My #ECTRIMS2019 highlight #3 is the elevation of fatigue to be the first secondary outcome measure in a clinical trial. Was this genius or a marketing coup? I would have loved to be a fly on the wall when the steering committee of the OPTIMUM study made the decision to bump fatigue to the top of the secondary outcomes.
If you have MS you know that the most troubling symptom the majority of MSers complain about is fatigue. Therefore for a DMT to be able to claim it reduces fatigue is a big deal. I suspect MSers will find the promise of fatigue reduction a very compelling reason to choose one DMT over another.
The Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis (OPTIMUM) study was positive. Compared to teriflunomide ponesimod reduced the relative annualised relapse rate (ARR) by 30.5% (P<0.0003) and3-month CDP (confirmed disability progression) by 17% (not significant).
If you recall this study was one of the studies we asked the Crowd to predict the results of. In fact, they were almost spot-on; they predicted that ponesimod would reduce the ARR and CDP compared to teriflunomide by 33.8% (interquartile range=24.5-44.3%) and 21.2% (interquartile range=10.0-25.0%), respectively. My interpretation is that the Crowd did very well; well done!
Please note that I will be contacting the winners of the #ECTRIMS competition very soon. There will two awards one for the OPTIMUM study and a second award for the ASCLEPIOS I & II studies.
When it comes to the S1P wars ponesimod is setting itself up very nicely to go head-2-head with newer entrants, i.e. siponimod and ozanimod. In my opinion, the safety profile of ponesimod is reasonably good, the lack of need for 1st-dose monitoring will put it alongside ozanimod in the S1P Me-Too wars. The question everyone is now asking ‘Will fatigue be the trump card?’. What do you think?
It is time to set in stone our #CrowdThink competition results. We had over 110 responses; thank you. If you want to know more about the rationale behind this competition you need to read my post on the DODO trial and the post explaining the rationale behind the COMPETITION.
Study 1: Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis (OPTIMUM).
The Crowd has predicted that ponesimod will reduce the ARR (relative annualised relapse rate) and CDP (confirmed disability progression) compared to teriflunomide by 33.8% (interquartile range=24.5-44.3%) and 21.2% (interquartile range=10.0-25.0%), respectively.
This would suggest that ponesimod is probably batting in the same league as fingolimod. I wouldn’t put too much weight on the TRANSFORMS study that compared fingolimod to interferon-beta-1a. The majority of subjects were failing interferon who went into that study and were then randomised to fingolimod or back onto interferon-beta-1a. This study inflated fingolimod’s relative efficacy as it was being compared to interferon-beta failures on interferon-beta.
Study 2: Efficacy and Safety of Ofatumumab Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis (ASCLEPIOS I & II)
The Crowd has predicted that ofatumumab will reduce the ARR (relative annualised relapse rate) and CDP (confirmed disability progression) compared to teriflunomide by 41.2% (interquartile range=34.0-49.0%) and 29.3% (interquartile range=20.0-37.3%), respectively.
These results are interesting and broadly put ofatumumab in the same ballpark as ocrelizumab as well; 41% is close enough in my book to 47% for it not to register as being meaningfully different to ocrelizumab. In comparison, 29.3% for CDP is too far away from 40% to be dismissed. The question is this because of ofatumumab being inferior to ocrelizumab? Or teriflunomide is superior to interferon-beta-1a (Rebif)? I would favour the latter interpretation. The former interpretation would support the hypothesis for the need to target intrathecal B-cells and that the higher dose of ocrelizumab is superior at doing this compared to the smaller but more frequent ofatumumab dosing. These results would support us pushing for the DODO study to be done.
However, would it not be a more interesting story if ofatumumab out-performed ocrelizumab? This would be against my predictions, but it opens a new vista on how anti-CD20 therapies work. If ofatumumab outperforms ocrelizumab it would argue for a peripheral mode of action, i.e. keeping peripheral B-cells depleted continuously, rather than using intermittent depletion paradigm of rituximab and ocrelizumab. It would also challenge the hypothesis that we need to have CNS penetration for targeting of the intrathecal B-cell compartment.
