Wednesday, 22 January 2014

Therapeutic lag: is it time for a new paradigm in progressive trials?

Can we do progressive MS trials more intelligently? #MSBlog #MSResearch

"The study below shows that interferon-beta treatment may work in PPMS provided the follow-up is long enough; in this case 5 years. PPMSers who had only been treated with IFNbeta for 2-years clearly do better at 5-years than PPMSers 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 over the next 2 years was primed by inflammation two years ago. Suppressing inflammation today will have not impact over the next 2-years as the damage priming progression over the next 2 years has already occurred. In other words all anti-inflammatory therapies will have a lag in terms of showing a treatment response in progressive MS."

"What do you think of this concept? Does it make sense?"

"I drew this picture last year to illustrate the concept of the therapeutic lag. I hope you can understand it. What has made me refocus on this are my own clinical observations from using highly-effective therapies. I am beginning to see this therapeutic lag in clinical practice. In MSers who have advanced highly-active MS who go onto natalizumab continue to progress for about 18-24 months before they flat-line and stabilise with a fixed level of disability. This observation is different from MSers with early MS who still have reserve capacity; in contrast they tend to improve."

"If I am correct about the 'therapeutic lag' then the MS community has to start taking this into account when designing future progressive MS trials. Is this feasible? Are 5-year studies doable? They will be very expensive to do. Will Pharma have the balls, and resources, to go after progressive MS with a 5-year study?"

"One way of doing this is to de-risk the trials and allow multiple trials to be done in parallel using an adaptive design. In other words we need to get several pharma companies to run their drugs head-2-head in same study. The would share the cost of the study, which would make it cheaper to do. Adaptive shared trials of this nature are not new and happen in other fields, in particular oncology.I-SPY 2 is a phase 2 breast cancer trial that was launched in 2010 by 5 Pharma companies, which uses an adaptive design to randomised patients to one of 7 experimental therapies. This has now been followed by an I-SPY 2 a phase 3 adaptive trial. Similarly the IMI (Innovative Medicines Initiative) has called for proposals for a similarly designed trial in Alzheimer's disease; at least 12 drug companies have expressed an interest in being involved. May be we can do the same  thing as part of the Progressive MS Alliance (PMSA)?  Will the PMSA adopt and champion this idea in the MS space?"

"If we don't learn and adopt best practice from other specialties we will be doing MSers a disservice."

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.


  1. This is nonsense. I have am a moderately young PPMS sufferer and was put on a year intensive course of five infusions of mitoxantrone in 2009. Back then I could walk unaided but now use a wheelchair outdoors and have chronic numbness in my hands. My MS is yet to plateau the way your academic theorising suggests.

    MS is a bad disease, Prof G.

    1. Re: "MS is a bad disease"

      Apologies, I know (see my infographic at the bottom of the blog on "why gray matter, matters"; it tells you how bad MS is.

      Flat-lining is something we aspire to in progressive MS. I have altered to the picture to include a delayed progression. The latter is simply an average of trial participants; some will get worse, others will improve or flat-line. The problem is that if a drug slows down your progression, and does not stop or improve your disability you won't know it is working.

  2. A long-term 5 year study would also be better at showing long-term side effects that might show up in years 3 or 4 rather than the first 2 years. That might work against Pharma's best interests (although for MSers' best interests).

    1. If you have 5 year trials it means 8 to nine year trials when you have years of recruitment and data analysis now think if you do phase ii then phase ii by the time you get to licensing the patent will have expired and people will be able to get generics there will be no insentive for pharma to do these studies.
      for cns diseases that develop slowly is the current patent system broken

  3. The current studies have shown the incidence of Gd-enhancing lesions in progressive disease to be less than RRMS. I was under the impression that inflammation is not the main driving force in progressive disease. If you believe that progression is primed by on going inflammation then inflammation is the driving force in PPMS and SPMS. If inflammation is the culprit then shouldn't the lesions be lighting up? It seems counter intuitive to suggest long term anti-inflammatories will ameliorate the neuro-degenerative disease process.

    1. The problem is that dogma dictates that inflammation = Gad-enhancing lesions. We know that this is only the tip of the iceberg. Progressive MSers have subtle Gad leakage indicative of breakdown of the blood brain barrier; is this inflammation? Yes, it is. At post-mortem the brains of progressive MSers is stuffed full of inflammatory cells including 'hot microglia'. The idea that SPMS and PPMS is not inflammatory is not based on science. I have posted on this many time in the past. We need to treat progressive MS with the same approach that we treat RRMS; an anti-inflammatory with a neuroprotective agent.

    2. Prof G, there is nothing more depressing as a PPMSer to hear this. Personally, I would be willing to do whatever it took to adopt this approach of an anti-inflammatory and neuroprotective agent (whether that be amiloride, laquinimod, statins or both) in the here and now. I know that you will trot out that same old line that we need more clinical trials, but are they ever going to come into fruition? Can we afford to wait any longer? I don't know for how much longer I will walking, once these nerves have sustained enough damage I know there will likely be no way of coming back. Why can't we try your approach now??

    3. I don't understand... if it is known (maybe it isn't?) that inflammation is implicated in progressive MS, why can't progressive MSers have anti-inflammatories prescribed for them? I'd really appreciate a reply in easy to understand language, thank you very much as always :-)

    4. The answer is because, apart from one trial of IFNbeta-1b, in SPMS all the trials have been negative. The point I am making is that they may have been negative because the trials were too short. In other words the concept of a therapeutic lag was not taken to into account. Unless we have positive trials we can't get drugs licensed and payers won't pay for them.

  4. There was quite a lot of email ping pong between members of the PMSA over the concept of therapeutic lag. At least it is being considered/ Whether or not it is real entity needs more investigation. Biogen-Idec are best placed to answer this. I have asked them to have a look into their data.

  5. It seems there is evidence that some first line drugs slow progression in PPMSers (at least in males at two years).

    Yes, the problem is extrapolating results based on a two year trial to longterm effectiveness. But longterm placebo controlled trials are inhumane, so you need a different method to measure effectiveness.


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