Saturday, 18 April 2015

AAN 2015: embargo lifted early on optic neuritis trial

Delivering on a PROMISE, or not? #MSBlog #MSResearch


"It looks as if the AAN embargo on clinical trial results has been lifted early this year. The result of our phenytoin in acute neuritis trial are all over the web and news channels. Here are two examples below."

"Complements to Raj Kapoor, Rhian Raftopoulos, Simon Hickman and the whole team who made this trial happen. It was an impressive undertaking. Well done! And thank you to the NMSS and MS Society of the UK for funding the trial."


News 18 April 2015
WNYT

Epilepsy drug may help multiple sclerosis patients
It's designed to prevent epileptic seizures but when given to multiple sclerosis patients it seemed to prevent or limit damage to the optic nerve which is ...
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News 17 April 2015


mirror.co.uk
Multiple sclerosis sufferers could be saved from blindness with new drug treatment
A drug which prevents epilepsy seizures can stop multiple sclerosis sufferers going blind, scientists have found. More than 100,000 people have MS in ...
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"Yes, the administration of phenytoin within 14 days of the onset of acute optic neuritis reduced the amount of nerve fibre, or axonal loss, in the eye by 30% compared to placebo. Yes, this is a positive neuroprotective trial with a hard outcome. In this trial the nerve fibres were measured using OCT (optical coherence tomography) a validated and widely used outcome measure that correlates with clinically meaningful outcomes such as visual acuity and quality of life linked to visual function."

"Why is this trial important? Firstly, it shows that acute neuroprotection is possible and vindicates our work defining the so called inflammatory penumbra, i.e. a window in which acute neuroprotection will work. We have shown in our animal models of MS that if you start neuroprotective drugs after 3-days they do not protect nerves. This window of 3 days correlates with how long the blood-brain-barrier remains open in the animal model and correlates with how long gadolinium the contrast agent used with MRI to show newly inflammed lesions leaks across the barrier. We extrapolated this 3 day animal window, or inflammatory penumbra, to MS and defined it as probably being in the order of 21 days; the average time a new MS lesions enhances with gadolinium for. But the longer you delay starting the neuroprotective drug the more fibres are lost. From a logistical perspective it is difficult to start a trial drug too soon  after the onset of new symptoms as many MSers, or people, with optic neuritis only present to their doctors several days after the onset of visual symptoms. This is why we finally settled on a 14 day window; 14 days is well within our projected inflammatory penumbra in humans, but was not too short to make it difficult to recruit trial participants."

"The phenytoin study also vindicates a large body of work from many laboratories studying sodium channel blockers as neuroprotective drugs in animal models of MS; ours included. In fact in our animal model phenytoin was not the best drug, but we went with it as it is the only sodium channel blocker that can be loaded, i.e. you take a large first dose to get the drug levels therapeutic as soon as possible."

"Why are we so proud of this work? The therapeutic concepts and study design are a direct output from our PROMISE 2010 programme grant. One of our stated aims was to design new trials and treatments to address progressive MS. One of the drivers of progressive MS is acute nerve or axonal damage. This study demonstrates proof of principle that this strategy works. I would like to pause and thank the NMSS and UK MS Society and all the people who funded our PROMISE 2010 programme grant. It has been a long and arduous road, with 'many miles to go before we sleep'."

"Where to next? Dr Kapoor, a good colleague of mine and the principal investigator of this study, has already tested another sodium channel blocker, lamotrigine, in SPMS. The so called per protocol analysis of the study was negative. The problem with this study was that most of the participants were unable to tolerate the lamotrigine because of side effects. Put simply progressive MSers with a lot of disability tolerate sodium channel blockers poorly; it causes their symptoms to get worse. However, when we analysed the blood samples of these MSers who took the drug (adherent) and compared them to the placebo-treated MSers we found that lamotrigine significantly reduced neurofilament levels compared to MSers on placebo. High neurofilament levels indicates ongoing nerve damage. Therefore we think sodium channel blockers will work in SPMS if they can be tolerated."

