The year 1993 saw the release of the first disease-modifying drug, Betaseron®, for multiple sclerosis. By the turn of the century, three other disease-modifying drugs had also been approved. Now with more than 10 products are available, patients not only have treatments but treatment options. It is important to note that none of the currently approved disease-modifying agents are not a cure for MS. However, all of these products can alter the course of the disease by decreasing the number and severity of relapses, by slowing the progression of the disease, and by reducing the accumulation of new lesions.
MS Treatment Guidelines
Research demonstrates that potentially irreversible axonal damage may occur early in relapsing-remitting MS. These therapies appear to be more effective in preventing new lesions than in repairing old lesions. Based on these findings, it is the consensus of researchers and clinicians with expertise in MS that the following treatment guidelines be followed:
• Therapy with a disease-modifying drug should be initiated as early in the disease course as possible. Such treatment may also be considered for those who have experienced a first attack and are at high risk of developing MS. (This is known as clinically isolated syndrome or CIS.)
• Treatment should be continued indefinitely except in the case of clear lack of benefit, intolerable side effects, new data, or if a better treatment becomes available.
• Individuals should be allowed to change therapies.
• Treatment should not be interrupted for insurance purposes.
• None of these medications are approved for use in women who are pregnant, nursing, or may become pregnant.
A Closer Look at the Interferons
Avonex ®, Betaseron ®, Extavia ®, and Rebif ® are all interferon beta products. While their exact mechanism of action is unknown, in theory, the interferon drugs seal off the blood brain barrier and inhibit the T-lymphocytes (T cells) from being activated. This prevents the T cells from entering the central nervous system and destroying myelin, and ultimately the nerve axons.
Avonex is given at a lower dose than the other interferons. Avonex is administered by intramuscular (IM) injection, meaning into the muscle, once per week.
Betaseron, Extavia, and Rebif are “high dose” interferons because they are given more frequently, and at a higher dose than Avonex. Betaseron, Extavia and Rebif are administered by subcutaneous injection (SQ), into the first layer of skin. Betaseron and Extavia are given every other day, while Rebif is given three times per week.
The newest interferon option is Plegridy. This could be considered a "in-between dose" interferon. It is long-acting, given as a subcutaneous injection every two weeks. Plegridy is twice the dose of Avonex and about half the dose of Betaseron, Rebif or Extavia.
While there are low, in-between and high dose interferon options, it is not always clear what the best dose is for an individual. While some people with MS need a high dose interferon, others may do well on a lower dose.
All interferon drugs have similar side effects. Flu-like symptoms (including fever, chills, fatigue, etc.) are the most common. Injection site reactions are also common. These can be minimized by rotating the injection site. Less common side effects include depression, mild anemia, allergic reactions, and heart problems. In rare cases, the interferons can cause liver damage. Consequently, patients new to interferon therapy must have their liver enzymes checked more frequently.
Interferon - Clinical Trials
In clinical trials, all of the interferon products reduced the number of exacerbations and improved MRI measures of disease activity in the brain in patients with MS and CIS. Several clinical trials have compared the low dose to high dose interferons. The EVIDENCE trial compared Rebif to Avonex, concluding that patients on Rebif had fewer relapses and better MRI results as compared to patients on Avonex.
The INCOMIN trial compared Betaseron to Avonex, concluding that the patients on Betaseron had fewer relapses, better MRI results, and less chance of worsening after two years than patients on Avonex. Another trial compared standard dose Avonex to double-dose Avonex. In this trial double-dose Avonex was not superior to standard dose Avonex. These trials demonstrated that the high dose interferon products are more effective than Avonex in preventing relapses. It appears that this is primarily due to the fact that they are administered more frequently.
Copaxone ® (glatiramer acetate) is a totally different compound than the interferons. Like the interferons, its exact mechanism of action is unknown. The Copaxone molecule resembles myelin basic protein. It is hypothesized that the T cells produced in response to Copaxone can suppress the immune attack on myelin, preventing demyelination and axonal damage. Preliminary research also suggests that Copaxone may have some neuroprotective properties, but more research is needed.
Copaxone in Clinical Trials
Like the interferons, clinical trials have shown that Copaxone reduces the number of exacerbations. In contrast, Copaxone does not exert as dramatic an effect on MRI measures of disease activity in the brain as do the interferons. However, this may reflect its different mechanism of action.
Copaxone is given daily by SQ injection. Unlike interferon’s, Copaxone does not have any flu-like symptoms as a side effect.
