Made in Mouse. It is Neuroprotection day and a great move against progressive MS

#MSResearch Neuroprotection in progressive MS is a probably an achievable reality.

We (MD & MD2) have taken quite a bit of flak recently about being excited but gagged and friday we will find out the results, which we have not seen! (Honest).

Dr Raj Kapoor will present “Phenytoin is neuroprotective in acute optic neuritis: Results of a phase 2 randomized controlled trial” at the American Academy of Neurology in Washington. 
However, the press embargos have been lifted and it is clear that nerves were saved.  This was supposed to be launched on friday but as the whole world has blabbed, we may as well post.

We believe this good news for RR and Progressive MSers, as we are cracking that progressive nut. we have tested a hypothesis in animals and now we have done this in humans and it works!

We knew the take home message and this has been on the web (on the AAN website) for weeks and you haven’t spotted it. 

As a scientist it is incredibly frustrating when neurologists do not translate our ideas as it can be years of our lives wasted, as the case with the CUPID trial. If they succeed you will get limited or no credit….. I guess there is no i in team:-)

However, it is incredibly rewarding when your ideas come to fruition and shows some value to humans and we are incredibly proud of the MD Team. TeamG and UCLP and this story has taken many years of hard work.

Please remember. The idea of sodium channels blockers (e.g. phenytoin-an anti-epilepsy drug) to protect nerves in MS was dead and buried by 2010!

The idea and concept of today’s (partial) breakthrough have their roots firmly in animal studies. TeamG can take credit for reviving this phoenix.

The first failure for sodium channel blockers was that of Prof Waxman from Yale. He had pioneered the idea with Ken Smith & Raj Kapoor in London.

Watch the video of Marija and the Bouncers that explain this

(CLICK). (Sodium channel blockers are the locks) and how it relates to nerve energy.

We had helped ProfWaxman find the sodium channel problem in EAE that he had been looking for and helped them get the EAE going and off they went doing their own thing.

After showing that phenytonin was (somehow?) immunosuppressive in acute EAE. Prof Waxman had lined up a phenytonin trial in progressive MS.

However, this was bottled after it was found (as should have been expected-if they were used to EAE research) that EAE mice get EAE after one withdraws an immunosuppressive drug. This can take a couple of days to a few weeks dependent on the drug…but decent EAE comes back!

(In our hands. Phenytonin or other sodium channel blockers at human relevant doses were never immunosuppressive and we would have not predicted such a problem as seen by the Waxman group. (We have used the same mouse strain and the same drugs) We would deliver doses compared to putting it in drinking water as….maybe it tasted so awful that mice got stressed out and the problem of drinking was that it was artificially immunosuppressive). Its not worth the effort to test this, is it?

This also delayed the next percieved failure, which was the Lamotrigine trial done by Dr Kapoor and Smith. They had to do extra monitoring to check for the massive rebound that never materialised after drug was stopped. The trial was seen as a failure too. This trial was blighted by side effects and the fact that phenytonin seemed to be worse than placebo for the first year using the MRI endpoint.

TeamG saves the Class
Gnanapavan et al. Biomarker report from the phase II lamotrigine trial in secondary progressive MS – neurofilament as a surrogate of disease progression. PLoS One. 2013 Aug 1;8(8):e70019.

We (NeuroDocG/ProfG) with Dr Kapoor did two things:

(1) We tested the bloods of people in the trial to see if they were taking drug and found that 50% of people on the trial were not taking their medication property. So is it any wonder the trial failed. However, did it?

(2) We looked to see who had neurofilaments as a marker of nerve damage and it was found that people who took the drug had less neurofilament in their blood than the people who where not taking their drugs. Therefore this strongly suggested that sodium channel blockade can be neuroprotective.

This information has also been ignored and lamotrigine has been tarred as a failure probably never to be used again.

Undeterred we carried on.

At the same time, as part of Promise 2010….the MD’s (MD1-MD4) were looking for neuroprotective drugs and we tested a number of different classes of drugs. We had also decided that optic neuritis was going to be one of the better ways to test things in humans.

