Tuesday, 5 September 2017

#ClinicSpeak: managing PPMSers expectations

Are you expecting to be eligible for ocrelizumab under the NHS? #ClinicSpeak #MSBlog #MSResearch

Summary: This post is an attempt to dampen enthusiasm amongst PPMSers for ocrelizumab and to manage expectations in relation to what we can expect from NICE. 

It may seem to you that in recent days that HSCT has taken over the blog. It hasn't so let's get back to basics. I want to dampen down your enthusiasm for the emerging DMTs, i.e. ocrelizumab and oral cladribine. As with all DMTs their effectiveness will depend on how soon they are given. If they are started too late and you have acquired a lot of damage from your MS in the past, and you have already noticed worsening of disability prior to starting them, you may not necessarily notice a major treatment effect.

I have always warned that we should not expect too much from the first effective anti-inflammatory DMTs in more advanced MS (formerly progressive MS). They will not be miracle drugs. The ocrelizumab results in PPMS are in line with these predictions.  I would like to remind you of the survey we did on this blog a few years ago (see slideshow below); about 40% of progressive MSers were expecting an effective DMT to improve their functioning or to result in a full recovery. This has not happened; at best ocrelizumab may stabilise your disease or more likely slow down the rate of disability worsening. Due to therapeutic lag, length-dependency and reduced neuronal reserve ocrelizumab is better at slowing down worsening in upper limb function compared to lower limb function. This is an important observation. Another factor is age. In the ORATORIO study pwPPMS had to be 55 years of age or younger. An analysis done for the ATGA (Australian Therapeutic Goods Administration) showed that pwPPMS 50 years of age or younger, and those with active MRIs, did better than older study subjects or those with out active baseline MRIs. This is not unique to ocrelizumab and was also seen in the Rituximab PPMS trial. The following is the paragraph from the ocrelizumab ATGA product information sheet

'A post-hoc analysis suggested that patients who are 50 years of age or below, or patients who have inflammation determined by MRI (Gd enchancing or T2 lesion) may receive a greater treatment benefit than patients who are over 50 years of age or patients who do not have inflammation by MRI.'

It will be interesting to see how age and MRI activity will affect the NICE cost-effectiveness analysis of ocrelizumab. I can envisage a scenario in which NICE may limit the prescribing of ocrelizumab on the NHS to patients with PPMS who are 50 years of age or younger and to those with active MRI scans. This may be very disappointing for older subjects, but in the era of austerity Britain, we need to be realistic about what the NHS can, and cannot, afford. To address this problem I think we need to start doing trials in older and more disabled patients targeting upper limb function as the primary outcome measure. The latter is one of the aims of our #ThinkHand campaign.

An even worse outcome will be if NICE says no to ocrelizumab in PPMS. This will create all sorts of problems for us, including inequity of access. This is one of the reasons why I ran the recent survey on this issue on the blog.  

Despite my relative pessimism ocrelizumab as a moderately effective treatment for PPMS is a start and will allow us to begin to target different pathological processes in MS with the hope of developing add-on neuroprotective and neurorestorative therapies. Innovation tends to be incremental; having an effective anti-inflammatory therapy for progressive MS provides the treatment at the base of the pyramid; we now need to add the neuroprotective, remyelinative and neurorestorative tiers on top.






CoIMultiple

10 comments:

  1. What about cladribine? You mention it but don't discuss it in any detail.

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    1. I will need to do a specific post around cladribine. But the issues raised are not that relevant in that cladribine has been licensed for relapsing-forms of MS.

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  2. Thanks for this post. Hyperbole surrounding Ocrevus for PPMSer's, at least here in the states, has reached a fever pitch, especially on social media. Expectations are being raised beyond anything that is reasonable. Some sober words are extremely welcome.

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  3. How do you (or any of your Bart's neurologists) treat any of your current progressive or advanced patients in your clinic today, not in 10-20 years from now, when a successful neuro-protectant, remyelination and neuro-restoration product is available? Do you go off-label?

    It may be naive on my part but why have these neuro-protectants, remyelination and neuro-restoration products not been worked on CONCURRENTLY and not sequentially after the anti-inflammatory model has not been very successful in progressive patients?

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    1. We have been using various drugs based on phase II evidence, recently mainly off-label cladribine: https://www.slideshare.net/KlausSchmierer/bartsms-informationpackcladribine

      Your second question is one we have been asking for a long time; it would be ideally suited for a trial design the MS Society has been toying for some time. There may be more appetite for this once the MS-SMART trial has been analysed.

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  4. Not gonna put my name on thisTuesday, September 05, 2017 7:42:00 pm

    Will you continue treating with injectable cladribine if PO cladribine is approved?

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  5. Thanks for your response and time Dr. Schmierer.

    Any luck with Cladribine in progressive MS treatment thus far? What other therapies would you suggest that a progressive patient should talk about with their neurologist currently? If you or a family member were to have progressive forms of MS, what would you suggest taking/doing?

    Time is not a luxury that progressive patients have on their side. Current patients with progressive MS do not have 10-20 years to wait for trial designs, results and approval. I just would like to know what your current approach to your progressive MS patient is today? Thanks again for your help.

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  6. Forgive me the impertinence, but were you not extolling the virtues of beta interferon, or any DMT for PPMS on this blog a little while ago? I find a lot of inconsistecy of approach on this blog.

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    1. I will never extoll the virtue of any of the CRAB drugs as I am not convinced of their virtues, although I accept they may do something. In animals their activities are in most cases marginal. Their use was not based on logic that I bought into or was wrong.

      In terms of influence on rate they are not that great.

      I also do not extol the virtue of immunosuppressive for progressive ms although they clearly have value if there is evidence of disease activity.ProfG is extolling this.
      He will also extol the virtue of beta also.

      We are our own people and are not a collective cyborg so we will have differences in opinions for some things but tend to sing from the same have a look sheet

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    2. Thank you for this clear and forthright answer.

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