The peripheral B-cell hypothesis would raise very interesting questions about whether or not anti-CD20 therapy is working as an anti-EBV agent and keeping the memory B cell compartment, which hosts EBV, suppressed.
I have already been criticised by a few people at this conference for my musings on the potential results of these trial. Don’t we live in a world where free and open thought is allowed? I speculate and write these sorts of posts deliberately to be controversial. But I would hope that they stimulate you to think more deeply about MS and what these results could mean for us and in particular people with MS.
Let’s hope it is not the same-old, same-old; i.e. another me too study of an anti-CD20. Let’s hope the results support either the central B-cell depletion hypothesis or the peripheral-continuous B-cell depletion hypothesis. The former supports our programme of activities to scrub the brain clean of B-cells and plasma cells and the latter to treat MS with anti-virals, in particular, anti-EBV drugs.
To conclude, I was very disappointed that two-thirds of you chose the MRI lego set over my #ThinkSocial T-shirt as a prize. I am clearly not a very good T-shirt designer ;-(
The MouseDoc and I want to have a little bit of fun in anticipation of the late-breakers at ECTRIMS and at the same time do a thought experiment.
We want to see how wise the crowd is when it comes to predicting trial results.
Aware crowds may be wiser than individuals. In the book ‘The Wisdom of Crowds: Why the Many Are Smarter Than the Few and How Collective Wisdom Shapes Business, Economies, Societies and Nations’ James Surowiecki argues that the aggregation of information in groups, results in decisions that are often better than could have been made by any single member of the group. He opens the book with an anecdote about Francis Galton’s surprise that the crowd at a county fair accurately guessed the weight of an ox when their individual guesses were averaged (the average was closer to the ox’s true butchered weight than the estimates of most crowd members).
We want to see how wise you are when it comes to guessing the outcome of the two phase 3 trials programmes being presented at ECTRIMS. We know they are positive, but how positive is the question? To make it a competition we will be giving away two prizes; a lego MRI scanner set or one of our #ThinkSocial Bart-MS T-shirts. You can choose your prize.
Lego MRI scan set
Barts-MS #ThinkSocial T-shirt
Study 1: Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis (OPTIMUM)
Please note the Janssen Pharmaceutical Company announced positive top-line results stating the study met its primary and most secondary endpoints. As you know ponesimod is a second-generationn S1P modulator. The question is how good will it be compared to Teriflunomide? It may help to remind you that fingolimod, the first licensed S1P modulator, reduced the annualised relapse rate by 52% compared to interferon-beta-1a (Avonex) in the TRANSFORMS study, but had no significant effect on disability progression.
Study 2: Efficacy and Safety of Ofatumumab Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis (ASCLEPIOS I & II)
Novartis has announced that both of their phase 3 trials of ofatumumab vs. teriflunomide met their primary outcome. In ASCLEPIOS I and II, ofatumumab (OMB157) met primary endpoints to reduce the annualized relapse rate over Aubagio (teriflunomide) in patients with relapsing forms of MS (RMS) and that key secondary endpoints of delaying time to confirmed disability progression were also met.
Ofatumumab is a 3rd-generation anti-CD20 monoclonal antibody. Ocrelizumab is already licensed and was compared to interferon-beta-1a (Rebif) in two parallel phase 3 trials (OPERA I & II); ocrelizumab reduced the annualised relapse rate by 47% and the rate of 3-month confirmed disability progression by 40% compared to interferon-beta in these trials.
I have recently argued that ofatumumab may be underdosed and that as a result, it won’t do as well against teriflunomide (which has similar efficacy to Rebif), compared to what ocrelizumab did against Rebif. Do you agree with me or not?
So please complete the survey below and leave your email address and name if you want to enter the draw for the prize.
