Is No Evidence of Disease Activity an Achievable Goal in Patients with RRMS?

VBCN - July 2014 Volume 1, No 2

Philadelphia, PA—Achieving no evidence of disease activity (NEDA) in the treatment of patients with relapsing-remitting multiple sclerosis (RRMS) is a clinically meaningful goal, but a strategy to achieve it remains untested, said Robert Bermel, MD, a neurologist at the Mellen Center for Multiple Sclerosis, the Cleveland Clinic, at the 2014 American Academy of Neurology meeting.

The idea of a “treat-to-target” strategy is adopted from rheumatologists who developed the strategy in the last decade for the treatment of rheumatoid arthritis. The principles are early and aggressive treatment with rapid treatment escalation to target remission.

Newer, more effective drugs for RRMS and the widespread availability of magnetic resonance imaging (MRI) to monitor the inflammatory component of the disease while the patient is receiving treatment make NEDA a worthwhile and potentially achievable management goal, said Dr Bermel.

Clinical and MRI monitoring while receiving therapy are common approaches, although there are no standards or defined targets in the clinic. As such, NEDA has been a therapy goal defined only in the clinical trial setting.

The adoption of a treatment target into clinical practice will mean overcoming challenges, including the need for agreement on how to define the target and how to accurately measure response to therapies for MS, said Dr Bermel. The definition of NEDA used in clinical trials is the absence of new or enlarging T2 lesions, the absence of new gadolinium-enhancing lesions, an absence of relapses, and no confirmed worsening on the Expanded Disability Status Scale (EDSS) score.

The concept of “disease-free status,” or NEDA, in RRMS was first reported after the completion of the AFFIRM study. Over 2 years, 37% of patients receiving natalizumab were free of disease activity compared with 7% of those receiving placebo. Similar superiority in achieving NEDA versus placebo was demonstrated in post hoc analyses for daclizumab in the SELECT study and peg-interferon beta at 1 year, and for cladribine in the CLARITY study, fingolimod in the FREEDOMS study, and dimethyl fumarate in the DEFINE study at 2 years.

“There is a great deal of enthusiasm in using NEDA as a measure in clinical trials and in employing it in the MS clinic to potentially guide care as a treatment target,” said Dr Bermel.

Evidence is developing that achieving NEDA is clinically meaningful, he noted. In the AFFIRM study, NEDA status correlated strongly with brain atrophy, cognition, ambulation, vision, disability management, and patient-reported outcomes at 2 years. Cognition was significantly improved, and measures of brain atrophy had a tendency to be lower in patients who met the NEDA criteria compared with patients who did not. “It looks like 2 years of early treatment achieving NEDA actually portended quite the long-term benefit and segregation among groups,” Dr Bermel pointed out.

NEDA can be a realistic outcome goal, although existing immunomodulatory and disease-modifying drugs do not address the entire pathology of MS, he said. Up to 47% of patients in clinical trials have been able to achieve NEDA with a treat-to-target strategy, although a comprehensive strategy remains untested. “It’s quite possible that although we achieve suboptimal results with a single agent in a single clinical trial, when we implement a strategy of changing therapies based on the NEDA treatment target, that we can achieve significantly better results,” he said.

The evidence also supports that short-term disease control has long-term benefit. In the ASSURANCE study, early MRI relapses while receiving interferon predicted poor long-term outcome. In fact, “MRI activity on interferon was the dominant factor predicting EDSS worsening,” Dr Bermel said.

Implementing the NEDA strategy seems complex in the clinic, he noted, because there is no consensus on the appropriate way to analyze MRI, and there is no easy way to track the components of NEDA in most electronic medical records. Furthermore, the threshold to act, be it a new T2 lesion or a relapse, and how to act, are unclear.

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