NEDA-4 – an update


REPORT FROM THE 67TH AMERICAN ACADEMY OF NEUROLOGY (AAN) ANNUAL MEETING – WASHINGTON DC, APRIL 18-25, 2015 – A number of analyses of phase III studies have shown that about one-third of patients treated with a higher efficacy disease-modifying therapy can achieve no evidence of disease activity (NEDA), defined as no relapses, no MRI activity and no EDSS progression (see Optimizing patient assessment in MS: NEDA and beyond, NeuroSens, March 12, 2015).

Moreover, preliminary data suggest that 2-year NEDA rates are prognostic of better outcomes at long-term follow-up. In the STRATA extension study (which included patients from AFFIRM), at 7.4-year follow-up the mean ARR was 0.08 in those with NEDA in the first two years of treatment and 0.13 in those who didn’t achieve NEDA (O’Connor et al. AAN 2015; abstract P7.221). The cumulative probability of EDSS progression confirmed at 6 months was 23.3% and 37.5%, respectively, for the two groups. An improvement in EDSS scores was seen in 38.7% and 26.8%, respectively, in the NEDA+ and NEDA- groups. 

A further refinement of this aggregate metric is NEDA-4, which includes no brain volume loss beyond the extent seen in healthy controls (a cut-off value of 0.4%/year has been proposed). In one analysis to date, 19.7% of patients receiving fingolimod 0.5 mg in the FREEDOMS and FREEDOMS II trials achieved NEDA-4 compared to 5.3% receiving placebo (odds ratio 4.41) (Kappos et al. ECTRIMS 2014; abstract FC1.5). (New/enlarging T2 lesions but not new Gd-enhancing lesions were used for the MRI component.)

A new post-hoc analysis of data from the two phase III studies has examined the NEDA-4 rate in the subset of patients with high disease activity at study entry, defined as >1 relapse in the preceding year, or >1 Gd-enhancing lesion or >9 T2 lesions at baseline (De Stefano et al. AAN 2015; abstract P3.246). The NEDA-4 rate at two years was 20.5% in the fingolimod group compared to 3.90% in the placebo group (OR 6.35). The cut-off value for annual percent brain volume loss was 0.4%, but similar differences were seen with other cut-off values. A separate analysis of patients stratified by age reported a NEDA-4 rate of 15.7% in fingolimod-treated patients aged 30 years or younger compared to 2.8% on placebo (OR 6.37) (Ghezzi et al. AAN 2015; abstract P3.277).

For the TRANSFORMS trial comparing fingolimod with intramuscular IFNb-1a, the one-year NEDA-4 rates were 27.9% with fingolimod and 16.7% with IFNb (OR 1.93) (Montalban et al. AAN 2015; abstract P4.001). In the subset of younger patients, the NEDA-4 rates were 21.0% with fingolimod and 8.7% with IFNb (OR=2.77) (Ghezzi 2015).

Guest Reviewer: Dr. Daniel Selchen, Head of Neurology, St. Michael’s Hospital, Toronto, Canada

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