Ocrelizumab has a greater impact on protecting hand function than lower limb function #ThinkHand #ECTRIMS2016 #ResearchSpeak #MSBlog
“The poster below is another of my ECTRIMS highlights. As you know the ocrelizumab in PPMS, or ORATORIO, trial was ‘positive’ in that ocrelizumab reduced disability progression on the EDSS, compared to placebo, by 25%. A lot of you have been quite down on this result saying it is not good enough and was driven by the inflammatory subgroup. This is not correct, but that is a debate for another time. Please remember incremental gains; 25% reduction over 2-3 years may end-up being >50% over 5-10 years.”
“What is more important is the observation that the impact of ocrelizumab treatment on upper limb function was even more impressive; nearly double (45%) that seen on the EDSS (25%) and timed-25-ft walk (27%). Why the difference in outcomes between lower and upper limbs? I have made the argument many time before that if you have lost reserve capacity in a particular system, which is the case in the lower limbs in PPMS, then it takes longer to see a positive outcome; i.e. therapeutic lag. However, if you have neuronal reserve in a pathway, in this case the arms and hands, then you get a read-out in relation to anti-inflammatory effects sooner and to a greater degree. These results are therefore compatible with our length-dependent axonopathy and therapeutic lag hypotheses and stress the importance of our current focus on arm & hand function as the primary outcome in progressive trials.”
“I hope Roche are see the light and are tempted to do a trial in more advanced MS including a cohort of progressive MSers in wheelchairs. If I had PPMS I would want to be on ocrelizumab; I value my hand and arm function. The question is: ‘Is the MS community brave enough to do trials in MSers who are already in wheelchairs?’. MSers want this; see our survey results which or overwhelming in favour of MSers wanting wheelchair users to be included in trials. If Pharma won’t do it we will. Our challenge is to convince the world and to get funding in place to do our trial.”
CoI: multiple
“The poster below is another of my ECTRIMS highlights. As you know the ocrelizumab in PPMS, or ORATORIO, trial was ‘positive’ in that ocrelizumab reduced disability progression on the EDSS, compared to placebo, by 25%. A lot of you have been quite down on this result saying it is not good enough and was driven by the inflammatory subgroup. This is not correct, but that is a debate for another time. Please remember incremental gains; 25% reduction over 2-3 years may end-up being >50% over 5-10 years.”
“What is more important is the observation that the impact of ocrelizumab treatment on upper limb function was even more impressive; nearly double (45%) that seen on the EDSS (25%) and timed-25-ft walk (27%). Why the difference in outcomes between lower and upper limbs? I have made the argument many time before that if you have lost reserve capacity in a particular system, which is the case in the lower limbs in PPMS, then it takes longer to see a positive outcome; i.e. therapeutic lag. However, if you have neuronal reserve in a pathway, in this case the arms and hands, then you get a read-out in relation to anti-inflammatory effects sooner and to a greater degree. These results are therefore compatible with our length-dependent axonopathy and therapeutic lag hypotheses and stress the importance of our current focus on arm & hand function as the primary outcome in progressive trials.”
“I hope Roche are see the light and are tempted to do a trial in more advanced MS including a cohort of progressive MSers in wheelchairs. If I had PPMS I would want to be on ocrelizumab; I value my hand and arm function. The question is: ‘Is the MS community brave enough to do trials in MSers who are already in wheelchairs?’. MSers want this; see our survey results which or overwhelming in favour of MSers wanting wheelchair users to be included in trials. If Pharma won’t do it we will. Our challenge is to convince the world and to get funding in place to do our trial.”
‘Now that I can’t walk, my hands and arms have become my legs….’
a person with MS
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| ProfG looking smug having just won a rosette for his poster! |
CoI: multiple
Prof G how do you explain the poor effect of fingolimod on disability progression in PPMS? Are these results compatible with your theories?
Not ProfG, but here you are: Fingolimod is currently the odd one out, or perhaps the S1P modulators given we weren't shown EXPAND results on upper limb function yet? Perhaps the difference between S1P and B-cell depletion was driven by different demographic (age, active MRI)? We're discussing the hypothesis of length-dependency quite regularly, and one needs to remember what textbooks of neuroanatomy tells us that >50% of cortico-spinal (= motor) tract fibres terminate in the neck proportion of the spinal cord, which makes it even less surprising that when it comes to spinal cord pathology lower limbs and bladder function are affected earlier. I won the motion in favour of including pwMS in wheel chairs at ECTRIMS; will put up my slides shortly…
Re; "Prof G how do you explain the poor effect of fingolimod on disability progression in PPMS?"I can't. It may be simply that fingolimod was not effective enough as an anti-inflammatory. But this is unlikely to be the case as fingolimod was pretty effective in switching-off inflammation on MRI in the PPMS trial. The other possibility is that it may have something to do with the biology of fingolimod, and S1P receptors, within the CNS in relation neuroaxonal mechanisms.
