Introduction
DMT (trade name) | Administration route | Dosing frequency | Dose level | US Approval year | Indication |
---|---|---|---|---|---|
IFN beta-1b (Betaseron®; Extavia®) | Subcutaneous injection | Every other day | 250 mcg | 1993a
| RMS [134] |
IFN beta-1a (Avonex®) | Intramuscular injection | Once a week | 30 mcg | 1996 | RMS [135] |
IFN beta-1a (Rebif®) | Subcutaneous injection | Three times per week | 22 and 44 mcg | 2002 | RMS [136] |
Peginterferon beta-1a (Plegridy®) | Subcutaneous injection | Once every 2 weeks | 125 mcg | 2014 | RMS [137] |
Glatiramer acetate (Copaxone®; Glatopa®) | Subcutaneous injection | Daily | 20 mg | 1996b
| RMS [138] |
Three times per week | 40 mg | 2014 | |||
Dimethyl fumarate (Tecfidera®) | Oral capsule | Twice a day | 240 mg | 2013 | US: RMS [67] |
Europe: RRMS [139] | |||||
Teriflunomide (Aubagio®) | Oral tablets | Daily | 14 and 7 mg | 2012 | US: RMS [72] |
Europe: RRMS [73] | |||||
Fingolimod (Gilenya®) | Oral capsule | Daily | 0.5 mg | 2010 | US: RMS [13] |
Europe: second-line treatment or rapidly evolving severe RRMS [12] | |||||
Daclizumab beta (Zinbryta®)d
| Subcutaneous injection | Once monthly | 150 mg | 2016 | US: RMS, generally after an inadequate response to ≥2 DMTsc [82] |
Alemtuzumab (Lemtrada®) | Intravenous infusion | First course: daily for 5 days; second course: daily for 3 days, 1 year after the first course | 12 mg | 2014 | US: generally reserved for patients who have had an inadequate response to ≥2 drugs for RMSc [100] |
Europe: active RRMS defined by clinical or imaging features [141] | |||||
Natalizumab (Tysabri®) | Intravenous infusion | Every 4 weeks | 300 mg | Approved 2004; reintroduced 2006 | US: RMS when the expected benefit is sufficient to offset PML riskc [20] |
Europe: high disease activity despite IFN beta or glatiramer acetate; rapidly evolving severe RRMS [19] | |||||
Ocrelizumab (Ocrevus®) | Intravenous infusion | Twice a year | 600 mg | 2017 | US: RMS or PPMS [118] |
Mitoxantrone (Novantrone®; Onkotrone®) | Intravenous infusion | Every 3 months | 12 mg/m2
| 2000 | US: secondary (chronic) progressive, progressive-relapsing, or worsening RMS (but not PPMS) as an early, transient, high-efficacy strategy [142] |
Every 3 months | 5 mg/m2
|
DMT | Molecular mode of action | Effect on immune cells and mediators | Time taken for immune system reconstitution after DMT cessation |
---|---|---|---|
SC IFN beta-1b (Betaseron; Extavia) IM IFN beta-1a (Avonex) SC IFN beta-1a (Rebif) IM peginterferon beta-1a (Plegridy) | Exert autocrine and paracrine actions via activation of the IFN receptor on leucocytes | Reduces inflammatory cell migration across the blood–brain barrier, reduces the production of proinflammatory cytokines, and induces anti-inflammatory cytokines [18] | |
Glatiramer acetate (Copaxone) | MBP mimetic; thus competes with MBP antigens to bind with MHC II [58] | Protects neurons by diverting T cell responses away from myelin in a dose-dependent manner. Increases production of anti-inflammatory cytokines and reduces the production of proinflammatory cytokines [18] | Effects on the immune system endure for five times the elimination half-life [138] |
Dimethyl fumarate (Tecfidera) | Activates the nuclear factor (erythroid-derived 2)-like 2 pathway to protect against oxidative stress–induced cellular injury and loss in neurons and astrocytes [61] | Mean absolute lymphocyte count decreased by 30% during the first year then remained stable above the lower limit of normal (i.e., 0.91 × 109/L) [63] 6% of patients had lymphocyte counts <0.5 × 109/L [67] Effective immune response to recall antigens, neoantigens, and T cell-independent antigens similarly to nonpegylated IFN therapy [143] | >4 weeks for lymphocyte counts to increase, but did not return to baseline values [67] |
