Saturday, 15 July 2017

#ClinicSpeak & #ThinkHand: therapeutic lag

At times I feel like I am trapped in an echo chamber shouting therapeutic lag. #ClinicSpeak #ThinkHand

The Wheelchair Kamikaze raised the issue of responders vs. non-responders to ocrelizumab in the PPMS trial. I am partly to blame for this issue, but it is very difficult to know who is a responder and non-responder based on the current data from the ocrelizumab PPMS , or ORATORIO, trial. Why? Simply because clinical trials are designed, or powered, to get a significant read-out in a reasonbale period of time, for example 2-3 years. Does this mean that pwPPMS who don't read-out in that period are non-responders? No it doesn't, because it takes much longer to see a response to treatment in pwMS who are older and have less reserve capacity in the particular pathway (usually the legs) being assessed.

The study below showed that interferon-beta treatment would probably work in PPMS provided the follow-up is long enough; in this case 7 years. In this study PwPPMS who had only been treated with IFNbeta for 2-years clearly do better at 7-years than those people treated on placebo over the same period of time. There was a lag in the onset of action of interferon-beta

Why a lag? One interpretation is that the impact of anti-inflammatory medications in progressive MS may take several years to play out. In other words progression in someone with PPMS over the next 2 years was primed by inflammation two years ago. Suppressing inflammation today will have no impact over the next 2-years as the damage priming progression over the next 2 years has already occurred. All anti-inflammatory therapies will have a lag in terms of showing a treatment response in progressive MS.

I hope this concept makes sense.

To illustrate this concept I drew this picture, which has now been published in our length-dependent axonopathy paper. I hope you can understand it. Interestingly, the actively-treated subjects only did better than placebo-treated subjects on terms of upper limb function (9HPT), cognition and brain volume loss. There was no difference in terms of the EDSS (and T25FW), which in more advanced MS is essentially a walking scale. The reason why there was no difference in lower limb function is almost certainly due to loss of reserve, i.e. too many nerve fibres supplying the limbs had been damaged already for an anti-inflammatory to make a difference. The other issue is that in this study the treatment period was too short. Please note this study is only one of many studies showing the same effect, a greater impact of anti-inflammatory therapies on upper limb than lower limb function and is one of the reasons that is underpinning our #ThinkHand campaign. 

In the ocrelizumab PPMS, ORATORIO, trial the treatment effect was almost double in the arms compared to the legs. This is why I have little doubt that ocrelizumab is effective in PPMS. If the trial was extended for longer the treatment effect on lower limb function will have gotten greater simply because of lag. 

I am convinced we are correct about 'therapeutic lag' and the MS community is starting to take it into account when designing progressive MS trials. This means being clever about our studies and getting the regulators to accept the 9HPT as a primary outcome measure. The MS community have made it clear that they value arm and hand function more than leg function, we now need the wider community to help get this message across. There is also an economic argument for taking DMTs into wheelchair users to protect upper limb function; once people lose their arm function they lose their independence and the costs, both medical and social, for looking after these people is very high.

If you agree with therapeutic lag then you have to support our petition to the regulators and payers about the significance of the ocrelizumab PPMS results.

Tur et al. Interferon Beta-1b for the Treatment of Primary Progressive Multiple Sclerosis: Five-Year Clinical Trial Follow-up. Arch Neurol. 2011 Nov;68(11):1421-7.

OBJECTIVES: To investigate, during the 5-year period without treatment after termination of a 2-year clinical trial of interferon beta-1b for the treatment of PPMS.

MAIN OUTCOME MEASURES: After 5 years without treatment, the EDSS and MSFC measures were scored for 63 and 59 MSers, respectively. Neuropsychological and magnetic resonance imaging assessments were performed for 59 and 50 MSers, respectively.

EDSS = Expanded Disability Status Scale
MSFC = MS Functional Composite ( a composite 3 tests the PASAT, 9-hole peg test and the timed 25-ft walk)
9-Hole Peg Test = test of upper limb function
Word List Generation Test = cognitive task

RESULTS: After 5 years without treatment, the interferon beta-1b group had better 9-Hole Peg Test (p=0.02) and Word List Generation Test (p<0.001) scores, and MRI measures in the normal-appearing white matter were significantly better. During the entire study period (from trial baseline to assessment at 5 years without treatment), the placebo group showed a greater decrease in brain volume (p=0.004). The in-trial increase of lesions correlated with the worsening of the EDSS score during the 5-year period without treatment (p =0.004).

CONCLUSIONS: Modest but beneficial effects of interferon beta-1b on clinical variables and brain atrophy development were observed 5 years after trial termination. Moreover, in-trial lesion activity correlated with EDSS progression after trial termination. Therefore, we provide evidence to consider immunomodulation as a sensible approach to treat primary progressive multiple sclerosis.

CoI: multiple


  1. "The MS community have made it clear that they value arm and hand function more than leg function".

    Prof G - I think we need a correction here. People with MS (like all people) want full leg and arm function (I would have loved to have run the 10k with you). All we are saying is that once our leg function goes, we would welcome treatments to preserve our hand function. NEVER interpret MSers as being happy with their lot when they lose their leg function but retain enough arm function to operate their wheelchair of complete a stupid nine hole peg test. The best doctors get their patients better i.e. they get the patients back to full health / function. I've always felt short-changed by neurologists as their offer is pretty thin i.e. can't do anything to get you walking again but continue taking the medicine and we can preserve you ability to brush your own hair for a few years longer! This doesn't come across as a major breakthrough.