"Are there any other sodium channel blockers that are better than phenytoin and lamotrigine? Yes, absolutely. As part of our PROMISE 2010 programme we screened numerous sodium channel blockers and found that of the already licensed drugs carbamazepine and oxcarbazepine were the most effective. We also found that they were neuroprotective at one-tenth of the dose that is used for epilepsy. This is why we have chosen low-dose oxcarbazepine for the PROXIMUS study. We think by using it at low-dose it will have fewer side effects and be better tolerated. The other design feature of the PROXIMUS study that differs from the Lamotrigine and Phenytoin studies is that we are going for an add-on approach. We believe that the in progressive MS, in addition to protecting damaged nerves you need to stop ongoing inflammation. I predict that the PROXIMUS trial will be the beginning of a new wave of combination therapy trials targeting different pathological processes in MS. Please note the PROXIMUS trial is also a follow-on study from our PROMISE 2010 programme. Again thank you to the NMSS for generously funding this study; apologies for letting you down on the timelines for recruitment is proving to be very difficult trial to recruit for. We are hoping that all this positive news around sodium channel blockers will now lead to a flood of volunteers for the PROXIMUS trial. I simply can't state strongly enough how important this trial is for the field and for people with progressive MS. At a personal level the PROXIMUS trial is the culmination of over 15 years of work."


"Finally, I hope this data stimulates Pharma to go back to their labs and dust off all the files on their sodium channel blockers. We are aware that there are several very novel and effective sodium channel blockers sitting on the shelf that need to be tested in progressive MS. My esteemed colleagues David Selwood, David Baker (MD1) and Gareth Pryce (MD2) have been slaving away in our labs to come-up with a wonderful new class of sodium channel blockers; the lead compound (CFM6104) is by far the best neuroprotective drug we have seen in our animal models of MS. Yes, better than phenytoin, better than lamotrigine and yes, we think even better than carbamazepine and oxcarbazepine. What we need now is follow-on funding to take this drug forward into a full pre-clinical and clinical development programme. When I get back to London after the AAN, David Baker, David Selwood and I have a meeting with the MRC about this. But an easier and quicker route is to hand over the drug to a Pharma company; resource, speed and energy is what they have. It has taken us the better part of 15 years to get VSN16, our antispastic agent, from the bench into a phase 2 trial. The whole process of academic drug development is very very difficult. This is why I am meeting with a Pharma company this week to see if they would be interested in partnering with us on our sodium channel blocking programme. I wonder if the results of the acute optic neuritis trial may be a big enough carrot?"


Relevant papers underpinning this work from our PROMISE 2010 Programme:


The inflammatory penumbra

Al-Izki S1, 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 Jan;137(Pt 1):92-108.

Progressive multiple sclerosis is associated with metabolic failure of the axon and excitotoxicity that leads to chronic neurodegeneration. Global sodium-channel blockade causes side effects that can limit its use for neuroprotection in multiple sclerosis. Through selective targeting of drugs to lesions we aimed to improve the potential therapeutic window for treatment. This was assessed in the relapsing-progressive experimental autoimmune encephalomyelitis ABH mouse model of multiple sclerosis using conventional sodium channel blockers and a novel central nervous system-excluded sodium channel blocker (CFM6104) that was synthesized with properties that selectively target the inflammatory penumbra in experimental autoimmune encephalomyelitis lesions. Carbamazepine and oxcarbazepine were not immunosuppressive in lymphocyte-driven autoimmunity, but slowed the accumulation of disability in experimental autoimmune encephalomyelitis when administered during periods of the inflammatory penumbra after active lesion formation, and was shown to limit the development of neurodegeneration during optic neuritis in myelin-specific T cell receptor transgenic mice. CFM6104 was shown to be a state-selective, sodium channel blocker and a fluorescent p-glycoprotein substrate that was traceable. This compound was >90% excluded from the central nervous system in normal mice, but entered the central nervous system during the inflammatory phase in experimental autoimmune encephalomyelitis mice. This occurs after the focal and selective downregulation of endothelial p-glycoprotein at the blood-brain barrier that occurs in both experimental autoimmune encephalomyelitis and multiple sclerosis lesions. CFM6104 significantly slowed down the accumulation of disability and nerve loss in experimental autoimmune encephalomyelitis. Therapeutic-targeting of drugs to lesions may reduce the potential side effect profile of neuroprotective agents that can influence neurotransmission. This class of agents inhibit microglial activity and neural sodium loading, which are both thought to contribute to progressive neurodegeneration in multiple sclerosis and possibly other neurodegenerative diseases.

