#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

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