanism of action

Important side effects

Alemtuzumab

Lemtrada™

2014

Intravenous infusion on five

consecutive days, followed by intravenous infusion on

three

consecutive days 1 year later; 12 mg

Targets CD52,

depletes

lymphocytes

Autoimmune disorders including thyroid and ITP, renal failure, rash, headache, fever, nasal congestion, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, hives, itching, fungal infection, arthralgias, diarrhea, vomiting, flushing, infusion reactions

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studies, a head-to-head trial of Rebif® vs. Avonex® was undertaken [191]. The 16-month trial benefit favored Rebif® at each time point in the study. However, the “survival” curve of Avonex® appeared to approach that of Rebif® as the study progressed, however. The PRISM trial extension did show more benefit for patients at the higher dose who initially had received placebo and who were switched to either 22 or 44 micrograms three times weekly [192, 193].

Pegylated IFN-p-1a (Plegridy®) was approved by the FDA in 2014 and is administered subcutaneously at 2-week intervals at a maintenance dose of 125 ^cg /0.5 mL, available both as a pen injector and prefilled syringe. It is an IFN-p-1a to which a single, linear 20,000-dalton methoxy poly(ethyleneglycol)-O-2- methylpropionaldehyde molecular is covalently attached to the alpha amino group of the N-terminal amino acid residue. The efficacy of Plegridy® was demonstrated in the ADVANCE study, a randomized, double-blind, placebo-controlled study of RRMS that examined clinical and MRI outcomes at 48 weeks, comparing the treatment group against placebo. The primary outcome of related reduction of annualized relapse rate over 1 year was met, with statistically significant (p=0.0007) relative reduction of 36%. MRI outcomes at 48 weeks showed a 67% relative reduction of mean number of new or newly enlarging T2 hyperintense lesions and 86% relative reduction in the mean number of Gd-enhancing lesions (p<0.0001) [194]. The side-effect profile is quite similar to that of Rebif®, including flu-like symptoms, injection site reactions, hepatic injury, and depression. The dose-frequency blinded extension study (ATTAIN) is ongoing.

Glatiramer acetate (Copaxone®) was approved in 1997 as a result of a doubleblind placebo-controlled trial [195]. The outcome of the trial was a 30% reduction in the risk of relapse for glatiramer, compared with placebo, similar to the IFN-p studies. A follow-up of a subset of patients by the original investigators has shown apparent robust long-term benefits with the majority of the study subjects stabilized [196]. This information has become part of the package insert. More recently in the Glatiramer Acetate Low-Frequency Administration (GALA) study, glatiramer acetate at a dose of 40 mg/mL administered subcutaneously thrice weekly compared to placebo showed a 34.0% reduction in risk of confirmed relapses, and this new dosing regimen is now approved for use [197].

A marked reduction of gadolinium lesion enhancement has been found following initiation of IFN-p-1b [198] and IFN-p-1a [188] and for glatiramer acetate [199]. Similar results for natalizumab have been reported [200]. Interestingly, the serially studied placebo patients showed that while enhancement disappears with steroid administration, enhancement returns, finally disappearing about 2 months after its first appearance [185]. In recent years, increasing emphasis has been placed on techniques of measuring brain atrophy [201-203].

Natalizumab (Tysabri®) is a humanized monoclonal antibody that binds a4-integrin and blocks interaction of a4p1-integrin on leukocytes with vascular cell adhesion molecules (VCAM) and connects segment-1 on fibronectin sites on vascular endothelial cells [204]. Two phase III clinical trials demonstrated the efficacy of natalizumab, administered at a dose of 300 mg intravenously every 4 weeks. The AFFIRM trial showed that natalizumab reduced ARR by 68% over 2 years, disability progression by 42% over 12 weeks and 54% over 24 weeks, an 83% decrease in new or enlarging T2 hyperintense lesions, and decrease in gadolinium-enhancing lesions on MRI by 92% compared to placebo. The SENTINEL trial examined natalizumab in combination with IM IFN-p-1a is more effective than IM IFN-p-1a alone [205-207]. Natalizumab is generally tolerated well. Side effects include infusion-related symptoms, allergic hypersensitivity reactions, anxiety, fatigue, pharyngitis, bladder and respiratory infections, sinus congestion, and peripheral edema. The primary safety concern is the increased risk of PML, the risk of which increases with duration of therapy and serum JCV Ab status and index [208, 209]. Approximately 6% of patients develop persistent anti-natalizumab-neutralizing antibodies [210]. Switching of natalizumab to alternative agents like fingolimod more than 8 weeks after cessation of natalizumab may be associated with lower risk of MRI and clinical disease reactivation [211].

