Optimizing therapeutics in the management of patients with multiple sclerosis: a review of drug efficacy, dosing, and mechanisms of action

Figures & data

Table 1 Dosing and side-effects of currently approved multiple sclerosis disease-modifying therapeutics

DMT	Year of approval	Route of administration	Frequency of dosing	Dosage	Common adverse effects	Severe adverse effects
Interferon beta-1b (Betaseron®)	1993	Subcutaneous injection	Every other day	250 mcg	Influenza-like symptoms, urticaria, depression, injection-site reactions, leukopenia, headache	Hepatic injury, congestive heart failure, seizures
Interferon beta-1a (Avonex®)	1996	Intramuscular injection	Once a week	30 mcg	Influenza-like symptoms, depression, anemia, urticaria, fever, myalgia, asthenia	Hepatic injury, congestive heart failure, anaphylactic shock
Glatiramer acetate (Copaxone®)	1996	Subcutaneous injection	Daily	20 mg	Injection-site reactions, palpitations, urticaria, dyspnea, chest pain, vasodilation	Injection site lipoatrophy and necrosis
Interferon beta-1a (Rebif®)	2002	Subcutaneous injection	Three times a week	22 mcg 44 mcg	Influenza-like symptoms, depression, injection-site reactions, urticaria, myalgia, fever, abdominal pain, elevated liver enzymes	Hepatic injury, anaphylactic shock
Natalizumab (Tysabri®)	2006	Intravenous infusion	Every 4 weeks	300 mg	Headache, urinary tract infections, lung infections, abdominal pain, fatigue, joint pain, depression, gastroenteritis, urticaria, arthralgia	PML, anaphylactic shock, hepatotoxicity
Fingolimod (Gilenya®)	2010	Oral capsule	Daily	0.5 mg	Headache, influenza, gastrointestinal discomfort, back pain, abnormal liver-function tests, angina	Macular edema, bradyarrhythmia, PML, hypotension, herpes infection
Teriflunomide (Aubagio®)	2012	Oral capsule	Daily		Dyspnea, hypertension, gastrointestinal discomfort, leukopenia, urticaria, alopecia, paresthesia	Hepatotoxicity, peripheral neuropathy hyperkalemia, acute renal failure
Dimethyl fumarate (Tecfidera®)	2013	Oral capsule	Twice daily	120 mg 240 mg	Gastrointestinal disorders (abdominal pain, diarrhea, etc), flushing, pruritus, rash, erythema	Lymphopenia

Note: Mitoxantrone® not covered in this review.

Abbreviations: DMT, disease-modifying therapy; PML, progressive multifocal leukoencephalopathy.

Table 2 Efficacy of approved multiple sclerosis therapeutics: Phase III clinical trial results

Disease-modifying therapy	Study	Study design	Treatment	Patients, n	Study duration	ARR (% decrease compared to placebo)	EDSS (% decrease compared to placebo)	Gd-MRI (% decrease in T2 weighted lesions)
Interferon-β1b (Betaseron)	IFNB study group,^Citation42 Paty et al^Citation41	R, DB, PC	Placebo IFN-β 0.05 mcg IFN-β 0.25 mcg	123 125 124	36 months	0.92 0.8(13) 0.66 (28)	46 47 35	66 63
Interferon-β1a (Avonex)	Jacobs et al^Citation129	R, DB, PC	Placebo IM-IFN	143 158	104 weeks	0.9 0.61 (32)	34.9 21.9(37)	35
Interferon-β1a (Rebif)	PRISMS study group^Citation130	R, DB, PC	Placebo SC-IFN 22 mcg SC-IFN 44 mcg	187 189 184	12 months	2.56 1.82 (29) 1.73 (32)	37 29 (22) 26 (30)	67 78
Glatiramer acetate (Copaxone)	Johnson et al^Citation53	R, DB, PC	Placebo GA	126 125	24 months	0.84 0.59 (29)	28.8 20.8 (28)	NA
Natalizumab (Tysabri)	Polman et al^Citation1	R, DB, PC	Placebo Nat	627 942	116 weeks	0.73 0.23 (68)	29 17 (41)	83
Dimethyl fumarate (Tecfidera)	Gold et al^Citation99	R, DB, PC	Placebo 2 × DMF 3 × DMF	408 410 416	96 weeks	0.36 0.17 (53) 0.19 (48)	27 16 (38) 18 (34)	85 74
	Fox et al^Citation100	R, DB, PC, GA	Placebo 2 × DMF 3 × DMF GA	333 338 316 304	96 weeks	0.4 0.22 (44) 0.2 (50.5) 0.29 (28.6)	17 13 (21) 13 (24) 16 (7)	57 65 41
Teriflunomide (Aubagio)	O’Connor et al^Citation131	R, DB, PC	Placebo Ter 7 mg Ter 14 mg	363 365 368	108 weeks	0.54 0.37 (31.2) 0.37 (31.5)	27.3 21.7 (23.7) 20.2 (29.8)	16.7 31.3
Fingolimod (Gilenya)	Kappos et al^Citation124	R, DB, PC	Placebo Fing 0.5 mg Fing 1.25 mg	418 425 429	24 months	0.4 0.18 (52) 0.16 (62)	24.1 12.5 (37) 11.5 (40)	74 74
	Cohen et al^Citation125	R, DB, IM-IFN	IM-IFN Fing 0.5 mg Fing 1.25 mg	431 429 420	12 months	0.33 0.16 (52) 0.2 (40)	7.9 5.9 (25) 6.7 (15)	35 42

