Systematic approach to selecting licensed drugs for repurposing in the treatment of progressive multiple sclerosis.Cunniffe N, Vuong KA, Ainslie D, Baker D, Beveridge J, Bickley S, Camilleri P, Craner M, Fitzgerald D, de la Fuente AG, Giovannoni G, Gray E, Hazlehurst L, Kapoor R, Kaur R, Kozlowski D, Lumicisi B, Mahad D, Neumann B, Palmer A, Peruzzotti-Jametti L, Pluchino S, Robertson J, Rothaul A, Shellard L, Smith KJ, Wilkins A, Williams A, Coles A.J Neurol Neurosurg Psychiatry. 2020 Nov 12:jnnp-2020-324286
Objective To establish a rigorous, expert-led, evidence-based approach to the evaluation of licensed drugs for repurposing and testing in clinical trials of people with progressive multiple sclerosis (MS).
Methods We long-listed licensed drugs with evidence of human safety, blood–brain barrier penetrance and demonstrable efficacy in at least one animal model, or mechanistic target, agreed by a panel of experts and people with MS to be relevant to the pathogenesis of progression. We systematically reviewed the preclinical and clinical literature for each compound, condensed this into a database of summary documents and short-listed drugs by scoring each one of them. Drugs were evaluated for immediate use in a clinical trial, and our selection was scrutinised by a final independent expert review.
Results From a short list of 55 treatments, we recommended four treatments for immediate testing in progressive MS: R-α-lipoic acid, metformin, the combination treatment of R-α-lipoic acid and metformin, and niacin. We also prioritised clemastine, lamotrigine, oxcarbazepine, nimodipine and flunarizine.
Conclusions We report a standardised approach for the identification of candidate drugs for repurposing in the treatment of progressive MS.
This was planned that to have been access but Nick (Cunniffe) has sent me the accepted version. I have put it in dropbox
The MS Society are leading the charge to try and find treatments for progressive MS and they first undertook meta analysis of different treatments
Drug repurposing: a systematic approach to evaluate candidate oral neuroprotective interventions for secondary progressive multiple sclerosis. Vesterinen HM, Connick P, Irvine CM, Sena ES, Egan KJ, Carmichael GG, Tariq A, Pavitt S, Chataway J, Macleod MR, Chandran S.PLoS One. 2015 Apr 9;10(4):e0117705.
There a set criteria was used select potential treatments and they “identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation”. Ibudilast was already taken by the Americans for SPRINT-MS so riluzole, amiloride, fluoxetine were tested in a trial call MS-SMART. Sadly these all failed to influence progression as assessed by brain atrophy.
Therefore we got egg on our faces and it seemed it was “MS not so Smart”. People may say that Ibudilast fit the bill and it showed some effect
Fox et al.Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 week
However you can say that they they already knew it could work because of the failed relapsing study.
Barkhof F, Hulst HE, Drulovic J, Uitdehaag BM, Matsuda K, Landin R; MN166-001 Investigators. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010 Mar 30;74(13):1033-40
Ibudilast is a phosphodiesterase type IV inhibitor and both rolipram and pentoxyfylline had been found to be of no use or worse in relapsing MS
Now I will admit I was there, when the drugs were selected, but was not part of selecting the approach. I am not a big fan of meta-analysis if it is not interlinked with biology and proper understanding. For example meta-analysis of animal data was never going to be useful, as the way EAE is used it is a relapsing not progressive model.
Ibudilast was perhaps a reasonable candidate because it had shown positive effects on brain atrophy. Riluzole was found to inhibit motor neuron disease, but in our hands was really rather toxic in animals and pretty sedative. I thought amiloride was the best candidate at the time as it did seem to induce neuroptotection in mice, but had no experience of it. However, witinh a few months of the trial starting, other trials in MS questioned whether riluzole and fluoxetine were going to be of use.
Not deterred it is time for round two. There are alot of people involved
One group was charged with trial design. There is a desire for an adaptive design where you start off with a few drugs, if they fail you replace with other candidates. This approach was pioneered in cancer. In cancer the trial design and outcomes are easy as it is survival from cancer. In MS it is way more complicated as there are different processes occuring that influence the trial design and outcome. If it was a trial to inhibit relapsing MS I would say not problem, but for progressive MS, you are not working to a tried and tested formula for success.
I have strong opinions on clinical trials and firmly believe that it does not matter what candidates you select, if the trial design is wrong the trial fails. Whole brain atrophy can have issues as a main outcome and this was highlightd with the failed lamotrigine trial, in that it appearred to cause shrinkage. However it also highlighted that lamotrigine is a problem because the epileptic dose is too high for MS and people simple did not take the drug due to side effects. If you don’t take the drug it can’t possibly work no matter how much supportive data there is.
We have been arguing that to get protection that you need to do add-on studies with potent disease modifying treatment on the bottom. Once you do this the value of neurofilament light as an outcome measure will be an issue.
However, the other Group was a drug selection process and this paper describes that process. This was chaired by ProF Coles from Cambridge. The Chairs (Drug selection and clinical trial lead) had agreed that they would not be recipients of any grants. This time the approach was based on opinion of the some of the participants and it was decided that it would be mechanistically focused. The agreed mechanistic areas were: (1) energy, blood flow and mitochondria; (2) the neuron and axon; (3) sodium channels; (4) microglia and astroglia; (5) intrathecal B cells and plasma cells; (6) demyelination and myelin repair; and (7) antioxidants. It was also agreed that the process of drug selection should be literative.
A list was drawn up and drug characteristics were assessed.These were scored
However, it was decided that alternative appoaches would be used and other selection processes occurred and found similar options.
I was not at the final selection meeting and so cannot be credited or chastised for the choices. Some seemed obvious and others I have doubts. These doubts included thinking that they may not work. I guess top of the list was lipoic acid as there is clinical evidence that it may works and it will never be develoed by pharma. It is trial ready and you dont need to do any animal experiments. To develop some of the others you may need more work.
As you know there has been a lot of interest in metformin as a rejuvenator, so this was added to the mix. Therefore, you have a neuroprotective (lipoic acid) and a repair agent (metformin), surely it has to go on top of an effective disease modifying treatment!. But now you see that the trial design is key. Shoulf the trial design for a repair agent be the same as a neuroprotective agent?
I understand that another trial aims to examine clemastine and metformin as a repair agent.
However, I hope you can see that the UK scientists and clinicians are working together to try and bring treatments to progressive MS. The MS Society have been doing their bit co-ordinating this and fund raising.
There will be a calmor to start late to give options to people with progressive MS ….but this makes the task harder to get a positive answer . Start early to get maximum opportunity to show an effect.
What do you think?