When will ocrelizumab be available in the UK?
It will be in further trials later this year: https://clinicaltrials.gov/ct2/show/NCT02861014?term=ocrelizumab&cond=multiple+sclerosis&rank=523 sites in the UK (3 in London including BartsMS) are involved.There's likely going to be at least one more recruitung in the UK.
Will these trials be interested in poms sufferers who are relying on two sticks to get about in short distances and a mobility scooter for longer distances? Not currently in any meds apart from gabapentin and a station.
Justifiably, there is a lot of buzz around ocrelizumab, as it's the first which has shown efficacy on PPMS and it clearly shows how much science has advanced. Would you also consider it as an option for RRMS? If yes, where would you place it in the spectrum of the available DMTs? Is its efficacy similar to fingolimod?Regarding the comment about including those on wheelchairs in clinical trials and the ThinkHand campaign, isn't it going to result in vague outcomes? Those on wheelchairs have more disability, therefore more neurological damage. The scope of clinical trials is to have a clear outcome and I am afraid including those with more advanced disability will bias more clinical trials towards negative outcomes.
Based on efficacy it is in the realms of alemtuzumab
Dt – re including those with more advanced disability biasing clinical trials towards negative outcomes: what's the alternative? not having data that supports the use of DMTs in those in wheelchairs? having to rely on clinician's clinical experience to make decisions for people in wheelchairs because it's hard to obtain efficacy data on them?i don't quite understand. if the worry is that the results will be tainted – well, lol, that remains the problem in real life even if you don't do the clinical trail on people in wheelchairs. but more than that, it is actually possible to do 2 trials – one for people with an EDSS lower than the wheelchair threshold (which might need different endpoints) and one for people with lower EDSS score. don't they currently have different trials for PPMS, SPMS and RRMS? – it's a similar concept. The alternative is to call for decision making to be evidence based, unless it's too hard to deal with a certain group of people in which case we'll forget about evidence and just use our acumen?
What is your opinion about risks/side effects for PPMS patients? My neuro prefers Rituxan but most insurance in U.S. will not cover it.
Ocrelizumab is positive for PPMS and yet Natalizumab is negative for SPMS. Is PPMS different i.e. "under the microscope" than SPMS? Also, since they are both mabs and do not cross the BBB but act on the immune system in the periphery are we saying that dysfunctional B-cells are more important in progressive disease than T-cells? Does the rest of the neuro community and Biogen accept that the ASCEND trial was flawed and that there is benefit in progressive MS?
Re: " Does the rest of the neuro community and Biogen accept that the ASCEND trial was flawed and that there is benefit in progressive MS?"Not sure. I suspect Biogen know they can't get an indication for SPMS based on the current trial. The results of the two studies are compatible with each other. The ASCEND studied a much more advanced (median EDSS = 6.0) and the ORATORIO a less advanced population (media EDSS = 4.5). The ORATORIO was also by design a longer study (120 weeks). All this means, based on the hypotheses referred to above, that the ORATORIO had a much greater chance of being positive on leg or lower limb function.
Alot of people have taken these drugs and the obvious ones will be B dependent infections that will crop up.
My only concerns are about the most effective DMTs to come, and that target B cells: risk of opportunistic infections and cancer…
although not part of the trial do people believe that Ocrelizumab would be effective in secondary progressive?
Re: "although not part of the trial do people believe that Ocrelizumab would be effective in secondary progressive?"Yes. I suspect we will be able to identify a population of MSers who have SPMS in the two OPERA (RRMS) studies that will allow a post-hoc analysis.
"If I had PPMS I would want to be on ocrelizumab"Even with the shadow of breast cancer in later life? That scares me. I am afraid of what more PPMS may do to me in the future, but mine is quite slow moving thus far. I'd find the decision to take this drug difficult.
My same thought. Even one of my neuros thought the safety profile was ominous. He prefers Rituxan bc safety history is much better. I'd rather be in a wheelchair than face cancer as a single mom. Would need a lot more information about the risks — both in terms of cancer and the serious infections.
Another thought…are there any concerns that this drug could cause the kind of relapse I suffered when I came off Tysabri? Will there be a general rule at any point, as more drugs come on the market,that patients need to be managed with alternative medication if they switch therapies?