Teriflunomide (Aubagio) | Inhibits proliferation of activated T and B lymphocytes via mitochondrial dihydroorotate dehydrogenase inhibition [144] | Reduces neutrophils and lymphocytes by 15%, with mean counts remaining in the normal range [71] 16% and 12% of patients had neutrophil and lymphocyte counts <1.5 × 109 and <0.8 × 109/L with 14 mg dose, respectively [72] Effective immune response to H1N1, H3N2, and B influenza strains [145] | Unknown; reduced white blood cell counts of 15% may be related to bone marrow suppression [72] |
Fingolimod (Gilenya) | Dose-dependent reduction in peripheral lymphocyte count to 20–30% of baseline values [13] Lymphopenia incidence was 7% in placebo-controlled trials [13] Attenuated response to influenza vaccine in some patients [148] | ||
Daclizumab beta (Zinbryta)a
| Fivefold expansion in CD56bright NK cells at 1 year. Total lymphocyte, CD4+ and CD8+ T cell, and B cell counts decrease ≤10% from baseline during the first year of treatment [81, 82, 92] Effective immune responses to influenza vaccine [150] | ||
Alemtuzumab (Lemtrada) | Targets CD52 on lymphocytes and monocytes. It readily depletes B cells, T cells, monocytes, macrophages, and dendritic cells, leading to long-lasting changes in adaptive immunity, and reduces the pathogenesis of inflammatory response in MS [99] | Decrease in the level of circulating T and B lymphocytes very rapidly, with the lowest values observed within days posttreatment [99] | Lymphocytes repopulate within 8 months, but T cell populations take >1 year to fully repopulate [100, 101] T cell populations do not recover to baseline levels [101] |
Natalizumab (Tysabri) | Monoclonal antibody that selectively inhibits VLA-4 (α4β1) integrins, preventing leukocyte migration across the BBB [58] | Increases the number of circulating leukocytes (including lymphocytes, monocytes, basophils, and eosinophils) [20]. Natalizumab does not affect the absolute count of circulating neutrophils [20] Effective immune responses to recall antigen (tetanus toxoid) and neoantigen (keyhole limpet hemocyanin) [151] | ≤16 weeks to return to baseline levels [20] |
Ocrelizumab (Ocrevus) | Median (range) time to B cell repletion to either baseline or lower limit of normal was 72 weeks (range 27–175 weeks); within 2.5 years after last infusion, B cell counts rose to either baseline or the lower limit of normal in 90% of patients [118] | ||
Mitoxantrone (Novantrone) | Intercalates with DNA, causing strand breaks, and inhibits DNA repair via inhibition of topoisomerase II, leading to cytotoxicity [153] | Reduction of leukocytes primarily affecting neutrophils and most lymphocyte subsets except for naive and activated T lymphocytes [154] | Unknown |
DMT (trade name) | ARR reduction | Disability progressiona
| Neuroradiologic outcomes |
---|---|---|---|
IFN beta-1b (Betaseron; Extavia) 0.25 mg dose [155] | 34% | No effect | 0.9% reduction in lesion area from baseline versus a 21.4% increase with placebo [134] |
IFN beta-1a (Avonex) [156] | 18% for ITT population; 32% for completer population | 37% relative reduction in 24-week CDP by end of year 2 [135] | Reduction in number of Gd+ lesions (0.80 vs. 1.65) and volume of Gd+ lesions per patient (74.1 vs. 122.4 mm3) |
IFN beta-1a (Rebif) [157] | 29% (22 mcg); 32% (44 mcg) | 23% (22 mcg) and 31% (44 mcg) relative reduction in ≥12-week CDP [158] | Median 1.2% (22 mcg) and 3.8% (44 mcg) decrease in T2 lesion burden versus a 10.9% increase with placebo. Reduced the number of T2 active lesions by 67% (22 mcg) and 78% (44 mcg) |
Peginterferon beta-1a (Plegridy) [159] | 36% at 1 year | 38% relative reduction in 12-week CDP and 54% reduction in 24-week CDP at 1 year | 67% reduction in new or newly enlarging T2 lesions; 86% reduction in Gd+ lesions; 53% reduction in new T1 hypointense lesions at 1 year |
