ORLANDO—After years of waiting, patients with multiple sclerosis (MS) can now choose between three approved oral agents. Patients’ choices will be improved, however, if they first investigate which of the three drugs would be most appropriate for them.
All three oral drugs—fingolimod, teriflunomide, and dimethyl fumarate—are “definitely” suitable as first-line therapy in selected newly diagnosed patients with MS, said Mariko Kita, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.
But the three oral drugs are not interchangeable. Each has a different mechanism of action and its own side effect profile, emphasized Dr. Kita, Director of the Virginia Mason MS Center in Seattle and Director of the MS Clinical Trials Unit at Virginia Mason’s Benaroya Research Institute.
Few neurologists are prescribing an oral agent as a first-line therapy, partly because of cost and reimbursement issues, but mainly because most physicians do not believe that the oral agents’ safety profiles are fully understood. Most practitioners hesitate to administer new drugs. The hesitation may be understandable in light of the cautions added to the labels for natalizumab—considered the most effective of the injectable agents—and fingolimod—the first oral agent to receive marketing approval—shortly after they were introduced.
Nevertheless, physician experience with the oral medications is expected to grow quickly. Barring revelations of new side effects, observers anticipate that the use of oral agents for MS will surge within the next few years, leading to a corresponding decline in the popularity of injectable therapies.
Oral Therapies May Appeal to All Patients With MS
Demand for oral therapy will be high among all types of patients, predicted Dr. Kita. Newly diagnosed patients and individuals with a lengthy disease history who have tried all the available disease-modifying therapies with unsatisfactory results will be interested in oral medications, she said. The same will be true for patients who cannot tolerate a given first-line injectable agent or who experience breakthrough disease while using it. Likewise, patients who are stable on their current injectable disease-modifying therapy but are tired of injections or concerned about the parenteral therapy’s long-term risks will consider the oral drugs, added Dr. Kita.
Choosing an appropriate oral medication requires a focus on patient-specific factors, including comorbid conditions, reproductive status, and how the oral drug would fit into a long-term, staged therapy plan, she added.
Fingolimod
Fingolimod is best reserved for patients with MS who are otherwise relatively healthy, said Dr. Kita. It is a less favorable option for patients with diabetes, smokers, individuals with reduced pulmonary function, and those with an increased risk of infection, including people with a high Expanded Disability Status Scale score.
Fingolimod is a sphingosine-1-phosphate agonist. It sequesters lymphocytes in the lymph nodes so that they cannot participate in autoimmune activity. The testing required before initiating fingolimod therapy, the need for careful observation during the first dose, and the necessary ongoing monitoring for the duration of treatment make this a labor-intensive drug, said Dr. Kita.
Bearing those factors in mind, she continued, fingolimod is “reasonable” to use as a first-line agent or as a second-line agent in the setting of intolerance to prior therapy or of breakthrough disease on therapy.
Expectations for First- and Second-Line Therapies
“I would caution those who are reserving these oral agents as second-line [treatments] that we need to think about what we can reasonably expect from them,” said Dr. Kita. “If we’re moving to them as second-line [drugs] because of tolerability issues with first-line agents, yes, I think that’s most reasonable. But if we’re moving because of breakthrough disease, our experience with these agents in cases of failure with standard first-line therapies is very, very limited. Sure, the differing mechanism of action offers a reasonable alternative option, but the expectation that the oral [medication] will be better than a failed injectable [medication] has not yet been proven,” she added.
Choosing the Right Oral Drug
Of the three oral MS agents currently available in the US, dimethyl fumarate has the most benign side effect profile, which consists mostly of short-term flushing and gastrointestinal complaints. Dimethyl fumarate could gain broad use as a first-line drug in newly diagnosed patients and as a second-line therapy in patients intolerant to other agents or in patients experiencing breakthrough disease.
It remains unclear whether any of the available oral agents is the best choice after natalizumab discontinuation. In several studies, patients who took fingolimod after natalizumab discontinuation had a high relapse rate. No data exist yet about the effects of the two newer agents under these circumstances, Dr. Kita said.