However, the original planned human testing arm was cut from the original Promise 2010 grant budget.

So we were tasked by ProfG with reverse engineering MS to produce an optic neuritis model in animals to get the evidence needed for the human studies. This is what we did.

Lidster K, Jackson SJ, Ahmed Z, Munro P, Coffey P, et al. (2013) Neuroprotection in a Novel Mouse Model of Multiple Sclerosis. PLoS ONE 8(11): e79188. doi:10.1371/journal.pone.0079188

We tested a number of different types of agent and showed that sodium channel blockers were one of the better classes of drugs, (There are a number of others) that could save nerves in the eye following the onset of optic neuritis.

The blue dots are nerves within the retina of the EAE seen at low magnification (Left) and higher magnification (centre & right). We
caused optic neuritis (centre & right) and nerves got damaged and died and the sodium channel blocker (centre) could save them despite the optic neuritis in the optic nerve.

We also showed that the optimal response was time dependent and you only have so long to start treatment of get the best response. In animals this was a few days to treat the inflammatory penumbra and we predicted it would be about a few 2-4 weeks in optic neuritis. Also steroids are not much use after this time point.

Al-Izki S, Pryce G, Hankey DJ, Lidster K, von Kutzleben SM, Browne L, Clutterbuck L, Posada C, Edith Chan AW, Amor S, Perkins V, Gerritsen WH, Ummenthum K, Peferoen-Baert R, van der Valk P, Montoya A, Joel SP, Garthwaite J, Giovannoni G, Selwood DL, Baker D.Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis. Brain. 2014;137:92-108

Therefore it was decided that people should be put on drug within to weeks of onset if possible. This makes sense when you see how nerves are lost in optic neuritis in humans.

Dr Raj Kapoor was recruited to the Promise 2010 team as sodium channels blockers were his baby. He has done a really fantastic job in recruiting about 100 people with optic neuritis (a common problem in pwMS), within two weeks of their first symptom, in a quick time. This is aided in London by a large population and having specialist eye hospitals with neurologists embedded in them so they can pick up optic neuritis quickly.

It was decided that phenytoin would be used as it could be loaded/dosed quickly our preferred other options needed the dose to titrated up slowly and time was of the essence.

The study was funded by the NMSS in the USA…so they and their US donors are the stars too! A big thank you!

All we can say that from the title it is clear that the results are Positive and this is fantastic news and translates our animal work and shows that we are on the right track, in targeting Progressive MS. This is great news for 2015.

The Doom & Gloomers will be saying chunter, chunter,chunter:-)
as the have been doing (But please don’t bother commenting!)

Yes you have a point because mores studies will indeed be needed before phenytoin could become available for progressive MSers. It has to be said in our hands pheytonin was not the best, so there is room for improvement, with a more neuroprotective sodium channel blocker and development of other drugs with better side effect profiles.

Phenytonin is a generic and it will be difficult to develop but pharma have plenty of new molecules up their sleeve and could do an accelerated drug development process. Maybe this is why Biogen splashed out over $600 million to buy a sodium channel company. Maybe Novartis that makes Oxcarbazeppine have more compounds in their closet.

However it says we can indeed use animals to find drugs to treat MS .

It says that we can detect neuroprotective drugs, probably within about 3 months in humans not a 3 year trial
We have a treatment that can help save sight.
It says that we should add neuroprotective agents on top of anti-inflammatory agents, as all people in the trial received steroids, to optimise saving nerves.
It says that nerve damage because of the imflammatory penumbra can be controlled. Which means one can get added treatment effects in relapsing MS.
It says we are understanding the process of progression, which will start to deliver treatments for progressive MS.
It says we can be hopeful that our other ideas are on the right track.
More agents of different classes should start to show benefit e.g. the amiloride optic neuritis trial if they have got their timing right.

So well done to Dr Kapoor and the UCLP (ProfG & DrK) team.

How can you get your hands on a sodium channel blocker right now?