Glatiramer acetate (Copaxone; Glatopa) [160] | 29% | No effect | 54% reduction in new or newly enlarging T2 lesions; 41% reduction in new T1 hypointense lesions; 61% reduction in mean Gd+ lesions [161] |
Dimethyl fumarate (Tecfidera) [162] | 49% | 29% reduction in 24-week CDP | 83% reduction in Gd+ lesion activity; 78% reduction in new or newly enlarging T2 hyperintense lesions; 65% reduction in new nonenhancing T1 lesions |
32–36% | 30–32% reduction in 12-week CDP | 80% reduced risk of Gd+ lesions; 67% reduction in total lesion volume; 31% reduction in T1 lesion volume; 77% reduction in T2 lesion volume [163] | |
38–52% versus IFN beta-1a 30 mcg/week IM over 1 year [167] | Data equivocal: FREEDOMS: 30% reduction in 12-week CDP [165]; no statistically significant effect in FREEDOMS II [166] No statistically significant effect in 12-week CDP versus IFN beta-1a 30 mcg/week IM over 1 year [167] | FREEDOMS: fewer Gd+ lesions (0.2 vs. 1.1) and new or newly enlarging T2 hyperintense lesions (2.5 vs. 9.8) [165] Data confirmed in FREEDOMS II [166] Fewer Gd+ lesions (0.2 vs. 0.5) and new or newly enlarging T2 hyperintense lesions (1.7 vs. 2.6) versus IFN beta-1a 30 mcg/week IM over 1 year [167] | |
SELECT: 54% over 1 year [92] DECIDE: 45% versus IFN beta-1a 30 mcg/week IM over 144 weeks [168] | DECIDE: 27% risk reduction in 24-week CDP versus IFN beta-1a 30 mcg/week IM over 144 weeks [168] | SELECT: over 1 year: 85% reduction in odds of new Gd+ lesions; 70% reduction in number of new or newly enlarging T2 hyperintense lesions [92] DECIDE: 75% reduction in odds of Gd+ lesion activity and 54% reduction in number of new or newly enlarging T2 hyperintense lesions over 96 weeks versus IFN beta-1a 30 mcg/week IM [168] | |
Alemtuzumab (Lemtrada) | Treatment-naive patients | ||
CAMMS223: 69 and 66% in relapse risk over 3 and 5 years, respectively, versus IFN beta-1a 44 mcg SC three times per week [37, 169] CARE-MS I: 55% in relapse risk over 2 years versus IFN beta-1a 44 mcg SC three times per week [170] | CAMMS223: 75 and 69% risk reduction over 3 and 5 years, respectively, versus IFN beta-1a 44 mcg SC three times per week [37, 169] CARE-MS I: No statistically significant effect over 2 years versus IFN beta-1a 44 mcg SC three times per week [170] | Improvement in lesion load on T2-weighted MRI, and cerebral volume on T1-weighted MRI in CAMMS223 [169] CARE-MS I: reduced the proportions of patients with Gd+ lesions (7% alemtuzumab vs. 19% IFN beta-1a 44 mcg SC three times per week) and new or newly enlarging T2 hyperintense lesions (48 vs. 58%) | |
Treatment-experienced patients | |||
CARE-MS II: 49% in relapse risk versus IFN beta-1a 44 mcg SC three times per week [105] | CARE-MS II: 42% reduction in 6-month risk versus IFN beta-1a 44 mcg SC three times per week | No between-group difference on T2 lesion volume; reduced the proportions of patients with Gd+ lesions (9% alemtuzumab vs. 23% IFN beta-1a 44 mcg SC three times per week) and new or newly enlarging T2 hyperintense lesions (46 vs. 68%) | |
Natalizumab (Tysabri) [171] | AFFIRM: 68% | AFFIRM: 42% risk reduction in 12-week CDP; 54% risk reduction in 24-week CDP | AFFIRM: 92% fewer Gd+ lesions and 83% reduction in new or newly enlarging T2 hyperintense lesions |
Ocrelizumab (Ocrevus) [120] | OPERA I: 46% versus IFN beta-1a OPERA II: 47% versus IFN beta-1a | OPERA I and II: 40% risk reduction in 12- and 24-week CDP versus IFN beta-1a | OPERA I: 94% reduction in Gd+ lesions; 77% reduction in new or newly enlarging T2 hyperintense lesions versus IFN beta-1a OPERA II: 95% reduction in Gd+ lesions; 83% reduction in new or newly enlarging T2 hyperintense lesions versus IFN beta-1a |