A novel new sodium-channel blocker:

Browne L1, Lidster K, Al-Izki S, Clutterbuck L, Posada C, Chan AW, Riddall D, Garthwaite J, Baker D, Selwood DL. Imidazol-1-ylethylindazole voltage-gated sodium channel ligands are neuroprotective during optic neuritis in a mouse model of multiple sclerosis. CJ Med Chem. 2014 Apr 10;57(7):2942-52.

A series of imidazol-1-ylethylindazole sodium channel ligands were developed and optimized for sodium channel inhibition and in vitro neuroprotective activity. The molecules exhibited displacement of a radiolabeled sodium channel ligand and selectivity for blockade of the inactivated state of cloned neuronal Nav channels. Metabolically stable analogue 6 was able to protect retinal ganglion cells during optic neuritis in a mouse model of multiple sclerosis.

A new animal model of optic neuritis:

Lidster K1, Jackson SJ, Ahmed Z, Munro P, Coffey P, Giovannoni G, Baker MD, Baker D. Neuroprotection in a novel mouse model of multiple sclerosis. PLoS One. 2013 Nov 4;8(11):e79188. doi: 10.1371/journal.pone.0079188. eCollection 2013.

Multiple sclerosis is an immune-mediated, demyelinating and neurodegenerative disease that currently lacks any neuroprotective treatments. Innovative neuroprotective trial designs are required to hasten the translational process of drug development. An ideal target to monitor the efficacy of strategies aimed at treating multiple sclerosis is the visual system, which is the most accessible part of the human central nervous system. A novel C57BL/6 mouse line was generated that expressed transgenes for a myelin oligodendrocyte glycoprotein-specific T cell receptor and a retinal ganglion cell restricted-Thy1 promoter-controlled cyan fluorescent protein. This model develops spontaneous or induced optic neuritis, in the absence of paralytic disease normally associated with most rodent autoimmune models of multiple sclerosis. Demyelination and neurodegeneration could be monitored longitudinally in the living animal using electrophysiology, visual sensitivity, confocal scanning laser ophthalmoscopy and optical coherence tomography all of which are relevant to human trials. This model offers many advantages, from a 3Rs, economic and scientific perspective, over classical experimental autoimmune encephalomyelitis models that are associated with substantial suffering of animals. Optic neuritis in this model led to inflammatory damage of axons in the optic nerve and subsequent loss of retinal ganglion cells in the retina. This was inhibited by the systemic administration of a sodium channel blocker (oxcarbazepine) or intraocular treatment with siRNA targeting caspase-2. These novel approaches have relevance to the future treatment of neurodegeneration of MS, which has so far evaded treatment. 

Proof that sodium channel blocker may be neuroprotective in SPMS:

Gnanapavan S, Grant D, Morant S, Furby J, Hayton T, Teunissen CE, Leoni V, Marta M, Brenner R, Palace J, Miller DH, Kapoor R, Giovannoni G. 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.

OBJECTIVE: Lamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate the value of neurofilament (NfH) and other biomarkers in predicting prognosis and/or response to treatment.

METHODS: SPMS patients who attended the NHNN or the Royal Free Hospital, UK, eligible for inclusion were invited to participate in the biomarker study. Primary outcome was whether lamotrigine would significantly reduce detectable serum NfH at 0-12, 12-24 and 0-24 months compared to placebo. Other serum/plasma and CSF biomarkers were also explored.

RESULTS: Treatment effect by comparing absolute changes in NfH between the lamotrigine and placebo group showed no difference, however based on serum lamotrigine adherence there was significant decline in NfH (NfH 12-24 months p=0.043, Nfh 0-24 months p=0.023). Serum NfH correlated with disability: walking times, 9-HPT (non-dominant hand), PASAT, z-score, MSIS-29 (psychological) and EDSS and MRI cerebral atrophy and MTR. Other biomarkers explored in this study were not found to be significantly associated, aside from that of plasma osteopontin.

