New Oral Agents for Multiple Sclerosis: A Healthcare Professional's Guide
Intro: The Pathology of Multiple Sclerosis (MS)
Experts believe that MS begins as an inflammatory immune-mediated disorder leading the body's immune system to attack the protective myelin sheaths around nerves in the brain, spinal cord, and optic nerve. When the myelin is damaged and forms scar tissue - also called sclerosis - this disrupts the flow of nerve impulses, causing the symptoms of MS.
The nerve damage that occurs with MS is not reversible or curable. However, early treatment and lifestyle changes can positively affect a patient's quality of life. Most people with MS will live a normal life-span.
MS: Symptoms and Clinical Diagnosis
For diagnosis, the patient's history and physical exam are initially evaluated. Typical presenting symptoms include:
- limb sensations such as numbness and paresthesia
- motor weakness
- vision loss, eye pain, diplopia (double vision) or ocular movements
- gait and balance disruption
- Lhermitte sign
- sexual and bladder dysfunction.
The diagnosis of MS requires clinical findings of CNS lesions; in addition a magnetic resonance image (MRI) is often used. The MRI, while not required, is the diagnostic test of choice to support the clinical findings. Gadolinium contrast enhancement of the MRI helps to gauge disease activity and inflammation.
Risk Factors for MS
Younger people - in the age range of 15 to 50 - are most frequently diagnosed with MS. There is a myriad of risk factors: being a woman, smoking, living further from the equator geographically, and vitamin D deficiency (possibly due to low sunlight exposure).
Women are three times more likely than men to develop this disorder. However, more studies are needed to confirm the risk of MS among different ethnic populations, although whites appear more at risk. MS is more common in countries with temperate climates; for example, Canada, the northern U.S., New Zealand, southeastern Australia and Europe.
The average risk of developing MS in the U.S is one tenth of one percent. While MS is not hereditary, the risk of children acquiring MS with a parent who has MS increases to 3 to 4 percent. Today, roughly 400,000 people in the U.S. have MS, according to the Multiple Sclerosis Foundation.
Progression of Multiple Sclerosis
There are 4 main types of MS:
- Relapsing-remitting MS (RRMS)
- Secondary-progressive MS (SPMS)
- Primary-progressive MS (PPMS)
- Progressive-relapsing MS (PRMS)
About 80 to 85 percent of MS patients are initially diagnosed with RRMS. In RRMS, relapses of new or worsening symptoms can last from a few days to a few months and patients may remain in remission (recovery period with few or no symptoms) for months or even years.
SPMS usually develops over time following RRMS; relapses can occur, but not remissions. Without treatment, approximately half of individuals with RRMS convert to SPMS within 10 years.
In PPMS, there is no recovery period - symptoms slowly worsen with no distinct relapses or remissions.
In PRMS, MS progresses with intermittent relapses, but no remissions.
Treatment Options for MS
Treatment of MS revolves primarily around three goals:
- treatment of the acute attack
- prevention of future relapses
- treatment of symptoms such as bladder dysfunction or depression
Clinicians initially recommend treatment of RRMS with a disease-modifying agent such as:
- injectable interferon beta (Avonex)
- glatiramer acetate (Copaxone)
- natalizumab (Tysabri)
- oral dimethyl fumarate (Tecfidera)
- teriflunomide (Aubagio)
Patient and clinician choice is really a matter of disease severity, drug safety, efficacy, patient preference, convenience (oral, self-injectable, infusion), child-bearing status, and cost concerns with specialty medications.
Disease modifying drugs work by:
- slowing the neurologic disease process in MS, reducing the frequency of attacks, and decreasing the severity of the attack
- suppressing the immune system and helping to reduce the accumulation of CNS lesions and destruction of the myelin sheaths
In patients with a definitive diagnosis of MS, most neurologists recommend treatment as soon as possible. Disease modifying drugs can slow down the rate of MS progression, and may best be started at or near the initial diagnosis. However, many of the disease-modifying therapies used to treat MS carry significant health risks.
For patients with RRMS whose symptoms are refractory to initial therapy, switching to another disease-modifying agent is recommended.
The Oral Agents for MS
Oral agents are now providing novel disease-modifying treatment options for patients with RRMS.
Although interferon beta or Copaxone are often selected as the first drug of choice, injections may be inconvenient for patients.