Abbreviations: ARR, annualized relapse rate; EDSS, Expanded Disability Status Scale; Gd-MRI, gadolinium-enhanced magnetic resonance imaging; PRISMS, Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sderosis; R, randomized; DB, double-blind; PC, placebo-controlled; NA, not available; DMF, dimethyl fumarate; 2×, twice daily; 3×, thrice daily; IFN-β, interferon-β1b (Betaseron); IM-IFN, intramuscular interferon-β1a (Avonex); SC-IFN, subcutaneous interferon-β1a (Rebif); GA, glatiramer acetate; Nat, natalizumab; Ter, teriflunomide; Fing, fingolimod.

Table 3 Disease-modifying therapies (DMTs) currently under review for use as multiple sclerosis therapies

DMT (target)	Study phase	Study design	Treatment	Patients, n	Study duration	ARR reduction (% decrease)	% disability progression (% decrease from placebo)	% reduction in T2-weighted Gd-MRI from placebo
Alemtuzumab (CD52 – lymphocyte depletion)	Phase III^Citation132	Randomized, double-blind, comparator arm	SC-IFN 44 mg Ale 12 mg	187 376	24 months	0.39 0.18 (54)	II 8 (30)	– NS
Laquinimod (Th1 and Th2 – inhibits leukocyte migration into CNS)	Phase III^Citation133	Randomized, double-blind, placebo-controlled	Placebo Laq 0.6 mg	556 550	24 months	0.39 0.30 (23)	16 11 (29)	– 30
Daclizumab (IL-2 signal modulator–inhibits innate lymphoid cells)	Phase III^Citation134	Randomized, double-blind, placebo-controlled	Placebo Dac 150 mg Dac 300 mg	204 208 209	52 weeks	0.46 0.21 (54) 0.23 (50)	13 6 (57) 8 (43)	– 70 79
Ocrelizumab (CD20–B cell depletion)	Phase II^Citation135	Randomized, double-blind, placebo- and IFN-β1a-controlled	Placebo IFN-β1a Ocr 600 mg Ocr 2,000 mg	54 55 56 55	24–48 weeks	0.16 0.14 0.09 0.28	NA	NS

Abbreviations: DMT, disease-modifying therapy; ARR, annualized relapse rate; NA, not available; NS, not significant; CNS, central nervous system; IFN-β1a, interferon-β1a; SC-IFN, subcutaneous interferon-β1a; IL, interkeukin; Ale, alemtuzumab; Laq, laquinimod; Dac, daclizumab; Ocr, ocrelizumab; CD, cluster of differentiation; Gd-MRI, gadolinium-enhanced magnetic resonance imaging; Th, helper T cell.

Figure 1 Optimizing the risk/efficacy balance of approved MS therapeutics: a physician perspective

Abbreviations: DMF, dimethyl fumarate; GA, glatiramer acetate; MS, Multiple Sclerosis; EDSS, Expanded Disability Status Scale; MR, magnetic resonance; CNS, central nervous system.

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