I bang on about this subject, over and over and over again about treatment failures. Animal studies are not the main reason for failure. It is trial design. This is the biggest threat. I am sorry to say that sometimes I get a pat on the head by the neuros and and get sent to the corner to shut-up.
They say “You will respect my authority”..Now piss off!
We are planning on doing trials in progressive MS and people with progressive MS say “Do the studies on us as we are not getting any options”. This is understandable and with PPI involved this will be high on the agenda
However, it seems trials upon trials are done just as they have always been done (the easy way) and we see trial failure after failure. Maybe we need to do the trials much earlier to get a success and then hope that approval is not restricted to a subgroup. Do we want two year trials with results or 5 year trial with large numbers of people with double/treble the cost and people get bored before it finishes. because they feel they are geting worse, but can’t tell that it is at a slower rate than doing nothing.
The study below looks at the difference between primary and secondary progressive MS. It says ibudilast is working, but it really says it is working because it is affecting PPMS more than SPMS. Some people may argue that this means it is because they are two different conditions. I would suggest this is claptrap. The key feature is because the people in the PPMS group were progressing.
If there is no worsening in the control group, a drug can never work. This is not rocket science.
If we do not learn this we will be here a decade later still searching. A two year trial with a EDSS disability outcome will stuggle to work. It is too short a time and it is hard to change walking as an outcome as a consequence trial fails.
We have seen it here with cannabinoids
Pryce, G., Riddall, D.R., Selwood, D.L. et al. Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids. J Neuroimmune Pharmacol 10, 281–292 (2015). https://doi.org/10.1007/s11481-014-9575-8
Everyone remembers this trial failure. End of the road for dronabinol. No one is interested in THC in the UK, the MRC have funded a failed trial there is no second chance. There is no interest. I have tried a few times and people remember the graph above and THC is on the maggot pile. You can only fight so many battles at one time
Systematic approach to selecting licensed drugs for repurposing in the treatment of progressive multiple sclerosis.Cunniffe N et al. Transl Neurol. 2021 Jan 18. doi: 10.1002/acn3.51251
Now if the trial had been on less disabled people who are progressing, a treatment could have been available 5 years ago
Do we learn from History? or Plough on?
Response to ibudilast treatment according to progressive multiple sclerosis disease phenotype.Goodman AD, Fedler JK, Yankey J, Klingner EA, Ecklund DJ, Goebel CV, Bermel RA, Chase M, Coffey CS, Klawiter EC, Naismith RT, Fox RJ; SPRINT-MS Investigators.Ann Clin Transl Neurol. 2021 Jan 18. doi: 10.1002/acn3.51251.
Objective: Determine whether a treatment effect of ibudilast on brain atrophy rate differs between participants with primary (PPMS) and secondary (SPMS) progressive multiple sclerosis.
Background: Progressive forms of MS are both associated with continuous disability progression. Whether PPMS and SPMS differ in treatment response remains unknown.
Design/methods: SPRINT-MS was a randomized, placebo-controlled 96-week phase 2 trial in both PPMS (n = 134) and SPMS (n = 121) patients. The effect of PPMS and SPMS phenotype on the rate of change of brain atrophy measured by brain parenchymal fraction (BPF) was examined by fitting a three-way interaction linear-mixed model. Adjustment for differences in baseline demographics, disease measures, and brain size was explored.
Results: Analysis showed that there was a three-way interaction between the time, treatment effect, and disease phenotype (P < 0.06. This shows there is not an interaction). After further inspection, the overall treatment effect was primarily driven by patients with PPMS (P < 0.01), and not by patients with SPMS (P = 0.97). This difference may have been due to faster brain atrophy progression seen in the PPMS placebo group compared to SPMS placebo (P < 0.02). Although backward selection (P < 0.05) retained age, T2 lesion volume, RNFL, and longitudinal diffusivity as significant baseline covariates in the linear-mixed model, the adjusted overall treatment effect was still driven by PPMS (P < 0.01).
Interpretation: The previously reported overall treatment effect of ibudilast on worsening of brain atrophy in progressive MS appears to be driven by patients with PPMS that may be, in part, because of the faster atrophy progression rates seen in the placebo-treated group.