With Copaxone, injection site reactions, including lipoatrophy (loss of fat under the skin at the site of injection), are common. Less common side effects include dilation of blood vessels, chest pain, and a reaction immediately after injection causing palpitations, shortness of breath, and flushing. This generally lasts between 15-30 minutes, passes without treatment, and has no known long-term effects.
Currently 2 monoclonal antibodies are approved for the treatment of multiple sclerosis. Tysabri ® (natalizumab) was initially approved in 2004 and Lemtrada ® (alemtuzumab) was approved 10 years later in 2014.
Tysabri was the first humanized monoclonal antibody approved for the treatment of MS. Tysabri works by blocking the receptors on white blood cells that allow them to enter the brain and spinal cord.
Tysabri is administered by IV infusion once every four weeks. Because of the risk of progressive multifocal leukoencephalopathy (PML) – a serious and potentially fatal viral infection of the brain – Tysabri has a Risk Evaluation and Mitigation Strategy (REMS) program. Therefore it can only be prescribed, distributed, and infused by prescribers, infusion centers, and pharamacies registered with the TOUCH Prescribing Program developed by Biogen Idec and Elan (manufacturers and distributors of the drug) in consultation with the FDA.
Tysabri in Clinical Trials
Data demonstrated that Tysabri slows the progression of disability and has a positive effect on MRI. Those taking the drug could experience a two-thirds reduction in relapse.
Side effects include an increased risk for a brain infection caused by the JC virus (PML), which is potentially fatal. Data suggests that the PML risk is low during the first 24 months of use. Prior to initiating therapy, an MRI is needed to help differentiate between potential future MS symptoms and PML. While on Tysabri, your neurologist will evaluate you regularly, including possibly ordering more MRIs. There is a lab test (called STRATIFY JCV) to see if you have been exposed to the JC virus in the past, and there may be a way in the future to risk stratify further.
Infusion reactions (e.g., rash, drowsiness, fever, chills, nausea, flushing, decreased blood pressure, shortness of breath, chest pain) are common. Such reactions usually occur within two hours of the start of the infusion and subside when the infusion ends. Patients should be monitored for signs of infusion reactions during the infusion and for one hour after the infusion. Other adverse effects include headache, fatigue, urinary tract infection, depression, lower respiratory tract infection, joint pain, and abdominal discomfort.
Tysabri is a laboratory-produced antibody. Consequently, the body may produce antibodies with the potential to de-activate the drug. Fortunately, less than 10 percent of people produce antibodies to Tysabri. However, persistently positive antibodies are associated with a decrease in effectiveness of Tysabri and an increase in infusion reactions.
Nothing is known about the safety of long-term use of Tysabri or if additional side effects will emerge.
Lemtrada is administered as intravenous infusions – for five consecutive days initially and for three consecutive days one year later. Because of its safety profile, Lemtrada should generally be reserved for people who have had an inadequate response to two or more MS therapies. According to the Lemtrada Prescribing Information, the product can cause serious or life-threatening autoimmune disorders, infusion reactions and malignancies. Lemtrada, like Tysabri, is only available from certified prescribers, and patients will be enrolled in a REMS program to ensure that ongoing periodic monitoring will be maintained to detect potential problems.
Lemtrada in Clinical Trials
In the CARE-MS I study, relapse rates after two years of treatment with Lemtrada (compared to Rebif) were reduced by 55 percent. In addition, 78 percent of patients on Lemtrada remained relapse-free, which was significantly more than the 59 percent who remained relapse-free on Rebif.
The CARE-MS II study, annual relapse rate at two years for patients on Lemtrada was 0.26 compared to 0.52 for those on Rebif, representing a 49 percent lower risk of relapses. Likewise, after two years, 65 percent of those on Lemtrada remained relapse-free compared to 47 percent on Rebif, which was also significant.
The most common adverse reactions observed in patients receiving Lemtrada included rash, headache, fever, nasal congestion, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral infection, hives, itching, thyroid gland disorders, fungal infection, pain in joints, extremities and back, diarrhea, sinusitis, sore mouth and throat, tingling, dizziness, abdominal pain, flushing and vomiting.
Oral Agents for MS
In 2010, the first orally-administered product for MS, Gilenya ®, was approved by the FDA. It was followed in 2012 by the oral medication Aubagio®, and then in 2013 by Tecfidera ®.
Gilenya (fingolimod) is a sphingosine 1-phosphate receptor modulator that sequesters lymphocytes. Gilenya is administered orally, once daily. Prior to initiating Gilenya, you will have testing, including laboratory tests and an eye exam. The first dose of Gilenya is given in a monitored setting, either at your doctor’s office or another location. You will have an EKG (electrocardigram) prior to taking the first dose and after six hours. Every hour for those six hours you will have your vital signs checked.
