58 NEUROLOGIC DISORDERS FEBRUARY 15, 2010 • FAMILY PRACTICE NEWS Oral Agents for Multiple Sclerosis Prove Effective

Discontinuation rates were low, but adverse event A. Cohen of the Cleveland Clinic’s 96 weeks at 155 centers in 32 countries. Mellen Center and his associates com- The agents were given in two or four rates ranged from 8% to 14%. pared the same two doses of daily oral short courses for 48 weeks, then again in fingolimod with intramuscular injections two short courses at weeks 48 and 52, for BY MARY ANN MOON need to take them their whole lives, ac- of interferon beta-1a (Avonex). The in- a total of 8-20 treatment days per year. cording to Dr. Carroll of Sir Charles vestigators conducted follow-up for 1 This schedule allowed for an extended ingolimod and cladribine, the first Gairdner Hospital, Perth, Australia. year with 1,292 patients treated at 172 hematopoietic recovery period during oral formulations for treating re- In the first study, which was funded by medical centers in 18 countries. the interval before the second round of Flapsing-remitting multiple sclerosis, Novartis Pharma, Dr. Ludwig Kappos of Compared with interferon beta-1a, the treatment courses. proved effective in three phase III clinical the University of Basel (Switzerland) and relapse rate was 38% lower with low-dose Both doses of cladribine significantly trials. his associates compared two doses of dai- and 52% lower with high-dose fingolimod. reduced the relapse rate by 55%-58%. In The two drugs have different mecha- ly fingolimod capsules (0.5 mg and 1.25 The time to relapse, proportion of relapse- addition, the drug lengthened the time nisms of action, but both target lym- mg) with a matching placebo in 1,272 pa- free patients, and proportion with multi- to relapse and decreased the rate of dis- phocytes that are potentially autoag- tients followed for 2 years at medical cen- ple relapses also favored fingolimod. ability progression by approximately gressive against the CNS and both also ters in 22 countries. The primary end Fingolimod-treated patients also ex- one-third. are believed to promote point—the rate of re- perienced a similar rate of disability pro- Cladribine also reduced measures of neuroprotective and All three trials were lapse—was 54% lower gression, time to disability progression, MS inflammatory activity on MRI brain reparative processes. In with the lower dose of and MRI findings as those that were re- imaging. separate multicenter, well conducted and the drug and 60% low- ported in the trial conducted by Dr. The rate of serious adverse events was randomized, double- ‘provide a new er with the higher dose, Kappos and his associates. 8% with low-dose cladribine and 9% blind, placebo-con- relative to placebo. In these two studies, serious adverse with high-dose cladribine, compared trolled clinical trials, horizon for patients Fingolimod was events were more frequent with fin- with 6% with placebo. The types of ad- both oral medications with relapsing- equally effective in pa- golimod than with the comparator, and verse events were similar to those with reduced the rate of tients who had never they appeared to be more common at other immunomodulatory agents: lym- multiple sclerosis (MS) remitting MS and a been treated and those the higher dose of the drug. Adverse phocytopenia, infection, and neoplasms. relapse, slowed the pro- welcome increase in who had already re- events tended to fall into the categories Twenty patients had reactivation of la- gression of disability, ceived other treatments expected for any immunomodulatory tent herpes infections, and 1 had a reac- and decreased the num- the range of options.’ for MS. The time to agent: lymphocytopenia, CV effects, in- tivation of latent tuberculosis that proved ber and severity of first relapse was signif- creased rates of infection, macular ede- fatal. “Cancers were isolated cases across brain lesions on MRI. icantly longer with active treatment than ma, liver-enzyme abnormalities, and different organ systems, and given the In one of the studies, fingolimod out- with placebo, and more patients in the neoplasms. small number, it is not possible to estab- performed interferon beta-1a injections, active-treatment group remained relapse Fingolimod caused transient and often lish a risk for the use of cladribine,” Dr. a widely used treatment for MS. “It is free at 2-year follow-up. asymptomatic bradycardia and atrioven- Giovannoni and his colleagues wrote (N. likely that the two oral therapies will be Both doses of fingolimod also reduced tricular block, which likely reflects the Engl. J. Med. 2010 Jan. 20 [doi:10.1056/ at least as effective as other currently the risk of disability progression and the drug's ability to bind to receptors in car- NEJMoa0902533]). available disease-modifying therapies,” time to progression. Scores on two mea- diac tissue. The long-term relevance of As with