Prof G what is therapeutic lag?

Worsening disability in someone with progressive MS over the next 2 years is primed by inflammation from years ago. Suppressing inflammation today, therefore, will have little, or potentially no, impact on worsening disability over the next one to two years as the damage priming progression over this time has already occurred. Therefore, all anti-inflammatory therapies will have a lag in terms of showing a treatment response in progressive MS.

The PPMS Barcelona study of interferon-beta-1b treatment was negative after 2-years of treatment; there was no difference between pwPPMS who had been treated with IFNbeta or placebo. The investigators’ concluded that interferon-beta was ineffective in PPMS. However, when these patients were reassessed 5-years after the end of the study there was a clear benefit (clinical and MRI) in favour of the interferon treatment. Based on this, and other observations, we have proposed that in progressive MS there is a lag between the onset of action of anti-inflammatory medication and its impact on the biology that underpins progression.

The impact of anti-inflammatory medications in progressive MS takes several years to play out in the system that is already in the ‘clinically apparent’ progressive phase. Please note the biology that results in progressive MS is there from the start. The only reason you don’t see progression clinically early on is that several compensatory mechanisms allow you to continue functioning relatively normally. Once these compensatory mechanisms have been shredded gradual worsening becomes apparent.

In progressive MS, worsening disability over the next 1-2 years is primed by focal inflammatory events that have occurred in the past. Therefore, suppressing inflammation today in progressive MS will have not have an impact over the next 1-2-years as the damage that has primed progression has already occurred. This is what I call therapeutic lag and it occurs with all anti-inflammatory therapies. Importantly the more disabled you are the longer the lag. Why? The more disabled you are the less reserve you have and therefore you are unable to compensate nor recover function.

This diagram below illustrates the concept of the therapeutic lag. The natalizumab SPMS trials (ASCEND) was only 2-years in duration, which explains why it was negative. However, at 3-years the trial became positive because of lag.

Neurological systems to be affected first by progressive MS are those that have the longest, or 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 clinically-apparent progressive disease starts. The other systems (vision, motor system to the upper arms and face, sensory systems, cognition (poorly tested), etc.) tend to be affected later by ‘overt’ progressive disease. I say overt because there is now good MRI evidence (brain volume loss, black holes, slowly expanding lesions (SELs)) that the progressive component of MS is present from the start of the disease. The only reason you don’t see progression clinically is that your nervous system compensates for the damage. However, once the compensatory systems fail in a particular pathway progressive MS ensues. What this means is that we may have different windows of opportunity for treatments to impact on the different functional systems. In other words there are multiple windows of therapeutic opportunity to act in MS and we should, therefore, shift our focus in progressive MS away from the systems already in the clinically progressive phase to those systems that still have reserve capacity and not yet in the clinically progressive phase, for example, arm and hand function (#ThinkHand).

In the natalizumab SPMS or ASCEND study, this is exactly what happened. The trial was positive on upper limb function (9-hole peg test) at 2-years, but not on the EDSS and the 25-foot timed walk, which are driven by lower limb function. If the ASCEND trial has been event-driven or was done for 3-years it would have been positive and we would have almost certainly had natalizumab licensed for SPMS. This is why I am so keen for Biogen to the ASCEND-2 study and extend it into wheelchair users. So far I have been unsuccessful in covincing them to do the study. Can you help?

The implications of the therapeutic lag and asynchronous progressive MS hypotheses is that we have been designing, and doing, trials in progressive MS incorrectly. More importantly, these concepts challenge the so-called therapeutic window concept. It also means that instead of writing someone off with progressive MS because their so-called therapeutic window has closed is that we can now focus on the other therapeutic windows that are still open.

It has never made sense to me not being able to prescribe a DMT to pwMS simply because they needed a wheelchair as a result of a devastating spinal cord relapse. What about their upper limb, cognitive and cerebellar function? Do we simply write these systems off because one, or two, systems are severely damaged? I personally think the therapeutic lag and asynchronous progressive MS hypotheses gives pwMS hope; hope for treatments that can at least preserve the function of pathways with reserve capacity, whilst we work on remyelination and neurorestorative strategies. This will at least buy us time and spread hope!

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 pwMS, respectively. Neuropsychological and magnetic resonance imaging assessments were performed for 59 and 50 pwMS, 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

4 thoughts on “Prof G what is therapeutic lag?”

  1. Dr. G you state "several compensatory mechanisms allow you to continue functioning relatively normally". This is probably a stupid question but are any of these compensatory mechanisms currently known? Why do they diminish as one ages with MS or when transitioning from RRMS to a progressive state about 15 years into the disease?If one was able to maintain their reserve then one would not progress and would continue to always remain remitting relapsing state rather than SPMS or in the case of PPMS not progress. It seems reserve capacity is extraordinarily important yet understudied?

  2. Compenatory mechanisms(a) Remyelination. This is the default pathway in animals so must occur in humans too. Indeed we see it by the presence of shadow plaques with thinnly remyelinatated axons.(b) Synaptic plasticity. Like the internet the information finds its target maybe by a different route. We can see this with fMRI functional magnetic resonance. In health do a task and maybe two brain areas light up, but in MS it may be 3 or 4 areas that are by-passing the MS road-block. This requires more brain energy and so contributes to fatigue no doubt.These processes diminsh with age, MS or no MS we are loosing nerves from the time we re 35 maybe 0.1% a year so in 10 years we have lost 1% and 50 years 5%. But in MS the rate is about 0.4-2% in alzheimers it is 1-4%. So in MS at 1% a year in 10 years you loose 10%. Whilst this process is occuring from disease onset until you reach the threshold of compensation you do alright, but in the above case you can see why aging MS shows a problem before aging in health. It is important and perhaps why young people with MS tolerate the insults better than adults

    1. Thanks so much for your response MD. Why do we fail with innate mechanisms of remyelination and synaptic plasticity/neurorestoration as we age? What changes?

  3. Brilliant entry. I posted an entry earlier this month asking why some neuros, mine being one,categorically tells me that there is no such thing and this is from someone based at one of the major Ms centres in London offering hsct thus appearing to be at the sharp endIf your evidence is watertight then neurologists refusing to accept this are basically sentencing their patientsWhen do you think this will become universally accepted and all stages of MS eligible 4 any therapies?

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