We want to build a sandwich to tackle the many facets of multiple sclerosis that result in neuroaxonal loss. At the base of treatment pyramid, we need an anti-inflammatory onto which we want to add a neuroprotectant, i.e. the combination therapy strategy.
You need to protect damaged and vulnerable axons so that you can then remyelinate them or restore their function. We assume this makes sense, but still, we get push back from many in the field who are determined to still do monotherapy neuroprotective trials.
What is the point of protecting an axon, allowing it to be remyelinated and to recover function for it to be damaged again in the next round of inflammatory attack?
Barts-MS Dictum: It makes no biological sense to do monotherapy MS neuroprotective trials in the modern era.
With this in mind, we had a ‘brainstorming’ session last week and came up with a new neuroprotective trial design in primary progressive MS; it is called the OXO PPMS trial or ‘Add-on OXcarbazepine to Ocrelizumab in PPMS Study’.
Why PPMS? We feel that PPMS has a massive unmet need and that as ocrelizumab is now licensed as the only DMT in PPMS it makes an ideal platform therapy. We have chosen oxcarbazepine, a sodium channel blocker, as our add-on agent because we have pilot data (animal and clinical) showing it may work and it seems to be better tolerated than other sodium channel blockers. In an ideal world, we would want this study to be done with a new agent that has a long patent life, which would allow Pharma to invest in the necessary studies to get the drug licensed. But alas we can’t find a Pharma company with a new sodium channel blockers who would be interested in MS.
Raj Kapoor, David Baker and I have spent an extraordinary amount of time trying to get Big Pharma to buy into the add-on sodium channel blocker neuroprotection paradigm. Sadly none of the decision-makers has bought into the paradigm, yet. Just maybe with new data and the fact that all the low-hanging fruit on the MS tree has been picked they may change their minds.
Please note that neuroprotection is only a small part of the solution to worsening or progressive MS. To tackle this problem we need a lot more than neuroprotection, which is why we need to manage MS holistically.
To reiterate the philosophy of marginal gains “if you break down everything we can think of that goes into improving MS outcomes, and then improving it by 1%, we will get a significant increase when we put them all together. This also means avoiding things that make MS worse”. This is why anti-ageing strategies, in particular, lifestyle factors, need to be included in the longterm treatment strategy to manage MS.
What do you think of the OXO PPMS study? If you have PPMS would you volunteer for this study?
CoI: multiple
Hi Dr Giovannoni,
Great initiative! Why not safinamide? As you know it is a potent sodium channel blocking agent which is also an inhibitor of monoamine oxidase-B. It had minimal side effects when used as add-on therapy to levodopa in a phase III clinical trial in patients with Parkinson’s disease (1). Safinamide has been shown to have significant protective effect against axonal degeneration in EAE likely by suppressing the production of microglial superoxide and enhancing generation of anti-oxidant glutathione (2).
Afsaneh
1) Borgohain R, Szasz J, Stanzione P. Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson’s disease. Mov Disord 2014. 29(10):1273-80.
2) Morsali D, Bechtold D, Lee W, et al. Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis. Brain 2013;136(Pt 4):1067-82.
Yes, safinamide is on our list of compounds, but we don’t have MS data at hand.
we looked at about 6 different Na channel blockers but not safinamide. As for the EAE we are aware of the data. It may get tried
Great study, great name too!
Look forward to seeing PROXIMUS results
(add on Oxcarb in MS)
CoI: GP Rx me off-label oxcarbazepine 300mg bd for neuroprotection/pain 3 years ago. Well-tolerated 🙂
I think this is double the dose we used…stand to be corrected
You’re correct MD
https://clinicaltrials.gov/ct2/show/NCT02104661
🤔 interesting, half the usual starting antconvulsant dose
https://bnf.nice.org.uk/drug/oxcarbazepine.html
I’ll be the high-dose arm, every good study needs one! 😉
I’m always a bit split with these posts – a thank you for all the effort, but also frustration that this sort of trial should have started long ago. We’ve had good candidates for neuroprotection for ages but MS research seems to be about barriers to innovation.
Why not have another arm to this trial – for PPMSers who do not meet the inclusion criteria for Ocreluzimab, just give them oxcarbazepine. You’ll probably say there is still ongoing inflammation in this group, so what anti inflammatories can they be prescribed?
It takes years of effort to get trials off the ground even when Pharma do it. The Mouse Doctor and I had the first round of meetings with Pharma about this strategy about a decade ago. Raj Kapoor and I did the same thing after our positive optic neuritis phenytoin trial. It is not for lack of trying. Resilence is what is needed, which is why we are starting again.
As an example, it has taken DrK ~4 years to get the #ChariotMS trial funded. Nothing in MS happens quickly.
Yep and another 3 years before that:-(
Yes please
Dr. G, very interesting study. Especially since I’ve been prescribed Trileptal for neuropathic pain. However, a quick Google search revealed a study indicating that oxcarbazepine may actually be neurotoxic. I did find your 2013 study indicating that it appears to be neuroprotective in EAE. Any insights as to the discrepancies between studies? Here is the study that found oxcarbazepine to be neurotoxic…
https://www.ncbi.nlm.nih.gov/pubmed/11020481
This is an old ex vivo study. Our in vivo animal and other data suggest that both these compounds are neuroprotective.
AS a PPMSer (dx 2012 but symptoms for far longer) constantly being told there is nothing on offer in terms of DMT (I do take Fampyra which helps walking speed, Biotin and Simvastatin, in case they might help) I support any initiatives like this. You make a persuasive case for combining therapies addressing different parts of the problem. I would take part.
Now there are options for treatment hopefully it will speed up the dx and as ocrelizumab works in PPMS and RRMS there is no need to wait for the course to show itself.
great initiative!
Thanks. We think so too.
I thought NICE had refused approval for Ocrelizumab for PPMS?
They did, but after doing a deal with Roche on the price it is now approved. We can start dosing PPMSers in September. Overall very good news.
Would happily take part of this trial have ppms for three years with me taking vitamins and following terry wahls mitochondria diet plant based with some fasting too- just been offered hyperbaric chamber use – but working so waiting to try and fit in with work etc but hopefully start in October- I would like the opportunity if possible
Interesting to read about this, I was in the PROXIMUS trial whilst also being a long term tysabri user. I managed to get my gp to prescribe oxcarbazepine after the trial finished having noticed the benefits of this drug in a neuro protective capacity. I recently switched therapy to ocrelizumab and even though I am a PWRRMS I feel the benefit of this as a combination therapy. I truly hope an effective reymylinator and a neuro restorative can be found trialed and made available for this innovative therapeutic approach.
yes sure i’d like to partecipate to this project, how can i?
Ar last – some combination therapy!
Add some clemastine + perhaps a statin + vit D and we might start getting somewhere … !
I have ppms diagnosed in 2016. I’m interested in any trial that might improve my quality of life and that of all ppmsers
i want to help
How can we help?
i an join a study
It is not funded yet
keep my name handy
OK
Let there be drums 😉