fingolimod, the risks of treat- Dr. William M. Carroll wrote in an edi- sures of disability either remained stable this effect is not yet known. ment with cladribine must be carefully torial (N. Engl. J. Med. 2010 Jan. 20 or improved slightly with fingolimod, The drug also raised the rate of infec- weighed against the benefits, and longer [doi:10.1056/NEJMe0912019]). but worsened with placebo. tion, including pneumonia. Several pa- follow-up is essential, the investigators Both fingolimod and cladribine had ac- MRI scans showed significantly fewer tients developed herpes infections, two added. ceptable safety profiles with low rates of brain lesions, as well as fewer new or en- of which were fatal, and reactivation of All three clinical trials were well con- adverse events leading to discontinuation larged lesions and a smaller overall vol- latent herpes remains a concern. ducted and “provide a new horizon for of the drugs. However, these rates still ume of lesions, with fingolimod than Both research groups emphasized that patients with relapsing-remitting MS and were twice as high with active therapy as with placebo. In addition, characteristic longer studies are needed to assess safe- a welcome increase in the range of treat- with placebo (ranging from 8% to 14%), reductions in brain volume were 30% ty issues adequately. ment options,” Dr. Carroll noted. and were associated with patient death smaller with fingolimod, Dr. Kappos and In the third study, sponsored by Mer- All three first authors and many of in at least two cases. his colleagues reported (N. Engl. J. Med. ck Serono, Dr. Gavin Giovannoni of their coauthors reported receiving con- “Clinicians and patients will need to 2010 Jan. 20 [doi:10.1056/NEJ- Queen Mary University, London, and sulting or lecture fees or research support evaluate the risks and benefits of each of Moa0907839]). his associates compared two doses of from many manufacturers of drugs for these drugs,” and long-term safety re- In the second study, which also was oral cladribine with a matching placebo MS, including Biogen Idec, Merck mains a concern because patients may funded by Novartis Pharma, Dr. Jeffrey in 1,326 patients who were followed for Serono, EMD Serono, and Novartis. ■ FDA Approves First Drug to Improve Walking in MS Patients

BY ELIZABETH Dalfampridine will be mar- those with severe renal insuffi- according to the FDA statement. increased risk of seizures. The MECHCATIE keted as Ampyra by Acorda ciency. The drug has a long history of sustained formulation was de- Therapeutics Inc. of The recommended dose of use in the United States despite veloped to overcome these lim- sustained-release formula- Hawthorne, N.Y. dalfampridine is 10 mg twice a never having been approved, ac- itations. Ation of the potassium chan- At a meeting in October 2009, day. However, higher doses have cording to background docu- In clinical trials, the most nel blocker dalfampridine has the majority of an ments filed by the common adverse reactions in been approved by the Food and FDA advisory panel There is ‘substantial evidence’ of FDA for the advisory patients taking dalfampridine Drug Administration as a treat- voted that Acorda panel meeting. For included urinary tract infec- ment to improve walking in had provided “sub- effectiveness for this indication, but more than 20 years, tions, insomnia, dizziness, people with multiple sclerosis. stantial evidence” of only one-third of the patients in the two dalfampridine has headache, nausea, weakness, In a statement, the FDA an- effectiveness for this been compounded back pain, balance disorder, nounced that dalfampridine ex- indication, although pivotal trials were responders. in pharmacies and swelling in the nose or throat, tended-release tablets had been only one-third of the used off-label to im- constipation, diarrhea, indiges- approved for this indication, patients in the two pivotal trials been associated with seizures, prove walking in people with tion, throat pain, and skin sen- based on studies that found pa- were considered responders. and the drug should not be tak- various neurologic conditions. sations including burning, tin- tients treated with the drug had Most of the panel also agreed en by patients with moderate to However, fampridine’s narrow gling, and itching. faster walking speeds than did that the drug could be consid- severe kidney disease, whose therapeutic range makes plasma At the meeting, representa- those treated with placebo. This ered safe for use in people with blood levels with dalfampridine levels difficult to regulate with tives of Acorda said that dal- is the first drug approved for this MS, but not in patients who approach the levels that have the immediate-release formula- fampridine improves conduc- indication, according to the FDA. have a history of seizures and been associated with seizures, tion, which is associated with an tion in demyelinated axons. ■