ECTRIMS 2021 | The predictive value of NEDA-3 for long-term disability in MS

So we conducted a systematic review and meta-analysis to evaluate the relationship between no evidence of disease activity or NEDA, and no long term disability progression in relapsing-remitting MS. I think a key question today, as we take care of MS patients, is whether we can determine an early evidence-based benchmark to help guide us in determining optimal response to disease modifying therapy in MS. So of course we’re fortunate that we have higher efficacy therapies today and the treatment landscape has been evolving, and I think there’s a sense that we can aim for a higher standard in terms of disease activity than we did in the past. But we still need to know what do we consider to be a treatment failure early on, and when should that motivate a switch in therapy? So even when people with MS start on high efficacy therapy, sometimes we see breakthrough disease activity with new relapses, new lesions or disability progression, and we want to be able to optimize their outcomes long term.

So in this systematic review and meta analysis, we analyze NEDA over the first one or two years on therapy. We used NEDA-3, which is defined in the typical way by no relapses, no new T2, or gad-enhancing lesion on MRI, and no disability progression. And we required a minimum of four years of follow-up for determination of long term disability progression. And we decided to analyze studies that were done on platform versus high efficacy therapy separately. And the reason for that is we know that rates of achieving NEDA are substantially different based on therapy type. On average, we saw that about 30% of people achieved NEDA at two years on platform therapy compared to 50% on high efficacy therapy. And we were able to identify many studies, so we had 27 studies that entered the meta analysis that covered nearly 11,000 participants, and we’re also very grateful to the many investigators around the world who contributed data to this project.

So what do we find? Our primary outcome was the odds ratio for no disability progression with NEDA compared to EDA, or evidence of disease activity. And we did see a significant predictive value of NEDA on both platform and high efficacy therapy. However, the odds ratios were relatively moderate in magnitude. And we do know that if somebody has a single new MRI lesion, it doesn’t necessarily portend a poor prognosis. So the moderate magnitude in the odds ratios seem to be driven by the fact that many with evidence of disease activity, or EDA, still did relatively well long term. However, the predictive values of NEDA were quite high. They did decline modestly over time, which I think we know occurs with extended longitudinal follow-up in MS studies. So we know that it can be very challenging long term over 15 to 20 years to predict how people with MS are going to do.

And I think at the end of the day, the study leaves us with the question, how can we improve on NEDA-3 moving forward, in terms of determining an early optimal benchmark for treatment success in relapsing-remitting MS. So we have various candidates. We could consider using NEDA-3 or minimal evidence of disease activity or MEDA, or even NEDA-2, which is clinical NEDA with no relapses or disease progression, perhaps in combination with a biomarker such as neurofilament light chain, which captures elements of neurodegeneration. And hopefully our results do provide basis for comparing the performance of other early surrogate composite outcome measures moving forward.