Where to next for PPMS? #ClinicSpeak #MSBlog #MSResearch
Is PPMS a different disease?
Unlikely; all the evidence from epidemiological, pathological, genetic and clinical studies imply that PPMS and non-relapsing SPMS are the same disease. You must also remember that apart from one interferon-beta trial in relapsing-SPMS there has yet to be a positive phase 3 SPMS study. So SPMSers and PPMSers are in the same situation.
Is PPMS and intractable problem?
Yes and No. Yes, in the sense that by the time someone presents with progressive weakness in the lower limbs a clinically apparent progressive disease course is primed and can’t be modified by anti-inflammatory medications alone. The same scenario exists for other neurodegenerative diseases, for example Parkinson’s and Alzheimer’s disease. By the time someone presents with clinical dementia and diagnosed with Alzheimer’s disease it is probably too late to modify the course of the disease as too many neurons have been lost. The same applies for the motor symptoms and signs of Parkinson’s disease. This is why we have a research project to try and screen the population to detect PD early so that we can try and modify it in the pre-clinical phase, i.e. before too many neurons are lost in the pathways we want to protect. The same is probably true for PPMS; therefore, we need to focus on the pathways yet to be clinically affected by clinically-apparent progressive MS, for example upper limb, brain stem, vision and cognitive function. The latter is what underpins the asynchronous progressive MS hypothesis.
Do MSers with progressive disease have another pathology?
What I mean by this is that may be MS triggers a different pathological process that is not responsive to MS DMTs that have been shown to work in early MS. A good analogy is the rheumatoid joint; once rheumatoid arthritis damages the joint it triggers osteoarthritis that is driven by other processes that don't respond to anti-inflammatory medications. A similar thing may happen in MS. The strongest predictor for the onset of progressive MS is age. I suspect that inflammation in the brain triggers premature ageing and a large part of what we see with progressive MS is premature age-related changes. This may mean we require an additional therapeutic approach that targets ageing. Interestingly, simvastatin worked in SPMS in both year 1 and year 2 suggesting it is working on non-specific MS mechanisms. I suspect simvastatin is working as an anti-ageing drug, by impacting on age-related comorbidities (e.g. vascular disease). I suspect we may need to go this route in future trials, i.e. add simvastatin onto an anti-inflammatory drug.
Is fingolimod good enough?
Clearly it is not good enough. When you look at fingolimod’s impact on end-organ damage, i.e. it reduces brain volume loss to ~0.4% per year in year 2. 0.4% may not be good enough as this is as only at the upper limit of normal. In comparison, natalizumab and alemtuzumab reduce brain volume loss to ~0.20-0.25% in year 2, closer to the normal rate of brain volume loss, and they may reduce brain volume loss more than this in year 3 and beyond. Interestingly, with these two drugs you are more likely to get an improvement in disability another indication that they are more effective than fingolimod. However, in relapsing MSers fingolimod reduced and normalised CSF neurofilament levels at 12 months in the majority of treated subjects, similar to natalizumab treatment. On balance this data suggests fingolimod may not be up to the task of switching off smouldering inflammation in MS. This is why I am not giving up hope just yet, may be we need very high efficacy to have an effect in progressive MS; this is why we need to wait to see the results of the natalizumab in SPMS and ocrelizumab in PPMS trials.
Was the INFORMS trial long enough?
May be not. I have alluded to therapeutic lag on this blog many times. In the Barcelona PPMS trial it took 5 years follow-up to see an impact on IFNbeta on clinical outcomes. Maybe the INFORMS study needed to be longer.
Was the INFORMS treatment strategy correct?
I have been making the case for combination therapy strategy in progressive MS for a few years now. We need to build a treatment pyramid on top of anti-inflammatory pyramid. Novartis has been building a case for fingolimod being a dual-action drug, i.e. anti-inflammatory and neuroprotective. I think their claim may now be in tatters. If it was a dual-action drug it should have worked in PPMS. I think before shooting fingolimod down we need to wait for the second-half (all the results) and see what impact fingolimod had on upper limb function and other functional systems. Based on the asynchronous progressive MS hypothesis and therapeutic lag I suspect fingolimod will have a positive disease-modifying effect on neuronal systems with functional reserve, in particular upper limb function that was part of the composite outcome used in this study. If this is the case we as a community need to seriously rethink the way we are doing clinical trials in progressive MS.
Where to from here?
I want to do a progressive MS trial with our most potent anti-inflammatory therapies, preferably an induction therapy, in combination with a neuroprotective drug. At the moment I would punt for alemtuzumab in combination with laquinimod or simvastatin or cladribine in place of alemtuzumab. Why and induction therapy? Induction therapies are easier to use and guarantee adherence. Why laquinimod or simvastatin? Simple, we have proof-of-concept data that both these drugs are effective in targeting brain volume loss and disability progression.
"Finally, I want to thank all our patients with PPMS who volunteered for the INFORMS study. Without your contribution this study would not have been possible. Hopefully, we will learn and move on and insights from this study will lead to a treatment that works in PPMS. We are not going to give up or surrender. The challenge is simply not one game of football; I predict that by the end of the INFORMS game it will MouseDoctor 1: ProfG 1 and by the end of the tournament we will have a drug licensed to slow down the rate of progression for both SP & PP MS."
Labels: asynchronous progressive MS hypothesis, ClinicSpeak, fingolimod, PPMS, therapeutic lag, therapeutic pyramid