NEDA on natalizumab

Prosperini L, Fanelli F, Pozzilli C. Long-term assessment of No Evidence of Disease Activity with natalizumab in relapsing multiple sclerosis. J Neurol Sci. 2016;364:145-7.

In this study we assessed the proportion of patients with relapsing multiple sclerosis (R-MS) who had No Evidence of Disease Activity (NEDA-3), defined as absence of relapses, absence of confirmed disability worsening, and absence of radiological activity (detected by magnetic resonance imaging of the brain and spinal cord) up to 7 years after starting natalizumab. Out of 152 patients considered, 58 were still on treatment and 94 discontinued treatment after a median time of 3 years. According to an intention-to-treat approach, 52 (34%) patients maintained the NEDA status at the end of follow-up. The proportion of patients with NEDA increases to 41% after excluding from the analysis 64 patients who discontinued natalizumab due to concerns about progressive multifocal leukoencephalopathy. Our findings suggest that natalizumab may ensure higher proportion of patients achieving sustained long-term disease remission than that previously reported with self-injectable treatments (<10%).

"Intention to treat" means that not all people have stayed on the drug they could have gone onto a more or less effective drug, but are treated for the purposes of analysis that they stayed on drug a nd 35% are NEDA and maybe more like 40%. We know that Natalizumab is better than the self-injectables at stopping relapses and it is hardly surprising that it is better than them at inducing NEDA. Maybe it should be better than that.

But what is the effect of having NEDA and the long term outcome. This was reported atthe AAN

Evaluation of the NEDA (No Evidence of Disease Activity) measure for predicting long-term outcomes from the pivotal trial of interferon beta-1b in multiple sclerosis 

Douglas S. Goodin, MD; Anthony Reder; Ralf Koelbach; Christoph Pohl; Gustavo Suarez 

Objective: To examine the predictive value of NEDA for negative disability outcomes (NDOs). 
Background: Lack of disease activity is thought to be an important endpoint in clinical trials. Follow-up from the randomized trial of interferon beta-1b (IFNB-1b) in RRMS can be used to assess the importance of NEDA in predicting long-term outcomes. Design/Methods: NEDA was defined in two ways; 1) no relapses and no new T2-active lesions since Baseline during the first 2 years of treatment, and no confirmed 1-point EDSS progression by Year 2 (standard); and 2) no relapses and no EDSS worsening from Baseline to Year 2 (clinical). NDOs were death, need for a wheelchair, progression to unremitting EDSS ≥6, or secondary progressive MS after Year 2. 
Results: Following the randomized trial, 245 and 371/376 total patients were evaluated at 16 and 21 years, respectively. At 16 years, standard NEDA did not predict NDO. By contrast, clinical NEDA did predict NDO (p=0.0029), as did baseline EDSS (p=0.0033) with a trend for change in 3rd ventricular size from Baseline to Year 2 (p=0.0854). Neither definition of NEDA was significantly associated with cognitive performance at Year 16. Standard NEDA did not predict survival after 21 years. By contrast, there was a trend for clinical NEDA to predict time to death (p=0.0865), as did IFNB-1b treatment (p=0.0251), relapse rate in the 2 years prior to study start (p=0.0260), T2-BOD at Baseline (p=0.0014), and change in T2-BOD from Baseline to Year 2 (p=0.0129). 
Conclusions: Although clinical NEDA did predict long-term outcomes, this effect was not seen for standard NEDA, which included measures of T2-activity. Thus, the MRI measures of T2-BOD and 3rd ventricular size (atrophy) may be more useful than T2-activity as predictors of outcomes.

Whilst this study implies that NEDA may not predict out come in the long term, why should it if NEDA is not maintained. However NEDA with addition measures at 2 years did  have predictive value. Interferons are known not to be high effective treatments what results will be seen when high active agents are used in early MS. My prediction is a good correlation between NEDA and long term disability outcomes

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