Since then, other oral therapies have become available:
A brief review of clinical studies, dosing, side effects, and special precautions for these newer agents are outlined on the following slides.
Clinical Trial Data: Tecfidera
Tecfidera (dimethyl fumarate or BG-12) has been shown in clinical trials to have positive benefits in MS. The exact mechanism of action is unknown, but may be due to activation of the nuclear factor-like 2 (Nrf2) pathway leading to a reduction in oxidative stress. This action is thought to protect nerve cells from damage and inflammation.
In the pivotal CONFIRM and DEFINE clinical trials, oral dimethyl fumarate significantly lowered relapse rates, the number of new brain lesions on MRI, and in one study, helped to delay physical disability progression. Over a 2-year study, 27% of those taking dimethyl fumarate experienced relapse (46% placebo). In addition, 38% fewer people had disability progression compared to placebo, and from 72-90% of MRI brain lesions slowed down in development.
Tecfidera: Dosing and Side Efects
Tecfidera comes in a delayed-release capsule dose form in 120-mg and 240-mg strengths. The initial adult dose is 120 mg two times a day for 7 days, followed by 240 mg two times daily thereafter. Patients may want to take the dose with food to reduce flushing. Alternatively, administration of a non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to Tecfidera dosing may reduce the incidence or severity of flushing. The capsule should not be opened, sprinkled on food, crushed or chewed.
Tecfidera is relatively tolerable from a side effect standpoint; common but possibly transient side effects include flushing (redness, itching and rash), diarrhea and nausea. A CBC is performed at baseline, after 6 months, and every 6 to 12 months thereafter to monitor for lymphocytopenia. Monitor liver enzymes at the start of treatment and as clinically indicated; stop treatment if liver injury.
Tecfidera has no activity in the cytochrome P450 system, which helps to limit drug interactions.
Tecfidera: Important Warnings
Serious allergic reactions can occur at first dose or any time during treatment. Stop Tecfidera permanently if serious allergic reactions such as anaphylaxis and angioedema occur. Also, consider stopping Tecfidera if lymphocyte counts are less than 0.5 x 109/L for longer than six months. If a serious infection develops, the provider may withhold treatment until resolved.
A fatal case of progressive multifocal leukoencephalopathy (PML) occurred in a patient with MS who received Tecfidera for 4 years while enrolled in a clinical trial. Typical symptoms associated with PML can progress over days to weeks and include weakness on one side of the body or clumsiness of limbs, vision disturbance, and changes in thinking, memory, and orientation leading to confusion and personality changes. At the first sign or symptom suggestive of PML, withhold Tecfidera and evaluate the patient.
Clinical Trial Data: Aubagio
Aubagio's (terifluamide) proposed mechanism in MS is via inhibition of pyrimidine synthesis leading to decreased inflammation, reduced white blood cells in the CNS, and nerve protection in MS.
In the TEMSO trial, Aubagio significantly reduced:
- annualized relapse rates at both doses of 7 or 14 mg once a day (0.54 for placebo vs. 0.37 for teriflunomide),
- disability progression at the higher 14 mg dose (27.3% with placebo and 20.2% with teriflunomide)
- MRI evidence of disease activity, as compared with placebo
In the study there was a high drop-out rate for all active and placebo groups, ranging from 25% to 29% of participants.
Aubagio: Dosing and Side Effects
The dose of Aubagio is 7 or 14 mg once a day given as an oral tablet. Aubagio may cause severe liver injury, and contains a boxed warning contraindicating use in patients with severe hepatic impairment. LFTs and bilirubin should be measured within 6 months of treatment initiation and ALTs should be monitored monthly for the first 6 months after treatment begins. If liver injury is suspected, patients should undergo accelerated drug removal outlined in the package insert. Patients should also receive all needed vaccinations prior to treatment.
The most common adverse effects include:
- elevated alanine aminotransferase (ALT) levels
Aubagio: Important Warnings
- Aubagio labeling has a boxed warning for teratogenicity, and it is contraindicated for use in pregnant women and females of reproductive potential not using effective contraception.
- Aubagio is also found in a man's semen and can remain in the blood serum for up to 2 years. Therefore, men or women using Aubagio who plan to conceive a child must first contact their physician to undergo accelerated drug elimination using cholestyramine or activated charcoal powder, which is outlined in the package insert.