In 2010, Fingolimod (Gilenya®) was the first oral disease-modifying drug to be approved by the Food and Drug Administration for MS. Fingolimod is a sphingosine- 1-phosphate receptor (S1P1) modulator, initially acting as an agonist of the S1P1 receptor, and then becomes a potent functional antagonist, leading to internalization of S1P1 receptors on lymph node T cells, resulting in sequestration of lymphocytes in the lymph node. Uniquely, circulating naive T cells and central memory cells are reduced by fingolimod, since both express the chemokine receptor lymph node homing CCR7. Fingolimod does not affect effector memory cells, but some of its mechanisms of action may be explained by the enhancement of function of potent circulating regulatory T cells. Other effects include the modulation of human oligodendrocyte progenitor cells, which potentially could affect myelin repair, astrocyte proliferation, migration and gliosis, and neuroprotection. The clinical efficacy of fingolimod was demonstrated in two large, phase III, double-blind, randomized trials: (1) FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) and (2) Trial Assessing Injectable Interferon Versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). The FREEDOMS trial enrolled 1272 patients who were assigned either oral fingolimod

  • 0.5 mg or 1.25 mg daily versus placebo for 2 years. The primary end point, ARR, was 0.18 in the 0.5 mg dose group, 0.16 in the 1.25 mg dose group, and 0.40 in the placebo group. There was also a statistically significant effect on reduction of sustained disability progression. After 12 weeks progression was seen in 17.7% in the
  • 0.5 mg dose group and 16.6% in the 1.25 mg dose group versus 24.1% in the placebo group. Fingolimod also showed a reduction in the number of new or enlarging lesions on T2-weighted imaged, gadolinium-enhancing lesions at year 2. Importantly, reductions in whole brain volume were less at both 12 and 24 months in the fingolimod group [212, 213]. The TRANSFORMS trial included 1292 patients randomly assigned to the 0.5 mg dose and 1.25 mg dose, but this time a comparator of 30 pg weekly IM interferon-beta-1a. Orally administered fingolimod at a dose of 0.5 mg daily was found to be superior to IFN-p-1a at reducing ARR and MRI activity, although the sustained use of IFN in patients prior to the initiation of the trial is considered a confounder of this data [214]. Fingolimod is generally well tolerated; however, low-frequency specific safety issues including first-dose bradycardia, herpes virus dissemination, macular edema, and elevated blood pressure require screening and regular monitoring. Of note, four cases of PML have now been reported with fingolimod use, without prior exposure to natalizumab.

Teriflunomide (Aubagio®) is an oral medication that interferes with the de novo synthesis of pyrimidines via inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase, resulting in blocking cell replication in rapidly dividing cells. The precise mechanism for its effect in RRMS is unknown. Teriflunomide is a derivative of leflunomide, used for many years in the management of rheumatoid arthritis. Two clinical trials examined the efficacy of teriflunomide: (1) TEMSO and (2) TOWER. The TEMSO study evaluated both 7 mg and 14 mg doses versus placebo in 1088 patients with active relapsing MS. Both doses showed a significant reduction in the primary outcome measure, ARR, compared to placebo by 31.2% (7 mg) and 31.5% (14 mg). Both the 7 mg and 14 mg dose reduced MRI outcomes, slightly more in favor of the14 mg dose. In the TEMSO extension study, adjusted ARR remained low 5 years after initial randomization [215-217]. In the TOWER study, 1169 were randomly assigned to a 7 mg dose, 14 mg dose, and placebo group. The ARR was higher in the placebo group (0.50) compared to the 14 mg (0.32) and 7 mg dose groups (0.39). Teriflunomide at the 14 mg dose reduced the risk of sustained accumulation of disability at 48 weeks; however, the 7 mg dose did not show this effect [218, 219]. A third head-to-head study compared the effectiveness and safety of teriflunomide and subcutaneous interferon-p-1a (44 pg three times per week) in patients with relapsing multiple sclerosis (TENERE) over a 2-year period. The primary end point was time to failure, defined as the first occurrence of confirmed relapse or permanent treatment discontinuation for any reason, and no statistical superiority between IFN-p-1a and the 14 mg dose of teriflunomide was found, although IFN-p-1a was superior to the 7 mg dose of teriflunomide [220]. The ongoing phase III TERACLES trial is examining the clinical usefulness of combination teriflunomide with IFN-p. (ClinicalTrials.gov identifier: NCT01252355)

The most common adverse effects of teriflunomide are mild-moderate, including elevation in transaminases, hair thinning, GI upset, and headache. We have had two apparent allergic reactions to this drug. The greatest concern is the potential for teratogenicity based on animal data, and teriflunomide is contraindicated in women in childbearing potential not using reliable contraception, and men with the potential to father a child are also advised to utilize contraception. As teriflunomide may remain in the serum for up to 2 years, an enhanced drug elimination procedure using cholestyramine or activated charcoal powder is used for patients planning on becoming pregnant or who already are pregnant [221]. Despite these precautions, as of 2013 the AUBAGIO Pregnancy Registry data indicated that 12 newborns have been conceived while on teriflunomide, with no structural or functional deficits reported [222].

