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