CONCLUSIONS: The relations between NfH and clinical scores of disability and MRI measures of atrophy and disease burden support NfH being a potential surrogate endpoint complementing MRI in neuroprotective trials and sample sizes for such trials are presented here. We did not observe a reduction in NfH levels between the Lamotrigine and placebo arms, however, the reduction in serum NfH levels based on lamotrigine adherence points to a possible neuroprotective effect of lamotrigine on axonal degeneration.



Time for some reflection

"Jet lagged and holed-up on my own in a dark hotel room in Washington DC, I can't help but reflect on the journey that has gotten us to this point. The Robert Frost poem, which I studied when I was in high school, sums up my mood very well." 
  
Stopping by Woods on a Snowy Evening

BY ROBERT FROST

Whose woods these are I think I know.   
His house is in the village though;   
He will not see me stopping here   
To watch his woods fill up with snow.   

My little horse must think it queer   
To stop without a farmhouse near   
Between the woods and frozen lake   
The darkest evening of the year.   

He gives his harness bells a shake   
To ask if there is some mistake.   
The only other sound’s the sweep   
Of easy wind and downy flake.   

The woods are lovely, dark and deep,   
But I have promises to keep,   
And miles to go before I sleep,   
And miles to go before I sleep.

CoI: multiple

32 comments:

  1. Prof G,

    Thanks for the update - I'm glad the trial was positive. What does it mean for someone recently diagnosed with progressive MS. Could a neuro prescribe a sodium channel blocker (even though it's not licensed for MS)? If no, what sort of timeframe are we looking at before a drug is licensed for progressive MS?

    PS 30 per cent is good, but we've been there before with first line injectibles. Could 30 per dent be improved on? Where does remyelinatioon fit in?

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    1. Re: "PS 30 per cent is good, but we've been there before with first line injectibles. Could 30 per dent be improved on?"

      30% is a start. I suspect if the drug is on board before the new lesion forms the better will be the neuroprotection. We haven't tested that strategy in our animal model but it can be done. But this is how we envisage sodium channel blocker being used in the future; you will have them on board continuously and not just as a treatment for relapses.

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    2. Re: "Where does remyelinatioon fit in?"

      If you see the pyramid above it fits in on top of neuroprotection. You need to have surviving axons to remyelinate. The issue about remyelination is that in early MS there does not seem to be a problem with remyelination. If you stop the inflammation with effective enough DMTs remyelination seem to happen spontaneously. This may not be the same in progressive MS when there is loss of axons and age may impact on the efficiency of remyelination.

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  2. It's dispiriting to think that in 15 years we are merely at this point: Some novel medicine of yesteryear demonstrates nominal efficacy if administered within a 2-week period.

    I suppose that this post is more of a signal to Big Pharma that there may be money to be made by taking on studies in this area as a result of phenytoin's outcomes in MS trials.. We are still miles away from bettering the lives of prog-MSers. This is too little news to be thrilled by the way that you expect us to be, Prof G.

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    1. Re: "It's dispiriting to think that in 15 years we are merely at this point..."

      Unfortunately, science and drug development tend to be incremental processes and take a long time. It is not for lack of trying.

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  3. Well done guys - groundbreaking stuff! Out of interest, would it be proposed that you take this permanently, ongoing? Or just following an attack?

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    1. Re: " Out of interest, would it be proposed that you take this permanently, ongoing?"

      Yes, permanently to prevent loss if there is ongoing inflammation. The problem is that phenytoin is not a great long-term drug for continous use. Too many side effects and complications. Other sodium channel blockers will be better. This is why we need new add-on trials; hence, the PROXIMUS trial.

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  4. Thanks for posting this, I had guessed the outome would be positive.

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  5. Does Optic neuritis cause permanent damage and loss of sight? How many times would an MS patient suffer ON in a lifetime? Is there a difference between a thin retina caused by ON and high myopia?

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    1. Re: "Does Optic neuritis cause permanent damage and loss of sight?"