Dimethyl fumarate (DMF) (BG-12, Tecfidera®) is the third oral therapeutic option. It is a fumaric acid ester in an enteric-coated microtablet. When it enters the CNS is immediately hydrolyzed by esterases to its metabolite monomethyl fuma- rate. DMF is associated with decreased GI side effects compared to MMF. It acts on nuclear factor erythroid2-related factor 2 (Nrf-2), which upregulates various antioxidative pathways and inhibits the translocation of nuclear factor-кБ into the nucleus, therefore avoiding the expression of a cascade of inflammatory cytokines, chemokines, and adhesion molecules. While the forgoing mechanism is thought to be responsible to it clinical effect, the exact mechanism of action in RRMS, however, is unknown [223].

Two clinical trials have evaluated the efficacy of BG-12 for RRMS: (1) determination of the efficacy and safety of oral fumarate in relapsing-remitting multiple sclerosis (DEFINE) and (2) comparator and an oral fumarate in relapsing-remitting multiple sclerosis (CONFIRM). The DEFINE study evaluated 1234 patients with RRMS and EDSS scores of <5 who were randomized to a 240 mg twice-a-day dosing regimen, 240 mg three-times-a-day dosing regimen, or placebo. The primary outcome measure was the proportion of patients relapsing at 2 years, whereas unlike other clinical trials, the ARR and risk for disability progression were secondary outcomes. Both doses of BG-12 met the primary outcome measure, with a reduction in the proportion of patients relapsing by almost 50%. Twenty-seven percent of patients on the twice-a-day dosing and 26% of patients on the three-times-a-day regimen had at least one relapse at 2 years, versus 46% of patients on placebo. ARR in both doses of BG-12 was reduced by 53% relative to placebo. EDSS progression was also reduced at 12 weeks in both dosing regimens, with 16% (twice-a-day regimen) and 18% (three-times-a-day regimen) progressing versus 27% of patients on placebo. Other measures, including new or enlarging MRI lesions were significantly lower in the BG-12-treated patients as well. The CONFIRM trial evaluated 1430 patients randomized to one of the two BG-12 dosing regimens or an active comparator glatiramer acetate (GA) 20 mg/d subcutaneously. The primary end point, difference in ARR over a 2-year period, was 44% lower with BG-12 at the twice-a-day regimen, 51% lower with the three-times-a-day regimen, and 29% lower with GA. There was no significant reduction in sustained increase in disability, but a preplanned analysis of the combined outcomes of the DEFINE and CONFIRM studies did reveal a significant reduction in the risk of sustained increase in disability. Of note, the study was powered to evaluate the doses against placebo, but not against GA. The most common adverse effects include abdominal pain, flushing, nausea, and diarrhea. These effects can be ameliorated with the administration of the medication with food and/or regular aspirin at a dose of <325 mg 30 minutes prior to administration. Severe lymphopenia may occur, and PML has been reported in four patients. It is recommended that a CBC with differential be obtained at least at 6-month intervals. Reduction of CD8+ T cells is more pronounced than that of CD4+ T cells, and this can be serially monitored with lymphocyte subset panels [224-226].