- Aubagio labeling also contains a boxed warning for hepatotoxicity and is contraindicated in severe liver disease.
- Measure transaminase and bilirubin levels within 6 months before starting Aubagio and monitor ALT levels at least monthly for six months. If drug induced liver injury is suspected, discontinue Aubagio and start accelerated elimination procedure
- Aubagio should also be avoided by patients taking leflunomide (Arava), a similar drug used in rheumatoid arthritis, due to possible additive liver toxicity.
- Drug interactions should be monitored.
Clinical Trial Data: Gilenya
The immunosuppressant Gilenya (fingolimod) modulates the sphingosine-1-phosphate receptor and reduces lymphocyte migration into the CNS. This proposed mechanism reduces inflammation and damage to nerve cells.
Gilenya has been shown to cut relapses by 52% when compared to interferon beta-1a (Avonex) in a one-year study. In addition, at one year, 13% more patients on Gilenya were relapse-free when compared to interferon beta-1a. Gilenya has also been shown to slow disease progression and the number of brain lesions on an MRI.
Data from a two-year placebo-controlled study showed a significant 54% reduction in relapse rate compared with placebo and a 30% reduction in risk of disability progression among Gilenya patients at three-month follow-up visit, compared to placebo.
Gilenya: Dosing and Side Effects
Gilenya is dosed as a 0.5 mg capsule once a day for RRMS; higher doses do not offer additional benefit but can worsen side effects. It can be used as a first line agent.
Patients with hepatic impairment should be monitored closely. Common side effects with Gilenya may include:
- elevated liver enzymes
Other serious side effects have included macular edema, heart rhythm abnormalities, syncope, skin and breast cancers, PML, and other serious infections.
First dose response bradycardia: Gilenya prescribing information states that patients should be monitored with a heart ECG before and 6 hours after the first dose of Gilenya, in addition to hourly measurements of blood pressure and heart rate. If a patient stops taking Gilenya for more than 14 days after their first month of treatment, they will need to repeat this observation.
Gilenya is contraindicated in patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization or Class III/IV heart failure.
Gilenya: Important Warnings
- After the first dose, Gilenya has caused symptomatic bradycardia, therefore first dose monitoring is required.
- Do not start Gilenya in patients with active infections. Obtain baseline CBC and monitor for infections during and for 2 months after discontinuation.
- Obtain baseline liver function tests before treatment. Stop drug if severe liver injuury occurs.
- Withhold Gilenya treatment if suspected progressive multifocal leukoencephalopathy (PML).
- Monitor for macular edema with a fundus exam before and 3-4 months after starting treatment.
- Stop treatment if suspected posterior reversible encephalopathy syndrome (PRES).
- Women of childbearing potential should use effective contraception during and for 2 months after stopping Gilenya.
- Monitor blood pressure during treatment.
Place in MS Therapy: Disease Modifying Agents
The choice of initial treatment in MS depends upon patient choices and their level of disease activity: convenience, safety, and effectiveness all come into play.
- Interferon beta and glatiramer (Copaxone), although self-injected, are often selected first-line based on longer-term history and a greater level of drug safety.
- Oral dimethyl fumarate (Tecfidera) or teriflunomide (Aubagio) offer convenience, with a preference to Tecfidera due to a better safety profile over Aubagio or fingolimod (Gilenya).
- Natalizumab (Tysabri) infusion may be an appropriate choice for patients with more severe disease.
- If a patient has a poor response or cannot tolerate one therapy, it's reasonable to try another.
Tysabri and Lemtrada: For Refractory MS Patients
Tysabri is given every 4 weeks by IV infusion and is linked with a rare, often fatal brain disease known as progressive multifocal leukoencephalopathy (PML). This agent has a boxed warning describing this serious side effect.
- autoimmune conditions
- infusion reactions
- the risk of cancer - including thyroid cancer, melanoma, and lymphoproliferative disorders. Perform baseline and yearly skin exams.
Zinbryta: A Once-a-Month Injection
In May 2016, FDA approved AbbVie and Biogen’s Zinbryta (daclizumab) for the treatment of adults with relapsing forms of multiple sclerosis (MS). Zinbryta is a monoclonal antibody and a long-acting injection that is self-administered by the patient monthly. Typically, it is used after a patient tried at least 2 other treatments without success.