      Yes, on average with an acute attack of optic neuritis there is loss of ~20% of the nerve fibres in the optic nerve or retinae. The reason why MSers are unaware of this is because the surviving fibres and brain adapt to the loss of fibres; we call this plasticity. However, if we interrogate the function of the retinae in MSers who have had ON we almost always find subtle problems; loss of colour vision or problems seeing in poor light or problems with depth perception.

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    2. Re: "Is there a difference between a thin retina caused by ON and high myopia?"

      Yes, there is a difference. The neuronal loss in ON is due to inflammation and in high myopia it is due to anatomical factors related to the shape and size of the eye and possibly the effect of the pressure inside the eye.

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  6. Excellent news, how will this effect us in real life? Will it be used in combination with lemtrada/tysabri in rrms or solely for progressive msers?

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    1. Re: "Excellent news, how will this effect us in real life?"

      No effect on real-life at present except to give you hope that there is a neuroprotective strategy worth studying further in MS, in particular progressive MS.

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    2. Re: "Will it be used in combination with lemtrada/tysabri in rrms or solely for progressive msers?"

      Yes, if the combination strategy pans out I would envisage a neuroprotective drug being taken in addition to an anti-inflammatory drug. A so called combination treatment strategy.

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  7. I was given carbamazepine 30 years ago. I had too many side effects so had to stop it. it worked, it took away the pains and enabled me to walk much further. I don't understand this. is there something I've missed?

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    1. Re: " is there something I've missed?"

      You were probably prescribed carbamazepine for the pain. Back then we didn't know about the potential neuroprotective effects of sodium channel blockers.

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    2. So had I been able to tolerate it, I would be in a better position today. It would be great if the side effects could be eradicated or halved.

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    3. I've been taking 600mg per day of carbamazepine for 2 years now. It was prescribed to me to control my trigeminal neuralgia. It's been amazing at eliminating my pain, I no longer have the constant tingling in my legs either. And my issues I was having walking with my right hip have disappeared. It took a few months to adjust, but now I have zero side effects from being on it.
      Not sure what long term effects it may have though?

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    4. Interesting indeed. If our mouse data is real it could also be neuroprotective but we need the PROXIMUS trial to confirm this.

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  8. Nice poem. I am a big Robert Frost fan.

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    1. Re: " I am a big Robert Frost fan."

      Me too; I am a particular fan of "mending wall" and its historical significance.

      Delete
  9. Docs could Gabapentin have the same neuroprotective effect?

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    1. Re: "could Gabapentin have the same neuroprotective effect?"

      No, gabapentin is not a sodium channel blocker. In fact, how gabapentin works as an anticonvulsant or anti-pain drug is not well defined. If gabapentin is neuroprotective it will be via a different mechanism.

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  10. Great result, congratulations! Can you explain how both sodium channel blockers AND potassium channel blockers (ampyra) can be beneficial?

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    1. I asked a while back if you could even do both at the same time safely and one of the MeeseDoctors wasn't sure.

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    2. Potassium channel blockers are having an effect on symptoms. They allow the nerve to work harder and there is a theorectical possibility that this could have opposite effect of sodium channel blockers and contribute to the problem. Our ion chanel expert does not thing this is going to happen but it would be good to test. If we could get this formally tested it would be good. Having to reply on 4 amino pyridine is less useful

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  11. There is obviously lots to read and digest here - but I am happy to hear there is positive news coming for this trial. As for the embargo lift - perhaps it wasn't lifted, just anxious web journalists who don't understand the rules on sharing this before the embargo date arrives. I'm sorry it came out before you were center stage to share these results. Enjoy the week in DC and I hope you get to see some cherry blossoms.

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  12. It was in the British Newspapers on friday

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  13. Extremely proud of all of you guys - just got the news so late due to broken internet.

    A ray of hope - thank you meeces, profs, lab peeps, msers who took part!

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    1. Thanks! We're feeling pretty proud of ourselves too, if that's allowed!
      All those weekends in the mouse house are finally paying off.
      Remember this is just the start.
      "It is not the end
      It is not the beginning of the end
      But it may be the end of the beginning"
      Onwards and upwards ;-)

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