MS Progress Notes... A newsletter for health professionals Volume 9, Number 2 Spring 2014

Update on Oral Medications For Multiple Sclerosis ROBERT CARRUTHERS, MD AND TANUJA CHITNIS, MD Introduction. Oral medicines represent a major infection and cause MS) trapped in lymph nodes through breakthrough in caring for patients with multiple sclerosis. modulation of the sphingosine-1 phosphate receptor. A major shift in the treatment landscape is under way There are some safety concerns that are largely covered as many patients previously managed with injectable by the extensive testing required to start therapy including therapies are switching to oral therapy and some newly VZV primary exposure, bradycardia & atrioventricular diagnosed patients are starting therapy with a pill rather conduction block with the first doses, macular edema, than an injectable. While it is understandable that patients elevated liver-enzyme levels, and mild hypertension. would be eager to swallow a pill rather than administer an Because of transient bradycardia, which was symptomatic injection, one must tailor therapy for each patient. There are in 5 of 19 cases reported in the pivotal trials where 1703 important risks and benefits with each pill that need to be patients received Gilenya, a 6-hour monitoring period weighed with each patient’s comorbidities and medications. is required at the time of first dose administration and is Dimethyl fumarate (Tecfidera®) is a pill that is taken generally performed in the outpatient neurologist’s office, twice each day and in two clinical trials, reduces relapse although some situations may warrant inpatient monitoring. rates compared to placebo by about 53%1 and 44%2 The cardiac effects of Gilenya are short-lived, as the respectively. It may take several months for the differences sphingosine receptors on cardiac myocytes are internalized between treatment groups to become apparent, so for with ongoing exposure. Nevertheless, patients with patients with recently active disease, monthly doses of cardiac disease or other medications that slow AV nodal methylprednisolone 1g IV q month for 3-6 months may be conduction or cause prolongation of the QT interval might warranted. Between those trials, there was inconsistent consider a different option, or hold those medications while data as to whether there was a difference in disability starting fingolimod. Fingolimod is categorized as pregnancy progression over two years. The precise mechanism category C, and should not be used during breast-feeding. of action of Tecfidera is not clear, but it does have anti- Teriflunomide (Aubagio®) is a daily pill that is available in inflammatory and anti-oxidant effects in part mediated two doses, 7mg and 14 mg. At the higher dose, it prevents by the Nrf2 pathway. Tecfidera is approved for relapsing 31.5% of relapses and does slow progression of disability forms of MS, and is administered at 120mg twice a day compared to placebo5. The lower dose has a similar for one week, and then escalation to maintenance dosage effect on relapses but does not have a significant effect on 240mg twice a day. A complete blood count is required disability. This medicine slows production of nucleic acids prior to starting. Flushing, nausea, cramping and diarrhea via the salvage pathway, required for rapid white blood may occur at treatment initiation or at escalation to higher cell proliferation. Prior to starting the medicine, one must dosages, but these side effects largely subside after the test negative for pregnancy and exposure to tuberculosis. first month. We generally recommend that patients take The medicine has a black box warning for teratogenicity the medication with food and otherwise use a symptom- (pregnancy category X) and should not be given during based approach for mitigating side effects. For flushing, breastfeeding. There are also rare cases of liver damage ASA 81mg PO daily can help. Stomach upset can respond that prompted need for six months of monthly liver function to Pepto Bismol, which also contains salicylates. Some testing. Furthermore, 13% of patients experience several patients with diarrhea respond to Lomotil. Tecfidera is months of hair thinning that is reversible, although this can classified as Pregnancy category C, and breast-feeding on be a concern for those with thin hair. Another concern is treatment is not recommended. that the medication has a long half-life and in the event Fingolimod (Gilenya®) is a 0.5mg pill taken once daily that there is a teriflunomide-related adverse event, and prevents 55% of relapses compared to placebo in some patients must undergo an “accelerated elimination one clinical trial3. When compared to Avonex, fingolimod- procedure” involving cholestyramine washout usually given treated patients had 48% fewer relapses over one year4. at a dose of 8g three times daily for 11 days. Fingolimod works by keeping white blood cells (that fight Choosing the right medicine. With three new options in the last three years, patients might ask how one approaches standing low white blood counts from Fumaderm. The FDA picking the best medicine for each patient. For patients is aware of these cases and approved Tecfidera without a having breakthrough disease from an injectable firstline black box warning. While the risk of PML with these agents agent, and patients who cannot tolerate an injectable, is not zero, it is most likely lower than the 3.3/1000 risk of these medicines will be most helpful. In general, given the PML with