63% of relapse risk [172] | 70% reduction in 24-week CDP [173] | Gd+ lesions (0 vs. 16% on placebo); mean increase in T2 lesions: 0.29 in the mitoxantrone group and 1.94 in the placebo group [172] |
Better prognosis | Poorer prognosis |
---|---|
White | African American or nonwhite |
Female | Male |
Younger age | Older age |
Monofocal onset | Multifocal onset |
Minimal cortical pathology | Early cortical involvement |
Onset with optic neuritis or isolated sensory symptoms | Onset with motor, cerebellar, or bladder/bowel symptoms |
Low relapse rate first 2–5 years | High relapse rate first 2–5 years |
High degree of remission after first relapse | Short interattack latency |
Long interval to second relapse | Short interval to second relapse |
Mild relapse | Severe relapse ≥1 moderate or severe attack Steroids/hospitalization required Severe effect on activities of daily living >1 functional system affected Severe motor/cerebellar brainstem involvement |
No or low disability at 5 years | Disability at 2 or 5 years |
Low lesion load on MRI | Abnormal MRI ≥2 Gd+/new or newly enlarging T2 hyperintense lesions or ≥ 2 T1 hypointense lesions ≥2 spinal cord lesions Baseline brain atrophy |
NEDA at 2 years | Disease activity at 2 years |
Early treatment | Late treatment |
Low (≤386 ng/L) neurofilament light levels | Elevated (>386 ng/L) neurofilament light levels |
Absence of oligoclonal IgG bands | Presence of oligoclonal IgG bands and ≥10 brain T2 lesions |
Absence of IgM bands | Presence of IgM bands |
General principles of treatment sequencing in RMS
Escalation versus induction
Clinical pharmacology, safety, and monitoring of DMTs
Beta interferons, peginterferon beta-1a, and glatiramer acetate
DMT | Common AEs | Safety issues | Contraindications |
---|---|---|---|
IFN beta-1b (Betaseron/Extavia) [134] | Injection site reaction, lymphopenia, flu-like symptoms, myalgia, leukopenia (asymptomatic), neutropenia, increased liver enzymes, headache, hypertonia, pain, rash, insomnia, abdominal pain, asthenia, depression, hematologic abnormalities, arthralgia | Hepatic injury, anaphylaxis, depression (and suicidal ideation), injection site necrosis, congestive heart failure, leukopenia thrombotic microangiopathy, flu-like symptom complex, seizures, autoimmune disorders, decreased peripheral blood counts | Pregnancy (increased risk of spontaneous abortion) and breastfeeding Hypersensitivity reactions to active ingredient or formulation excipients |
IFN beta-1a (Avonex) [135] | |||
IFN beta-1a (Rebif) [136] | |||
Peginterferon beta-1a (Plegridy) [137] | |||
Glatiramer acetate (Copaxone) [138] | Injection site reactions, postinjection reaction (vasodilatation, rash, dyspnea, chest pain within minutes) | Cutaneous necrosis | Use during pregnancy only if clearly needed Hypersensitivity reactions to active ingredient or formulation excipients |
Flushing, abdominal pain, diarrhea, nausea (usually subsides within 3 months) [187] | Anaphylaxis and angioedema, PML, lymphopenia | Hypersensitivity reactions to active ingredient or formulation excipients | |
Headache, diarrhea, nausea, alopecia, increased alanine aminotransferase | Hepatic injury, teratogenicity (requires accelerated elimination procedure), bone marrow effects, potential immunosuppression, infection, peripheral neuropathy, skin AEs [including Stevens–Johnson syndrome or toxic epidermal necrolysis (Lyell’s syndrome)], increased blood pressure, respiratory effects (interstitial lung disease), pancreatitis, thrombocytopenia | Severe hepatic impairment Pregnancy and breast feeding Severe immunodeficiency Significantly impaired bone marrow function Severe active infection Severe renal impairment undergoing dialysis Hypoproteinemia (due to high plasma protein binding) Current leflunomide treatment Hypersensitivity reactions to active ingredient, leflunomide, or formulation excipients | |