If you fit the criteria, why not consider signing up for the oxcarbazepine trial (PROXIMUS CLICK). Oxcarbazepine was a miles better neuroprotective sodium channel blocker than phenytonin.

Disclaimer: please note Barts-MS can’t recruit subjects for clinical trials via this blog.

If you are interested in participating in the PROXIMUS trial you need to be referred to Barts-MS via your GP or treating neurologist.

The following are the inclusion and exclusion criteria for the PROXIMUS Trial (NCT02104661):

Inclusion Criteria:

  • A diagnosis of definite multiple sclerosis 
  • Treatment with DMDs for at least 6 months 
  • EDSS score between 3.5 and 6.0 
  • No history of relapses in the preceding 6 months 
  • A history of slow progression of disability, objective or subjective, over a period of at least 6 months 
  • Age 18-60 years 

Exclusion Criteria:

  • Pregnant or breastfeeding or unwilling to use adequate contraception. 
  • Participants who do not take a DMDs for MS. 
  • A clinical relapse or pulsed intravenous or oral steroids in the 6 months preceding the baseline assessment. 
  • Participants presenting with medical disorder deemed severe or unstable by the CI such as poorly controlled diabetes or arterial hypertension, severe cardiac insufficiency, unstable ischemic heart disease, abnormal liver function tests (>2.5 times ULN) and abnormal complete blood count (in particular leukopenia, as defined by a lymphocyte count <500, neutrophil count <1.5 or platelet count <100, or thrombocytopenia <1.5 LLN), or any medical condition which, in the opinion of the chief investigator, would pose additional risk to the participant. 
  • Infection with hepatitis B or hepatitis C or human immunodeficiency virus. 
  • Participants receiving other sodium or calcium channel blockers in the previous 12 weeks 
  • Exposure to any other investigational drug within 30 days of enrolment in the study. 
  • Judged clinically to have a suicidal risk in the opinion of the investigator based upon a clinical interview and the Columbia Suicide-Severity Rating Scale (CSSRS). 
  • Prior history of malignancy unless an exception is granted by the Chief Investigator. 
  • History of uncontrolled drug or alcohol abuse within 6 months prior to enrolment into the study. 
  • Past untoward reactions to Oxcarbazepine or carbamazepine. 

ProfG is at the AAN and hopefully will post more details on this and MD1003 once the work is presented.

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  • Mice, looks like your 60 years of combined MS research has finally delivered something. Well done. I could make a sarcastic comment… But I won't. You are the Accrington Stanley of MS research teams- you have won a game and deserve your time in the limelight. Congratualtions to the mice doctors. Angry of Tunbridge Wells.

  • Great stuff, MD. You go right ahead and ignore all the trolls and grumpy pessimists, and I'm genuinely pleased that the House of Mouses has something to sing about. And give your meeces a special treat of smelly sock cheese (aka Stilton).

    What are the implications of this for people with confirmed MS but who have never had optic neuritis? Will this work translate across for people without MS related optical problems? What about progressive MSers where there is no detectable inflammation – only degeneration – would anti-inflammatory drugs still need to be part of the treatment picture?

    • Optic neuritis was used because the read out was quick and the degeneration/neuroprotection was easy to measure. if it is neuroprotective here, it should also be neuroprotective generally in MS. We now need to get as many signed up to the PROXIMUS trial asap.

    • Sorry MD2 – can't help there – unless you run some extension arms of the PROXIMUS trial in places other than the UK, but given Prof G's note about participants needing to also be on a DMT that would count me out from signing up anyway, as I'm not on any DMT's (and feeling much better for it actually).

  • Congratulations to all involved. My husband is a medicinal chemist so I know just how hard it is to get to a positive result in a clinical trial. Ignore all the grumps out there.

  • Great to see this result! It's been a long journey. I'm really proud to see our experimental results finally translating to MSers. This is great news for primary and secondary progressive MSers.
    I endorse MD's point that in our hands there are other much better neuroprotectants than phenytion, such as oxcarbazepine, which makes it imperative that we get enough MSers signed up to the PROXIMUS trial, which could really get the momentum going for progressive MS and kick-start pharma who have lots of potential neuroprotectants sitting on their shelves.