    1. I agree. Preserving leg function is critical. But there are therapeutic nihilists out there who start DMTs late and stop them early. Our #BrainHealth is about early effective treatment and rapid escalation. The #ThinkHand campaign is to not stop treatments too early and to not give up on pwMS who are 'too disabled'. All we are trying to do is help pwMS regardless of where you are in the course of your disease.

    2. Anonymous 11:10 am-this is the best response I have ever read. There seems to be a massive disconnect between neurology/researchers and MS patients as to what MS patients need or wants.

      It is great that Dr. G. believes in length-dependent axonopathy and therapeutic lag and he is probably right, although not really sure how this magically will bring back damaged axons and myelin. Dr. G knock yourself out and study for the next 15 years but most of us do not have the luxury of this time. We believe you that all MS patients should be on a potent anti-inflammatory med early and prolonged and will leave this up to you to prove to governing bodies.

      We need neurodegeneration, remyelination and neurorestoration medications today, not in 15-20 years from now. We already have ~20 anti-inflammatory medications that generate 20+ billion/year revenue for pharma with pitiful effect on the progressive stage of the disease, including ocrezulimab and siponimod.

      Dr. G how do you know that stopping neurodegeneration or improving neuro-restoration and remyelination would not stop inflammation? Why is 3/4 of your treatment pyramid completely ignored by neurology/pharma to this point in time?

    3. "Dr. G how do you know that stopping neurodegeneration or improving neuro-restoration and remyelination would not stop inflammation?"

      Precisely. Spot on.

  2. Dr. G, thanks for the lengthy clarification. I still find it somewhat distressing that the Ocrevus PPMS study was frontloaded with patients who were likely responders, including twice as many with enhancing lesions than would be found in the general PPMS population. Makes it appear that the study was playing with loaded dice.

    That said, if your therapeutic lag theory is correct, and PPMS patients could have been benefiting from DMT's all of these years (I noticed that the interferon study you posted was from 2011), then it is tragic and even scandalous that such treatments have been withheld from progressive patients who have been left to simply watch themselves wither away.

    Still, if you look at long-term retrospective studies regarding HSCT – which might be looked at as the most draconian of immune related DMT's – it does appear that progressive patients fair much worse than their relapsing brethren, at least in regards to this form of therapy. I'm only citing numbers from memory here, so they might not be absolutely accurate, but a recent longitudinal HSCT study found upwards of 70% of Relapsing patients progression free at five years, but only about 35% of SPMS patients free of progression over that same time period. I would suspect that those SPMS patients that were progression free likely had more active disease (i.e enhancing lesions, etc.).

    Unfortunately, there were too few patients with PPMS included in the study (I believe there were only five, and only one was tracked for five years – that one patient had progressed). These results would seem to indicate that this therapy works best on patients with active inflammation ongoing in their CNS.

    Here's the link to this study:
    Longitudinal HSCT Study

    I would imagine that this is why the recent British inclusion criteria for HSCT included only those PPMS patients with enhancing lesions.

    Though HSCT is not the same type of therapy as long-term immunosuppressants such as Ocrevus, it does seem like these results can be used, at least in part, to evaluate the efficacy of immune system -related therapies as a whole.

    I'd also like to reiterate what the first commenter stated. It's all well and good to have drugs that slow the progression of disability, but I fear the very success of the current crop of DMT's has shifted much of the focus of MS research away from searching for the actual cause (and thus, cure) of MS and onto finding newer and better ways of suppressing the immune system. The success of these drugs, of course, has been of huge benefit to the pharmaceutical companies, but may actually work against the long-term interests of MS patients who desperately seek a cure. They may tangentially shed some light on MS causality (for example, B cells harboring EBV), but certainly don't directly address the issue.

    1. Thank you again, WCK - I am so grateful for your honest, grounded contributions to this blog.

  3. You have only one paper supporting you theraputic lag theory? And I wonder how better neuroprotectives would be for people with progressive MS, any kind of MS? Do you know that neuroprotectives wouldn't dampen down the inflammatory response?

    1. Neuroprotectives are the huge unmet need, not only in MS, it's an area we as a group have been working hard on for well over a decade but translation to pwMS remains frustratingly slow/absent as pharma still puts all its eggs in the immunomodulatory basket.
      On your second point, at the doses you would use for a neuroprotective there isn't likely to be any significant effect on the inflammatory response. High does might for some candidate compounds but the side-effects would be likely to be too severe for this to be realistic. In our mouse studies, we carefully titrate the dose so we can dissociate a true neuroprotective effect from any action of the inflammatory response.

    2. Thanks for you response MD2.

      I wondered about neuroprotectives more from the point of view of the unknowns of MS pathology, i.e. we don't know (as far as I know) that the unhelpful inflammatory response of the immune system is not in the first instance being triggered by neurodegeneration. So maybe, if this neurodegeneration can be controlled by neuroprotectives (early enough), the immune system does not start this diabolical cascade typical of MS? This has never been tested.

      My pet theory is that some individuals show a high degree of inflammatory response - RRMS. Whilst others (like me) have neurodegeneration but less pronounced immune system involvement - PPMS.

      At any rate, I certainly think that immune system modification is starting at the wrong end. Until we have good neuroprotectives, MS will remain a very slippery and dangerous serpent. (Though a lucrative one for pharma...)


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