Multiple Sclerosis Research: #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.

CoI: Multiple