ResearchSpeak: a New Year prediction

We need to focus on upper limb and bulbar function in progressive MS. #MSBlog #ResearchSpeak #MSResearch

Happy New Year! 


"The big challenge for 2016 is how we as a community, including the regulators, deal with the artificial separation between SPMS and PPMS. This is not a trivial issue and will affect how we manage MS and develop drugs for progressive MS going forward. As you are already aware ocrelizumab (anti-CD20) is effective in both relapsing-remitting (RRMS) and primary progressive (PPMS) MS. Will the regulators (EMA & FDA) give ocrelizumab a license for both RR & PPMS? If they do what will happen to people with SPMS? As you know I am a lumper, and not a splitter, and have rehearsed the arguments for making SP & PPMS the same disease many times on this blog.

What are the arguments for SP & PPMS being the same disease. MRI studies demonstrate that lesions on MRI in MSers with relapse-onset or PPMS are identical. The pathology and genetics of the two subtypes are the same. Similarly, when MS occurs in families and the first sibling develops RRMS the second and third siblings may develop either RRMS, or PPMS, in proportion to the incidence of these subtypes in the general population. The pathology of the two subtypes is similar. Once someone with relapse-onset disease develops SPMS it progresses, on average, at the same rate as PPMS. Importantly, a proportion of pwPPMS (~10-15%) will go onto to have relapses; although we classify these people as having progressive-relapsing disease they still have PPMS. I am not aware of any consistent biological differences between relapse-onset MS (RRMS & SPMS) and PPMS. In summary, relapse-onset MS (RRM & SPMS) and PPMS are the same disease.

If the regulators acquiesce and agree to lumping of SP & PPMS together they will have little choice but to give ocrelizumab a very wide indication. I suspect they may use other strategies to limit ocrelizumab's license, for example limiting its use to pwMS with active disease. The latter is usually defined as having had documented relaspes in the last 2 years or evidence of MRI activity in the last 12 months (increased lesion load or the presence of gadolinium-enhancing lesions).

My prediction is that ocrelizumab will be licensed for people with active MS regardless of initial presentation (relapse-onset or PPMS). The regulators will also limit its use to pwMS who are mobile. The latter criteria is based on the clinical trial entry criteria. So sadly MSers in wheelchairs will miss out yet again.

What about the people with inactive MS? If you are early in the course of the disease and you have inactive disease, careful monitoring is all that is required; if your disease becomes active you would then become eligible for DMTs. This wait-and-see strategy is how we practice already. If you have non-relapsing SPMS or PPMS (no relapses or MRI activity) but are still getting worse you will not be eligible for treatment. This does not necessarily mean that your disease is not modifiable. I suspect we have been unsuccessful in developing DMTs for this phase of the disease, because of poor trial design and our fixation with using the EDSS as a primary outcome measure. I remain hopeful that DMTs will help non-relapsing progressive MS for two reasons; firstly, I think there is a therapeutic lag and we simply need to do longer trials (please see previous post on this topic) and secondly, I think progressive MS affects different functional systems asynchronously; i.e. the asynchronous progressive MS hypothesis.

What is the asynchronous progressive hypothesis? I have made the argument in the past that the neurological systems to be affected first by progressive MS are those that have the most wiring and hence more likely to be hit by multiple lesions; this is why the motor system to the legs, bladder and the cerebellar or balance system are typically affected first when progressive disease starts. The other systems (vision, motor system to the upper arms, sensory system, cognition, etc.) tend to be affected later by 'overt' progressive disease. I say overt because there is evidence that the progressive component of MS is present from the start of the disease. The only reason we don't see it clinically is because the nervous system compensates. However, once the compensatory systems fail progressive MS ensues. This means that we may have different windows of opportunity to impact on these different functional systems. In other words there are multiple windows of therapeutic opportunity to act and we should therefore shift our focus in progressive MS on trying to delay the onset of progression in systems that are still not clinically affected by progressive MS. To do this we need to shift our focus away from the EDSS and use multi-dimensional outcome measures that focus on the importance of the other functional systems.

The natalizumab in SPMS trial (ASCEND Trial) supports this hypothesis; although it was considered to be a negative trial natalizumab did slow the rate of progression in loss of upper limb function. In my opinion this was a positive trial; once you lose the function of your legs your arms become your legs (see previous survey results). Despite the latter results and these new insights Biogen closed down their dimethyl fumarate (DMF) in SPMS trial. I have argued that this was a rather hasty decision as lessons learnt from the ASCEND study could have been applied to the DMF trial; adapting trials that are currently in progress is not a new concept. I am now convinced that our length-dependent axonopathy and asynchronous progressive MS hypotheses are correct. We should let these inform our current and future trial designs, i.e. adapt them and not stop them from happening.

My heart goes out to all the MSers with non-relapsing progressive MS. Don't get too despondent we will continue to work on getting progressive trials off the ground. We are currently in the process of designing a proof-of-concept study of testing a combination treatment in people with progressive MS who are EDSS 6.0 and above. Yes, we will include wheelchair users. We have also been lobbying Pharma to do the same. The primary outcome will deliberately ignore lower limb function and focus on the arms and bulbar function (swallowing and speech). From a Pharma perspective the problem with combination therapy strategies is that the regulators won't allow two novel agents to be tested simultaneously; in other words you have to take an already licensed treatment and add-on a second drug. The million, or billion, dollar question is which licensed DMT should be your platform treatment and what add-on drug will you use? We have some strong views on this and hopefully we will be able to generate good enough data in 2016, and beyond, to convince Pharma to do the necessary phase 3 trials to get a combination therapy licensed for non-relapsing (inactive) progressive MS in the future.

Our New Year message to you if you have progressive MS is that we won't give up on you, nor will we give up on your remaining arm and bulbar function."




CoI: multiple

Labels: , , , , ,