The need to rebaseline when using NEDA: ocrelizumab as an example. #ECTRIMS2016 #ResearchSpeak
Summary: This post looks at NEDA (no evident disease activity) as an outcome measure in clinical trials and in particular the issue of needing a new MRI scan, at a certain time point to set a new baseline, for comparison in the future. The latter is what is referred to as rebaseling.
In recent comments, the HSCT zealots have raised points about the use of NEDA as a treatment target and outcome measure to compare therapeutic strategies.
In the poster below there is little doubt that ocrelizumab is a highly effective DMT and shows why it is so important to rebaseline after an appropriate period of time before starting to monitor a treatment. For most maintenance DMTs 6 months is appropriate in that is pragmatic, logistically feasible and supported by data from clinical trials.
The analysis below shows that if you do this with ocrelizumab, then over 80% of subjects are NEDA from 6-24 months (figure 3). To the best of my knowledge this is the best NEDA data we have. I have yet to see HSCT rebaseling NEDA rates, but I suspect they will be in the same ballpark or higher.
The question I have asked my self is when is it appropriate to rebaseline after a IRT (immune reconstitution therapy)? I have argued in the past there is no point in doing it before you complete your course of treatment and are in a position to consider retreatment. For alemtuzumab and cladribine, this would be at 24 months. As an example, let's say we have a patient who has been treated with alemtuzumab and you do an MRI at month 12 just before her second course of treatment and find they have a Gd-enhancing lesion. Are you going to say the alemtuzumab has failed? No, you are not, as this person has not had the full course of treatment. What you should do is give this person the second course of alemtuzumab and then wait until 24 months to do the baseline MRI and start the clock ticking again. Therefore NEDA rates in the first 12 and 24 months on alemtuzumab and cladribine and other IRTs are not that helpful. What about with HSCT? The issue with HSCT is it a one-off treatment or do you think it should be used more than once? If the former then it makes sense to rebaseline at 6 months. In comparison, if you want to offer it again then how soon can you do a second cycle of HSCT? If 12 months or 24 months you may want to use these time points for rebaselining.
It is worth highlighting in the data below is the remarkable observation that 57% of the IFN-beta (Rebif) treated participants were also NEDA in the 6-24 month epoch. Based on earlier interferon NEDA data, this is much better than one would expect. It looks as if from contemporary trials that the efficacy of Rebif has improved. Why? One reason could be that the population of trial participants have included subjects with more benign MS or just maybe Rebif's efficacy has improved. I suspect both are correct. Most subjects in the Opera studies received RNF (Rebif new formulation). We know that RNF is associated with fewer NABs (neutralizing antibodies), which affect its efficacy; hence there are reasons to expect that Rebif's efficacy has improved. I am sure a lot of people will jump on the Rebif NEDA data to support its continued use as an effective DMT in the 'majority' of MSers. If you are risk averse and subscribe to the slow stepwise or even rapid escalation, treatment strategies for MS, why not?
I am interested to see how the regulators, payers and/or healthcare commissioners respond to this data. I sincerely hope the EMA give ocrelizumab a liberal label that will allow first-line use in pwMS with active disease. This will then allow HCPs and their patients to decide on which DMTs they want to use. However, as always in price-sensitive markets the payers and commissioner may have a different take on things particularly if ocrelizumab is priced at a premium.
Labels: #ResearchSpeak, HSCT, NEDA, ocrelizumab, Opera, rebaseling, Rebif, zealots