    • No, unfortunately PROXIMUS is only for people who are currently on disease-modifying treatment, which excludes people with PPMS. The concept of combining anti-inflammatory treatment with neuroprotection is promising for PPMSers too. However, given no immuno-modulator has been licensed for PPMS, it is much more difficult to acquire funding for such a combination trial.

    • Maybe talk to Crowdacure about getting a neuroprotection only trial going? I'm sure there would be plenty of progressive MSers around who could/would chip in.

  • Am I correct in thinking that for progressive Ms
    Phenytoin as a neuroprotective
    Bioti as a reparative drug
    Would do great help for people by slowing down degeneration and then repairing any that may occur?

    • Roll on friday. The wait is tough. I do hope there is a silver lining to all this PPMS tragedy with Biotin as a real treatment not fudged up trial data made to look positive.

  • In which case this isn't really good news for progressive Ms? At least not in the timeframe that many many people need
    Is there no compassionate use basis? I find all this crazy that everyone says they're doing so much for ppms but in truth they're not

  • History of uncontrolled drug or alcohol abuse within 6 months prior to enrolment into the study – sorry MD1, looks like you are ineligible for the Proximus trial.

  • Great work- but I'm amazed that the session on Friday at AAN is one and a half hours and they are discussing 5 clinical trials including this and the biotin one. 18 minutes each for such major results?!

  • First of all well done.

    But Surely if you are on DMDs then you are not progressive yet. . In PPMS could our neuros give us Phenytoin now as it is licensed already for epilepsy. Oxcarbazepine is not , is it ?

    If not Foot drop may have developed in the other foot before I get the chance for a sodium channel blocker.

    • The progressive processes being targeted occur in both RRMS and PPMS/SPMS just as the processes that drive relapse can be present in PPMS/SPMS therefore based on the treatment pryramid you neuroprotect on top of anti-inflammatory.

      Oxcarbazepine is an anticonvulsant and mood-stabilizing drug, used primarily in the treatment of epilepsy. It is also used to treat anxiety and mood disorders, and benign motor tics. Oxcarbazepine is marketed as Trileptal by Novartis and available in some countries as a generic drug.

    • Thanks for that. My neuro is pretty good in letting me try things that I want. I will ask for oxcarbazepine but which anti-infammatory should I ask for. I am still only possible PPMS.

  • Great results, it appears that your sodium channel blockers may be a very useful add-on therapy in relapse treatment.
    Stabilization of the inactivated form of sodium channels appears to decrease the nerve conduction; this helps protect demyelinated nerves, but perhaps interferes with compensatory mechanisms, since nerve impulses transmitted by still health, myelinated axons will slow down. Is there a way to selectively target sodium channels on demyelinated nerves (apart from using your new compounds which only enter CNS via "leaky" BBB)? One potential strategy may involve divalent interactions with relatively weakly binding molecules linked by a spacer which matches the distance between sodium channels on demyelinated axons, but this is probably easier said than done. For example, are there any differences in gated voltage?

  • First, I am so proud of you all, I feel like your mother!

    Secondly, I did spot the entry on the AAN but kept silent so my grey cells are obviously still working!

    GREAT NEWS and thank you all.

    • Thanks! My Mum's proud too! We saw it too but kept Mum as a courtesy to Raj Kapoor (it was difficult!) but now the embargo has been busted it's fair game.

    • MD2 – one question: I asked before but now with the news I wonder again if me taking natrium thyroxine 100mg daily for 25 years now is doing me greater harm than good?

      I have been wondering if the thyroxine doesn't overload my natrium channels making my nerve cells die off?

    • Simple answer is no, as far as I'm aware, assuming your taking thyroxine for insufficiency/underactive thyroid?