In clinical trials, patients using Zinbryta had fewer clinical relapses than patients taking placebo or Avonex (interferon beta-1a). However, Zinbryta can cause severe liver injury, and monthly blood tests are needed to monitor liver function. Patients must enroll in the Zinbryta REMS (Risk Evaluation and Mitigation) program and the drug must be obtained from a certified pharmacy.
View the boxed warning for Zinbryta detailing hepatic injury, including autoimmune heptitis and other immune-mediated disorders.
Treatment of Acute MS Symptoms
When MS symptoms flare up, added treatments can further ease the burden. For example:
- injectable corticosteroids (prednisone, methylprednisolone) may be used to reduce inflammation
- Plasma exchange (plasmapheresis) has been used to treat severe symptoms in patients who do not respond to corticosteroids
- Ampyra (dalfampridine) is an oral MS medication that inhibits potassium channels to increase action potentials in demyelinated axons. Ampyra has been shown to improve weakness and walking in those with MS.
Other symptoms of MS - from anxiety to bladder control to tremors - may be treated with various agents specific for those syndromes.
Does Medical Marijuana Ease MS Symptoms?
Spasticity is a painful symptom for MS patients, mimicking a charley horse muscle spasm. In a small study, researchers found smoking marijuana modestly reduced the spasticity by about a third compared to patients on placebo. Fatigue and lowered cognition occurred as side effects.
According to the American Academy of Neurology, studies of smoked marijuana do not provide enough evidence to show safety or effectiveness. There is strong evidence that oral cannabis extract (OCE), which is cannabidiol (CBD) or CBD plus THC in pill form, can reduce patients’ reported symptoms of spasticity in the short-term.
Moderate evidence suggests that synthetic THC (Marinol, Cesamet) or nabiximols (Sativex), a mixture of THC and CBD available in oral spray form but not yet approved in the U.S, can lessen reported symptoms of spasms and cramp-like pain.
Recommendations for Lifestyle Changes
Healthcare providers should encourage a healthy living style for patients with MS. In fact, certain behaviors can trigger MS symptoms, and patients should learn to manage or avoid these triggers.
- Avoid extreme heat or cold; cool down regularly when exercising
- Don't smoke and avoid second-hand smoke
- Encourage patients to enjoy life and reduce stress
- Educate patients about their various medications
- Encourage regular exercise
- Find emotional support
- Eat a healthy, balanced diet
- Attend their rehabilitation therapy regularly.
Patient Resources for MS
If patients are interested in joining a clinical trial, health care providers can refer patients to Clinicaltrials.gov., a comprehensive listing of federally and privately supported clinical trials. Centerwatch also lists trials. The Multiple Sclerosis Association of America maintains a website with easy-to-read patient resources. The NIH also has information on research studies and other MS facts.
Finished: New Oral Agents for Multiple Sclerosis: A Healthcare Professional's Guide
- O'Connor P, Wolinksy JS, Confavreux C, et al. TEMSO Trial Group. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011 Oct 6;365(14):1293-303. Accessed 10/13/2017 at doi: 10.1056/NEJMoa1014656.http://www.ncbi.nlm.nih.gov/pubmed/21991951
- Pot Might Help Ease Multiple Sclerosis Symptoms. Drugs.com. May 14, 2012. Accessed 10/13/2017 at https://www.drugs.com/news/pot-might-help-ease-multiple-sclerosis-38176.html.
- Multiple Sclerosis Association of America (MSAA). MS Overview. Sept. 2015. Accessed 10/13/2017 at http://mymsaa.org/ms-information/overview/process-symptoms/
- Koppel, BS, Brust J, Fife T, et al. Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders. Neurology 2014;82:1556-63. Accessed 10/13/2017 at http://www.neurology.org/content/82/17/1556.full.
- American Academy of Neurology (AAN). Medical Marijuana in Certain Neurological Disorders. Summary of Systematic Review for patients and their families. Accessed 10/13/2017 at https://www.aan.com/Guidelines/home/GetGuidelineContent/650.
- American Academy of Neurology (AAN). Rehabilitation in Multiple Sclerosis. Accessed 10/13/2017 at https://www.aan.com/Guidelines/home/GetGuidelineContent/722.
- Up To Date. Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults. Sept 2017. Accessed 10/13/2017 at http://www.uptodate.com/contents/treatment-of-relapsing-remitting-multiple-sclerosis-in-adults.