Oral Treatments for Relapsing-remitting MS

Pharmacology Watch

In this issue: Two oral medications for relapsing-remitting MS in phase III development; antihypertensives find new uses; Ginkgo biloba does not prevent cognitive decline in elderly; and FDA Actions.

Oral medications for relapsing-remitting MS

Two new oral medications are effective treatments for relapsing-remitting multiple sclerosis (MS) according to three studies published on-line in the New England Journal of Medicine. Fingolimod and cladribine differ in the mechanism of action but both reduce the number of potentially auto-aggressive lymphocytes that are available to enter the central nervous system. In the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial, two different doses of cladribine were compared to placebo with the endpoint being relapse at 96 weeks. Both doses were more effective than placebo at preventing relapses and reducing brain lesion count on MRI (P < 0.001 for all comparisons). The drug was associated with lymphocytopenia and a higher risk of herpes zoster.

Fingolimod was compared to placebo in the FREEDOMS trial and compared to injectable interferon in the TRANSFORMS trial. The 24-month FREEDOMS trial compared two doses of fingolimod to placebo and similarly found a lower rate of relapse (P < 0.001 for both doses) and disability progression (P = 0.02 for both doses). The drug also reduced the number of new lesions found on MRI. Significant side effects included bradycardia, AV block, macular edema, elevated LFTs, and mild hypertension. When compared to interferon, fingolimod was associated with significantly lower annualized relapse rates at both doses tested (P < 0.001 for both comparisons), although there was no significant difference with respect to progression of disability. Two fatal infections occurred with the higher dose of fingolimod (disseminated primary varicella zoster and herpes simplex encephalitis). (All three studies published on-line at www.NEJM.org, Jan. 20, 2010).

An accompanying editorial calls the arrival of oral formulations of MS drugs "welcome news for the estimated 2.5 million people worldwide with this chronic, disabling disease." While suggesting these drugs "support a change in treatment approach to directly prevent immune-related injury," the editorial also suggests that long-term goals of MS therapy are currently lacking (published online at www.NEJM.org, Jan. 20, 2010). Both drugs are in phase III trials for treatment of MS; cladribine is currently approved in parenteral form for treatment of hairy cell leukemia.

Antihypertension drugs for AF and dementia?

Different classes of blood pressure (BP) medications may have different benefits according to two new studies. In the first study, researchers from the United Kingdom performed a nested case-control analysis to evaluate whether different antihypertensive drug classes may alter the risk for atrial fibrillation. The researchers reviewed records from a large patient population, specifically patients who were on a single agent for lowering BP. A lower odds ratio (OR) for atrial fibrillation was noted with ACE inhibitors (OR, 0.75; 95% confidence interval [CI], 0.65-0.87), angiotensin receptor blockers (ARBs) (OR, 0.71; 95% CI, 0.57-0.89), and beta-blockers (OR, 0.78; 95% CI, 0.67-0.92) compared with current exclusive therapy with calcium channel blockers. Although the researchers were unable to assess why patients were receiving one class of blood pressure medicine over another, they concluded that long-term therapy with ACE inhibitors, ARBs, or beta-blockers reduces the risk for atrial fibrillation compared with calcium channel blockers. These findings generally relate to patients with mild hypertension, since patients on multiple drugs were excluded from the study (Ann Intern Med 2010;152:78-84).

In the second study, researchers from Boston set out to investigate whether ARBs reduce the risk of Alzheimer's disease and dementia or reduce the progression of both diseases. More than 800,000 predominately male participants, age 65 or older with cardiovascular disease, were studied. Patients were divided into three cohorts (ARBs, lisinopril, and other cardiovascular drugs as a comparator) and followed over 4 years, with adjustments for age, diabetes, stroke, and cardiovascular disease. Hazard rates for dementia in the ARB group were 0.76 (95% CI, 0.69-0.84) compared to the cardiovascular comparator, and 0.81 (95% CI, 0.73-0.90) compared to the lisinopril group. In patients with pre-existing Alzheimer's disease, ARBs were associated with significantly lower risk of admission to a nursing home. The combination of the ARB and ACE inhibitor was better than ACE inhibitor alone in preventing dementia and reducing admission to nursing home. The authors conclude that ARBs are associated with a significant reduction in the incidence and progression of Alzheimer's disease and dementia compared to ACE inhibitors or other cardiovascular drugs (BMJ 2010;340:b5465, doi: 10.1136/bmj.b5465, published on-line Jan. 12, 2010). An accompanying editorial points out that several studies have shown that treatment with any antihypertensive is associated with a lower risk of cognitive decline or incident dementia in older adults. What is not clear is whether some antihypertensives also have other biological mechanisms that help prevent dementia. It is plausible that ARBs are more neuroprotective than other drugs because of their effect on type 2 angiotensin receptors in the brain (BMJ 2010:340;b5409, doi: 10.1136/bmj.b5409, published on-line Jan. 12, 2010).

Ginkgo does not prevent cognitive decline

The National Center for Complementary and Alternative Medicine (NCCAM) was founded during the Clinton administration as part of the National Institutes of Health to investigate complementary and alternative medicines. Many of the NCCAM-funded studies, however, have shown no benefit from complementary or alternative treatments, and that is the case with a new study looking at Ginkgo biloba and cognitive function in older adults. Ginkgo biloba, which is widely marketed as an aid to preventing cognitive decline and dementia, was previously found to have no benefit in reducing the incidence of Alzheimer's disease or dementia overall (JAMA 2008;300:2253-2262).

In a new study sponsored by NCCAM, researchers set out to determine whether Ginkgo biloba slows the rate of global or domain-specific cognitive decline in older adults. More than 3000 participants age 72-96 years were enrolled and randomized to G. biloba 120 mg or placebo twice daily. Rates of change over time in two different objectives cognitive tests, as well as neuropsychological tests, were the primary endpoints. There was no difference in the decline in cognitive scores between Ginkgo biloba and placebo in any of the domains including memory, attention, and visuospatial abilities, language, or executive functions. There was also no difference in the rate of change in the standardized cognitive exams. The authors conclude that compared to placebo, Ginkgo biloba did not result in less cognitive decline in older adults (JAMA 2009;302:2663-2670).

FDA Actions

Novo Nordisk has received approval to market liraglutide, a once-daily injection for the treatment of type 2 diabetes in adults. The drug is a glucagon-like peptide-1 receptor agonist similar to exanatide (Byetta®). The company is required to perform additional post-marketing cardiovascular studies as well as a 5-year epidemiological study to evaluate the risk of thyroid cancer. Liraglutide will be marketed under the trade name Victoza®.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: paula.cousins@ahcmedia.com.