Just as the Lumpers appear the Splitters reappear…2 diseases or trial design problems-Ibudilast

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We have been making the case that MS is one disease, with different pathological features that may need different approaches. Therefore we Lump the different MS subtypes (primary and secondary progressive and relapsing MS together) This contrasts the splitting of MS into differnt MS subtypes.

Recently siponimod has been approved for relapsing and secondary progressive MS and so lumped together by the FDA. Why not approval for primary progressive MS?

There seems no biological reason why the processes that drive progressive MS are different.

However, I have said the most informative experiment is the human trial.

If a drug works for primary progressive MS it should work for secondary progressive MS..or so I thought…..however.

On the web today we have headline

#AAN2019 — Ibudilast Slows Brain Atrophy in PPMS But Not SPMS Patients, Phase 2b Trial Shows

Response to Treatment According to Progressive Disease Type: Analysis from a Phase II Progressive MS Trial of Ibudilast Andrew Goodman , Janel Barnes , Jon Yankey , Elizabeth Klingner , Sneha Natarajan , Robert Bermel , Christopher Coffey , Eric Klawiter , Kazuko Matsuda , Robert Naismith6 , Robert Fox

Objective: To report the effect of disease course (primary progressive vs secondary progressive) on the treatment effect of ibudilast in progressive MS.

Background: Despite recognition as different disease courses, primary progressive (PPMS) and secondary progressive (SPMS) are increasingly viewed as being more similar than different. Little is known about whether the two disease courses differ in treatment response. We evaluated the effect of ibudilast on the progression of brain atrophy according to disease course in a phase II clinical trial.

Design/Methods: SPRINT-MS was a randomized, placebo-controlled 96-week phase II trial that evaluated the effect of ibudilast on brain measures of integrity in both PPMS (n=134) and SPMS (n=121) patients. Separate linear mixed models were used in PPMS and SPMS to evaluate rate of change in primary outcome (progression of brain atrophy) measured by brain parenchymal fraction (BPF). Baseline demographics and disease measures were included when appropriate.

Results: Post-hoc analysis showed that there was a marginally significant three-way interaction between the treatment effect and disease course (p=0.0576 = MD HERE THIS MEANS THERE IS NO STATISTICAL EFFECT). After further inspection, the overall treatment effect was primarily driven by patients with PPMS (p=0.005), and not by patients with SPMS (p=0.97). This difference may have been driven (at least in part) by faster atrophy progression in the PPMS placebo group compared to SPMS placebo (p=0.016). Although backwards selection (p<0.05) retained age, T2 lesion volume, RNFL, and longitudinal diffusivity as significant baseline covariates, the adjusted difference in treatment effect was still marginally significant (p=0.0715. MD HERE AGAIN…SORRY I DISAGREE…THIS IS NO SIGNIFICANT WHAT IS THE POINT OF SETTING LIMITS IF YOU IGNORE THEM) and driven by PPMS (p=0.007). Conclusions: The overall treatment effect of ibudilast on progression of brain atrophy in progressive MS appears to be driven by patients with PPMS, which may in part be because of their faster atrophy progression rates in untreated patients.

So the headline is PPMS and SPMS are different. This sends out a message that I do not think is the real issue.

This data says that if you do a trial with people who are able to show a response, you can show a response but if you do trials on people that are unlikely to show a response, then the trial fails. Therefore trial design is key.

I have been saying this until I am blue in the face, Ineffective trial design kills treatments and therefore getting this right is the key to any drug selection approach. Without an effective trial design the best candidate drugs will fail.

This then contrasts with the will of the community who want action for people without treatment options. These studies may need to be very large and very long to show an effect and so cost a lot to do properly. Don’t do it properly… no drug.

If EDSS is an endpoint in a trial it says that if you include people with advanced MS that worsens slowly then it is likely to fail. Therefore start you trials early whilst the our s enough neurological reserve.

Maybe you do event driven trials where you keep going until there is enough activity in the control group. However with options becoming available this adds to the problems

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MouseDoctor

10 comments

  • I totally agree with you, drug trials must be very well designed. Good patients – maybe good outcome – maybe the drug gets approved.

    The problem is there should be more flexibility for us patients who initially don’t fit in the trial to try experimental drugs off the trial . We truly cannot wait until the outcome. There are drugs out there that they may provide some benefits, we must try before is too late even if the outcome is not good . When you are spiralling down, getting worse by the week, desperation is too high , we would try anything , we have absolutely nothing to lose . Again a parallel protocol should be established for patients who don’t fit the trial, even if the drug is experimental .

  • I did think that secondary and relapsing-remitting are probably the same disease at different stages but I am sure somewhere on this blog it has been mentioned sometime that primary had been mentioned as a potential separate disease

  • Speaking merely as someone with early onset, slow/stable “PPMS”, I feel that the categories used for different presentations of MS aren’t very helpful. They are artificial, almost arbitrary, are not really based upon solid, thorough knowledge of the fiendishly complicated pathology of MS. Which no one has yet elucidated.

    Given my experience of MS, I would tend towards saying that progression is closer to the core of the disease, that inflammation flares are the body’s damaging response, occurring in some to a greater degree than others.

    I think that categorising more on the basis of active or inactive disease might be more helpful. And may give clearer results in such cases as Ibudilast? But then, someone who has inactive disease one week may have active the next, due to nothing more than a cold virus?

  • OK. Again MD just playing devil’s advocate. Pharma is money making machine and they don’t over look anything unless the science is not established. I suspect primary is not sane as rrms or spms. Its immune mediated. But the target is different. For instance why don’t you get Dawson Fingers in ppms?

  • A little off topic but I would love to hear your views MD on siponimod.

    Simply put Mayzent/siponimod does not appear to work in the majority of SPMS at stopping progression as pointed out by the FDA. It works 21% above placebo for reducing progression at a “whopping” 3 months. This 21% of SPMS is made up of all SPMS, including the small subgroup of active SPMS who skew the results in siponimod’s favour (active SPMS group 33% reduction of progression above placebo). .

    One should take FDA’s statement (“in the subgroup of patients with non-active SPMS, the results were not statistically significant.”) very seriously before you pay for this ripoff clone of fingolimod/Gilenya, which is also owned by Novartis, who cancelled its trials in progressive MS second to its expiring patent.

    If someone has “active” SPMS or late RRMS, then why not take any more potent MS drug like alemtuzumab, ocrezulimab (ie.rituximab variant) or cladribine or even fingolimod?

    • If you have (active) SPMS in UK your choices are limited and you may not be eligible for treatment. As I have said before, people have learned that active disease respondto DMT so they load their trials with people with active ms, and the trials work and a treatment option becomes available. In US I believe cladribine just got approval for relapsing and active SPMS also .

      • So if cladribine has been approved for spms in US will Europe not follow?

        Will 0crelizumab still be the better option for active spms?

        Would this affect Dr K chariot trial?

        If available do neuros think the likes of alemtuzumab would be more effective for active spms?

        • Will Europe not follow?…No too late their approval was in 2017.
          Will ocrelizumab?…not sure why.
          Would this?…no
          If available..? I’m not a neuro

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