    • Yes MD2 – I'm having an underactive thyroid due to a latent autoimmune thyroiditis and have been taking the pills forever. I don't feel any symptoms so it's difficult for me to see any difference but I was wondering if the natrium didn't exacerbate/cause my MS.

    • Unlikely. I used to work on Hashimoto's thyroiditis many many years ago, which is of course another autoimmune disease.

    • I would think that the contribution of sodium from levothyroxine sodium compared to your daily consumption of sodium from your dietary intake of salt would be small by comparison.

    • It is Hashimoto I have MD2 – too silly I can't spell my own illness………

      would the fact change anything for the thyroxine intake? I lreduced my salt intake but would gladly bin the thyroxine alltogether.

      what did you work on about hashimoto's? Any news on the cause?

    • No, keep taking the thyroxine, you'd really notice it if you didn't!!
      I was looking at antibody responses in Hashimoto's but it's all so long ago I'm sure things have moved on a lot since then!

    • Thanks MD2 – I'll keep taking it. Funny enough, if I stopped in the past I couldn't detect the difference because many symptoms overlap with MS – that sucks!

  • This is great news and congratulations to all involved. MD2 said a few weeks ago that the big announcement would hopefully be taken up quickly clinically and also called it a soon to be announced treatment in another thread. To be fair it is not yet and may not be for a long while yet. Or is there something else? I assume he was not referring to biotin.

    • I suspect things might move sooner than you think. We're going to be pushing hard on this and I can see pharma jumping eagerly onto the bandwagon or should that be gravy train?

  • Thanks mice. Ground breaking work. However, as yet in means little for people with MS until they can starting a pill to slow down progression. What timescale are we talking about to get a sodium channel blocker to a position where it can be prescribed for MSers? I'm not trying to rain on your parade, but nothing changes for progressive msers until the treatment can be prescribed.

    • That's something we're acutely aware of. Hopefully this result will speed things up greatly. As I've said before lots of pharma comapanies have neuroprotectants sitting on their shelves for stroke, that went nowhere because they couldn't get them into patients quick enough, which is not going to be the case for MS. All these will have already gone through tox and phase I safety trials so the pace at which they could get to MSers would be speeded up. If pharma would subsequently like to show their gratitude for a new market for their drugs by bunging us some money, so much the better!

  • Here's some interesting stuff to do with a couple of Barts' favourite MS treatment candidates and their impacts on biotin levels:
    Extract (capitals are mine)
    "Preliminary studies suggest that biotin supplements may help counteract the biotin-reducing effects of antiepileptic medications. These drugs (e.g., CARBAMAZEPINE, phenobarbital, PHENYTOIN, primidone, and valproic acid) administered orally to help prevent seizures can significantly decrease available biotin levels in the body and cause biotin deficiency. This is a common side effect of some anticonvulsant medications (occurring in over 80% of epileptic patients) and is believed to be caused by the drugs and not the condition (the deficiency only occurs after the drug is taken)."
    (See the section on drug interactions)

    • Thanks for the info. It is well known that carbamazepine can induce liver enzymes that break down other drugs that is why we are using oxcarbazepine same holds true for a number of other drugs

    • I was actually thinking not of "liver enzymes that break down other drugs", but the risk of a biotin deficiency resulting from use of a drug being used to treat MS, given that biotin deficiency can cause neurological symptoms, some of which are the same as bog-standard MS symptoms (ataxia, fatigue, muscle weakness, optic nerve atrophy, vision loss). Look at ibuprofen and folate – if you've overdone the NSAIDs some of the symptoms of folate deficiency can seem to you to be just worsening MS symptoms, plus there are the potential changes in liver enzymes etc which can be attributed to interferons.

    • Re biotin being made by gut microbes – this makes the whole thing even more interesting, given some of theories floating around about how MS can be "influenced" or possibly even caused in some people by gut bacteria imbalances. If there is some substance in these theories it might explain why some people seem to get benefits from the various MS diets promoted – one thing they all have in common is eating lots of veggies, and are thus high in fibre, which has been shown to have significant positive impacts on your gut flora and fauna.

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