Despite hopes that oral therapy would lead to increased compliance, it has been shown that oral medications, particularly dimethyl fumarate which is dosed twice daily, is associated with poorer compliance, especially in the young population [227-229]. Alemtuzumab (Lemtrada®) is a humanized anti-CD52 monoclonal antibody. The exact mechanism by which alemtuzumab exerts its therapeutic effects in RRMS is unknown, but is thought to work via depletion and subsequent repopulation of both circulating T and B lymphocytes. These cell populations recover at variable rates, with CD4+ T lymphocytes being the slowest, leading to long-term adaptive immunity. The CARE-MS I trial was a phase III randomized clinical trial of 581 treatment-naive patients comparing alemtuzumab (12 mg/d over a 5-day IV administration with a second 3-day IV administration 1 year later) to subcutaneous IFN-p-1a administered three times a week at a ratio of 2:1. Two primary end points were identified: reduction in relapse rate and 6-month sustained accumulation of disability. Alemtuzumab reduced risk for relapse by 55% compared to IFN-p-1a, with a yearly relapse rate of 0.39 in the IFN-p-1a group compared to 0.18 in the alemtuzumab group, monitored over a period of 2 years. A secondary outcome measure, maintenance of relapse-free status for 2 years, was met in 77.6% of alemtuzumab-treated patients and 58.7% of IFN-p-1a-treated patients. Multiple MRI outcomes also favored alemtuzumab. These included a reduction in the percentage of new and enlarging T2 lesions, new gadolinium-positive lesions, or persistent gadolinium-positive lesions at 24 months and new T1-hypointense lesions. The alemtuzumab group had slower progression of brain atrophy as compared to IFN-p-1a (0.87 versus -1.49 median percent change at year 2) [230]. CARE-MS II evaluated 840 patients who, unlike CARE-MS I, had recently relapsed while taking a standard disease-modifying therapy. Randomization was performed in a 2:2:1 ratio of high-dose (24 mg) alemtuzumab, low-dose (12 mg) alemtuzumab, and IFN- P-1a. Yearly rate of relapse was significantly reduced in the low-dose alemtuzumab group (0.26) compared to the IFN-p-1a group (0.52) over 2 years. A 42% reduction in the risk for sustained accumulation of disability over 6 months was seen in the low-dose alemtuzumab group (12.7%) versus the IFN-p-1a group (21.1%). Of the low-dose alemtuzumab group, 28.8% had sustained improvement in their EDSS score compared to the IFN-p-1a group (12.9%). There was no significant change in total T2 burden, but fewer patients had new or enlarging T2 lesions or new gadolinium-positive lesions over 24 months in the alemtuzumab group. There was less reduction in mean brain parenchymal fraction in the alemtuzumab group (-0.615% versus -0.81%). No advantage of the 24 mg over 12 mg dose of alemtuzumab was seen [231].

Alemtuzumab is associated with several safety issues. Mild-moderate infusion- related reactions are seen in 90%. The incidence of infections is higher, most commonly upper respiratory tract infections, urinary tract infections, and oral herpes. The development of secondary autoimmune disorders is of primary concern, with 16-19% of alemtuzumab-treated patients developing thyroid-related problems and 1% developing immune thrombocytopenia. There is concern for development of antiglomerular basement membrane disease as well. Monthly CBC with differential, serum creatinine levels, and urinalysis with urine cell counts are recommended for 48 months after the last dose of alemtuzumab. Prophylactic medications for pneumocystis pneumonia and herpes viral infections must be administered during treatment and for at least 2 months following the last dose or until CD4+ counts recover to >200 cells/mm3 [232].

The management of primary and secondary progressive disease is far from satisfactory but based on prospective studies; two drugs are now approved: mitoxantrone [233, 234] (Novantrone®) and IFN-p-1b [235]. The use of IFN-p-1b varies greatly from one geographic area to another, varying on the impatience and experience of physicians and patients alike. Its use is tempered by the fact that many patients seemingly stabilized initially subsequently begin to progress despite continued use of the drug. In retrospect, this is seen in drug trials that included patients who no longer experienced relapses [235]. This observation is also in keeping with the meta-analysis of the US trial. The use of mitoxantrone resulted in cessation of exacerbations and apparent stabilization in the majority of drug recipients vs. controls in the study. This was accompanied by the realization that the drug is cardiotoxic [233, 234]. The results as published are difficult to under interpret for the non-statistician, and the specter of cardiotoxicity combined with the risk of promyelocytic leukemia has limited its use of this effective drug, despite clear-cut guidelines. It is best used in larger centers with experience with this drug.

High doses of oral biotin (100-300 mg daily) were studied in France for chronic progressive multiple sclerosis [236]. Data in an open-label study of 23 patients showed that 91.3% improved clinically suggested that biotin may have an effect on disability and progression. The results of a randomized, double-blind, multicenter placebo-controlled (2:1) trial of MD1003 (pharmaceutical grade biotin dosed at 300 mg/day) in patients with progressive MS were reported at both the 2015 AAN meeting and 1st Congress of the European Academy of Neurology [237]. A second clinical trial is underway evaluating the effect of biotin in MS patients with permanent visual loss following optic neuritis. A significant reduction in disability progression is preliminarily reported.

Other nonspecific immunosuppressants have been used in the clinical setting. Some were employed in open-label settings, and limited trials of azathioprine, methotrexate, and cyclophosphamide have been carried out. There appears to be a desirable effect from the use of these drugs, but potential infections are real risks, and other problems potentially complicate their use. Hopefully, pivotal trials of one or more of these agents will be organized in the near future. If employed, their use again should be limited or guided by neurologists who are experienced in their use.

 
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