Headache, liver transaminase elevation, diarrhea, cough, influenza, sinusitis, infection, back pain, abdominal pain, pain in extremity | Asystole and sudden death, infections (including herpes simplex virus and cryptococcal infections), PML, macular edema, posterior reversible encephalopathy syndrome, respiratory effects, hepatic injury, teratogenicity, increased blood pressure, basal cell carcinoma | Recent myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure with hospitalization, or class III/IV heart failure History of Mobitz type II second- or third-degree AV block or sick sinus syndrome, unless patient has a pacemaker Baseline QTc interval ≥500 ms Known immunodeficiency syndrome Active infection Treatment with Class IA or Class III anti-arrhythmic treatment Active malignancy Severe liver impairment Hypersensitivity reactions to active ingredient or formulation excipients | |
Nasopharyngitis, upper respiratory tract infection, rash, influenza, dermatitis, oropharyngeal pain, bronchitis, eczema and lymphadenopathy, depression, pharyngitis, increased alanine aminotransferase | Hepatic injury (including autoimmune hepatitis), other immune-mediated disorders (skin reactions, lymphadenopathy, noninfectious colitis), infections, and depression | Hypersensitivity reactions to active ingredient or formulation excipients Preexisting hepatic disease or hepatic impairment, including ALT or AST ≥2 times the ULN History of autoimmune hepatitis or other autoimmune condition involving the liver | |
Rash, headache, pyrexia, nasopharyngitis, nausea, vomiting, infection (urinary tract, upper respiratory tract, viral including herpes, fungal), fatigue, insomnia, urticaria, pruritus, thyroid gland disorders, arthralgia, pain in extremity, back pain, oropharyngeal pain, abdominal pain, diarrhea, sinusitis, paresthesia, dizziness, flushing | Infusion-associated reactions and anaphylaxis (including bradycardia), thyroid disorders and other autoimmune cytopenias, glomerulonephritis (Goodpasture’s disease), malignancy (thyroid cancer, melanoma, and lymphoproliferative disorders), infections (including opportunistic such as herpes virus, human papilloma virus, fungal infections, listeria, and nocardiosis) | HIV infection Hypersensitivity reactions to active ingredient or formulation excipients | |
Headache, fatigue, arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea, rash | PML, hypersensitivity reactions (including anaphylaxis), immunosuppression/infections (including herpes simplex virus, meningitis, and hepatitis B virus infection with acute fatal liver injury), hepatic injury | Patients who have or have had PML Patients at risk of opportunistic infections Concomitant beta IFN or glatiramer acetate therapy Known active malignancies (except cutaneous basal cell carcinoma) Hypersensitivity reactions to active ingredient or formulation excipients | |
Ocrelizumab (Ocrevus) [118] | Infusion-related reactions and upper respiratory tract infections | Infusion-related reactions, infections, neoplasms | Active hepatitis B virus infection and a history of life-threatening infusion reaction to ocrelizumab |
Mitoxantrone (Novantrone) [142] | Nausea, alopecia, urinary tract infection, menstrual disorders (including amenorrhea), asthenia | Congestive heart failure (can result in death) may occur either during or months to years after termination of therapy. Secondary acute myeloid leukemia, infection, leukopenia, depression, bone pain, emesis, renal failure | Baseline LVEF below the lower limit of normal Pregnancy and breastfeeding Hypersensitivity reactions to active ingredient or formulation excipients |