Gilenya in Clinical Trials
In the Phase III pivotal FREEDOMS trial, patients who received fingolimod (either dose) had reduced annualized relapse rate and progression of disability compared to the patients who received placebo at two years. In the one-year Phase III pivotal TRANSFORMS trial, patients who received fingolimod (either dose) had reduced annualized relapse rate compared to patient who received Avonex.
Safety concerns associated with Gilenya include first-dose effects such as slow heart rate and heart block. Because the drug sequesters lymphocytes, reversal of lymphopenia can take weeks after the end of dosing. In addition, opportunistic infections (such as shingles) and basal cell carcinoma of the skin have been reported with Gilenya. Gilenya is the oral medication with the longest long-term data, but we continue to have longer safety information on the self injectables (interferon’s and Copaxone).
Aubagio (teriflunomide) is a pyrimidine synthesis inhibitor that inhibits the function of specific immune cells that have been implicated in MS. Aubagio (7 mg or 14 mg) is a tablet taken once per day by mouth, with or without food. The prescribing information contains a boxed warning about the potential for liver damage in the parent compound (leflunomide). Also, Aubagio should not be used during pregnancy.
Prior to initiating Aubagio you will have lab tests (blood count and liver test) and tuberculin skin test (PPD) to make sure that you have not been exposed to tuberculosis in the past.The most common side effects of Aubagio include: abnormal liver test results, hair thinning, diarrhea, flu, nausea, and a burning or prickling feeling in the skin.
Aubagio in Clinical Trials
In the Phase III pivotal TEMSO trial, three groups of people took part in a 108-week study: a low-dose (7 mg) teriflunomide group, a higher-dose (14 mg) teriflunomide group, and a group that took a placebo. The results of the study showed that:
• People taking teriflunomide at either the lower (7 mg) or higher (14 mg) dose had significantly fewer relapses than those taking placebo.
• Progression of disability was reduced in people taking teriflunomide as compared with those people taking the placebo; however the reduction in progression of disability was statistically significant only in the higher-dose group.
• All MRI measures of disease activity showed greater benefit in the people taking teriflunomide than in those taking placebo; however, the benefits were somewhat greater for the group receiving the higher teriflunomide dose. People in both groups taking teriflunomide had significantly fewer new or active lesions on each MRI scan than those in the placebo group. People in both groups taking teriflunomide had a smaller increase in total volume of lesions on MRI than the group taking the placebo.
Tecfidera (dimethyl fumurate), an immunosuppressant, is thought to have anti-inflammatory and cytoprotective properties, though the exact mechanism of action is unknown. Tecfidera is indicated for the treatment of people with relapsing forms of MS. The starting dose of Tecfidera is 120 mg twice daily for seven days, then 240 mg twice daily thereafter. Tecfidera capsules should be swallowed whole and intact; they should not be crushed or chewed. Tecfidera capsules can be taken with or without food. Administration with food tends to decrease the incidence of flushing. Before starting Tecfidera, patients should have a complete blood cell count to identify individuals with pre-existing low lymphocyte counts. Because limited data exist in pregnant women or women who are breastfeeding, Tecfidera should be avoided in these patient populations.
Tecfidera in Clinical Trials
The FDA approved Tecfidera based on data from two Phase III clinical trials: the CONFIRM (COmparator and aN oral Fumarate In RRMS) and DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in RRMS) trials. More than 2600 people were enrolled in the CONFIRM and DEFINE trials. An ongoing extension trial is currently underway.
In the CONFIRM trial, twice-daily Tecfidera decreased the annualized relapse rate by 44 percent compared to placebo. At two years, treatment with Tecfidera significantly decreased the number of participants who relapsed by 34 percent.
In the DEFINE trial, twice-daily Tecfidera significantly decreased the annualized relapse rate by 53 percent compared to placebo. At two years, treatment with Tecfidera significantly decreased the number of participants who relapsed by 49 percent and decreased the 12-week confirmed disability progression, as measured by the Expanded Disability Status Scale by 38 percent. In addition, both trials demonstrated that treatment with Tecfidera significantly reduced lesions in the brain compared to placebo.
Hope for the Future
Active research is currently underway to identify new and better disease-modifying drugs, as well as combination therapies. These drugs have different mechanisms of action and unique side effect profiles. A few of these drugs are in Phase III trials and include more orally administered disease-modifying treatment for MS. To learn more, visit www.clinicaltrials.gov.
(Last reviewed: 02/2015)