natalizumab8. strength of the relapse reduction versus their respective Patients with Progressive MS. These medications are placebo groups, one might lean toward dimethyl fumarate approved for patients with relapsing forms of multiple and fingolimod as more efficacious agents. However, the sclerosis (which can include patients with SPMS). Whether relative efficacy of these agents cannot be determined these treatments impact “progressive disease” is unknown. with confidence until they are directly compared to one While it is rare, patients can suffer relapses late in their another within the same blinded trial. Deciding between disease course. A study of Gilenya in PPMS patients is dimethyl fumarate, teriflunomide and fingolimod can be underway9. tricky but medical co-morbidities and medicines can be helpful. Patient preference for a daily dosing regimen Conclusion. Oral medicines offer several exciting can sway some patients. Some patients who are eligible treatment options for some MS patients. Many patients for any of these therapies ask, “which is better?” It is not will benefit from making a switch, but while selecting possible to offer an iron-clad argument that either medicine an agent, clinicians must be mindful of the patient’s is indeed stronger. One approach that some find valid medications, co-morbidities and the side effects of the oral is that fingolimod was shown to prevent more relapses agent. Informing patients about the risks and benefits of than Avonex while dimethyl fumarate did not demonstrate each medication including potential fetal risk and PML is superiority over Copaxone. For patients with less active essential. Some patients would do well to remain on their disease who are tolerating their injectable medicine, one injectable medication as these medications are both safe can easily justify staying on an injectable medicine. The and efficacious. Despite some safety concerns, the oral rationale is that with the recent placebo group relapse rate medicines do offer much improved ease of medication of 0.4 relapse/year, one would need to treat a patient for administration, and in some cases, an increase in efficacy ten years with Tecfidera or Gilenya in order to prevent a from injectable medicines. single relapse as compared to treatment with an injectable References: medicine. For patients with frequent relapses, this math 1. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 does favor more efficacious medicines and justifies the study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098-1107. risks associated with these oral medicines. 2. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 Family Planning. Women in their childbearing years study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J should be counseled to use reliable forms of contraception Med 2012;367:1087-1097. 6 3. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial as Tecfidera and Gilenya are FDA Pregnancy Category of oral fingolimod in relapsing multiple sclerosis. N Engl JMed C – “Animal reproduction studies have shown an adverse 2010;362:387-401. effect on the fetus and there are no adequate and well- 4. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or controlled studies in humans, but potential benefits may intramuscular interferon for relapsing multiple sclerosis. N Engl J warrant use of the drug in pregnant women despite potential Med 2010;362:402-415. 5. O’Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial risks.” Aubagio is FDA Pregnancy Category X – “Studies in of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med animals or humans have demonstrated fetal abnormalities 2011;365:1293-1303. and/or there is positive evidence of human fetal risk based 6. FDA Pregnancy Categories [online]. Available at: http://depts. on adverse reaction data from investigational or marketing washington.edu/druginfo/Formulary/Pregnancy.pdf. experience, and the risks involved in use of the drug in 7. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab- associated progressive multifocal leukoencephalopathy. N Engl J pregnant women clearly outweigh potential benefits.” Med 2012;366:1870-1880. Patients with Positive JCV Serology. It is common 8. TYSABRI® (natalizumab): PML Incidence in Patients Receiving for patients to be started on oral medicines after testing TYSABRI. In: MD RC, ed.: Biogen Idec: 8. 9. FTY720 in Patients With Primary Progressive Multiple Sclerosis positive for JCV exposure. The JCV serologic test has (INFORMS) [online]. Available at: www.clinicaltrials.gov. been shown to determine risk of developing progressive multifocal leukoencephalopathy (PML) in patients treated Robert Carruthers, MD is a clinical fellow at the Partners with Tysabri7. Data concerning PML risk with these new oral MS Center at Brigham & Women’s Hospital, Boston, agents is limited. For example, of 70,000 patients treated Massachusetts. with fingolimod, there has been a single reported case of Tanuja Chitnis, MD is an Associate Professor of PML that is under investigation. With Tecfidera, there have Neurology at Harvard Medical School. She is a staff been no reported cases of PML. With a related medicine neurologist and Medical Director of the CLIMB study at the called Fumaderm, which contains the active ingredient Partners MS Center at Brigham & Women’s Hospital and of Tecfidera, there are rare cases of PML in patients with she is the Director of the Partners Pediatric MS Center at past exposure to immunosuppressive medicines and long- Massachusetts General Hospital for Children.