Virginia Thornley, M.D., Neurologist
February 17, 2018
Introduction
Research on multiple sclerosis occurs at a dizzying rate. Because there are many newer agents on the market, the treatment options may be confusing for both the patient and even for neurologists wading through a large morass of novel therapeutic options. This seeks to compare and summarize the most current immunomodulating agents in a quick and concise way based on the package inserts, original drug websites and clinical trials performed. It reviews the most common and most striking potential serious side effects, the annual relapse rate reductions and effects on brain MRI lesions (abnormalities in the brain). Some agents were tested against placebo (placebo is an agent with no medicine in it used in comparison studies) others were against older immunomodulatory agents which were previously the gold standard. Currently, there are no head to head clinical trials comparing each immunmodulating agent against each other. They are listed according to efficacy based on a reduction in annual relapse rate, although some authorities might prefer to compare the effect on MRI lesion burdens. Of note, the most efficacious agents also have some of the most potentially devastating side effects, including cancer and progressive multifocal leukoencephalopathy (PML) which is an irreversible destructive process affecting white matter in the brain occurring in the immunosuppressed state. Consult your neurologist.
Older immunomodulating agents
Avonex, Betaseron, Copaxone, Rebif
Mechanism of action: immunomodulation
Efficacy is about 23-25% all very similar
Side effects: flu-like symptoms, transaminitis
Pros: least amount of significant side effect
Cons: least efficacious
Newer agents
Aubagio (teriflunomide)
Mechanism of action: reduces B and T cell lymphocyte proliferation, inhibits DHODH required for rapidly dividing cells, exact mechanism is unknown
Efficacy: 30% relative risk reduction in TEMSO trial, 36% ARR (annualized relapse rate)reduction in TOWER trial
57% relapse-free after 108 weeks
Side effects: hepatotoxicity (can cause liver problems), teratogenesis (can affect fetus), bone marrow suppression, hypersensitivity
Pros: efficacious compared to older agents, to date still no reports of PML post-market
Cons: very little
Plegridy (peginterferon beta-1a)
Mechanism of action: reduces antigen presentation and proliferation, alters cytokine and matrix metalloproteinase
It is delivered by pegylation, where the medicine is bound to a glycol such that there is reduced renal clearance. Thus, delivery is long spanning 2 weeks.
Efficacy: 36% reduction in ARR
38% reduction in disability progression
Side effects: flu-like symptoms, seizures, suicidal ideations, anaphylaxis, congestive heart failure, autoimmune disorder, abnormal liver enzymes
Pros: efficacious
Cons: very little
Ocrevus (ocrelizumab)
Mechanism of action: Ab that target cells with B lymphocytes, Ag CD20 this results in less Ab-dependent cytolysis and complement-mediated lysis
Efficacy: 47% ARR reduction compared with Rebif in RRMS (relapsing-remitting multiple sclerosis)
24% less likely to have a disability in PPMS (primary progressive multiple sclerosis)
Side effects: infusion reactions, hepatitis B reactivation, you cannot receive live vaccine, possible breast cancer
Pros: efficacious
Cons: concern for progressive multifocal leukoencephalopathy found in 1 patient post-marketing, possible breast cancer
Tecfidera (dimethyl fumarate)
Mechanism of action: nicotinic receptor agonist, mechanism is unknown
Efficacy: 49% ARR reduction in the DEFINE and CONFIRM clinical trials
38% delay in disability progression compared with placebo
85% reduction in new MRI lesions
Side effects: anaphylaxis, lymphopenia, abnormal liver enzymes, liver injury
Pros: oral, efficacious
Cons: PML found in 1 patient during the clinical trial, few more cases found post-marketing
Lemtrada (alemtuzamab)
Mechanism of action: binds to CD52 and depletes T and B cells
Efficacy: 49% less relapses compared with Rebif
65% relapse-free compared to 47% in patients with Rebif
Side effects: joint pain, infections, autoimmune diseases, lymphomas, breast cancer, skin cancer, thyroid cancer and lymphoproliferative cancer, infusion reactions
Pros: efficacious
Cons: Can cause serious autoimmune diseases, lymphomas, breast cancer, skin cancer, thyroid cancer and lymphoproliferative cancer, infusion reactions
Gilenya (fingolimod)
Mechanism of action: immunomodulation, works on the sphingosine 1-receptor modulator
Efficacy: 52% reduction in ARR compared with Avonex
82% reduced disability progression
38% reduction in T2 lesions
60% reduced T1 gad + lesions
Side effects: most common are headache, transaminitis, bradycardia (low heart rate), PML, heart block, PRES or posterior reversible encephalopathy syndrome (reversible damage to the posterior portion of the brain), basal cell carcinoma, teratogenicity
Pros: very efficacious compared to older agents
Cons: some of the worst side effects include PML, PRES, macular edema (swelling of the optic disc)
Tysabri (novantrone)
Mechanism of action: blocks alpha-4 integrin, an adhesion molecule on vascular endothelium, reduces activation of autoimmune cells
Efficacy: 67% reduction in ARR compared with placebo
85% reduction in new MRI lesions
Side effects: PML, herpes simplex virus, infections, abnormal liver enzymes, bradycardia, heart block
Pros: efficacious
Cons: risk of PML, bradycardia, heart block
In summary, the least efficacious medications are the most benign in terms of side effect profile, while the strongest immunomodulators have the more devastating potential side effects. While clinical trials reflect beneficial conclusions, attention must still be directed towards potential side effects occurring over a prolonged time which may not be reflected in clinical trials which usually involve a timeframe of a few years and do not span over decades. The real test is in the post-marketing groups. Speak to your neurologist. See package insert for more complete information of side effects.
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