Tuesday, 2 February 2016

ResearchSpeak: neuroprotection in optic neuritis and beyond

How to make a PROMISE a reality, or not? We now need some momentum for the PROXIMUS trial. #MSBlog #MSResearch #ResearchSpeak

"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, because  it is an output from our PROMISE 2010 grant.  However, more importantly 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 blood brain barrier in our animal model. 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 for with gadolinium. The  underlying principle is that the longer you delay starting the neuroprotective drug the more nerve 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 a neurologist several days after the onset of visual symptoms (in the NHS it may take months to see a neurologist). This is why we finally settled on a 14 day window; 14 days is well within our projected inflammatory penumbra in humans, but not too short to make it too 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, and still '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 still proving to be very difficult. 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, we 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 preclinical and clinical development programme."

"Please note phenytoin is an off-patent drug. Taking it forward as a treatment for MS in itself will be difficult. The issue of using off-patent drugs for proof-of-concept studies raises many questions that has been addressed by us in the past. More on this next time."

Epub: Raftopoulos et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016. pii: S1474-4422(16)00004-1. doi: 10.1016/S1474-4422(16)00004-1.

BACKGROUND: Acute demyelinating optic neuritis, a common feature of multiple sclerosis, can damage vision through neurodegeneration in the optic nerve and in its fibres in the retina. Inhibition of voltage-gated sodium channels is neuroprotective in preclinical models. In this study we aimed to establish whether sodium-channel inhibition with phenytoin is neuroprotective in patient with acute optic neuritis.

METHODS: We did a randomised, placebo-controlled, double-blind phase 2 trial at two UK academic hospitals in London and Sheffield. Patients with acute optic neuritis aged 18-60 years, presenting within 2 weeks of onset, with visual acuity of 6/9 or worse, were randomly assigned (1:1) by minimisation via a web-based service to oral phenytoin (maintenance dose 4 mg/kg per day if randomised before or on July 16, 2013, and 6 mg/kg per day if randomised on or after July 17, 2013) or placebo for 3 months, stratified by time from onset, centre, previous multiple sclerosis diagnosis, use of disease-modifying treatment, and use of corticosteroids for acute optic neuritis. Participants and treating and assessing physicians were masked to group assignment. The primary outcome was retinal nerve fibre layer (RNFL) thickness in the affected eye at 6 months, adjusted for fellow-eye RNFL thickness at baseline, analysed in a modified intention-to-treat population of all randomised participants who were followed up at 6 months. Safety was analysed in the entire population, including those who were lost to follow-up. The trial is registered with ClinicalTrials.gov, number NCT 01451593.

FINDINGS: We recruited 86 participants between Feb 3, 2012, and May 22, 2014 (42 assigned to phenytoin and 44 to placebo). 29 were assigned to phenytoin 4 mg/kg and 13 to phenytoin 6 mg/kg. Five participants were lost to follow-up, so the primary analysis included 81 participants (39 assigned to phenytoin and 42 to placebo). Mean 6-month RNFL thickness in the affected eye at 6 months was 81·46 μm (SD 16·27) in the phenytoin group (a mean decrease of 16·69 μm [SD 13·73] from baseline) versus 74·29 μm (15·14) in the placebo group (a mean decrease of 23·79 μm [13·97] since baseline; adjusted 6-month difference of 7·15 μm [95% CI 1·08-13·22]; p=0·021), corresponding to a 30% reduction in the extent of RNFL loss with phenytoin compared with placebo. Treatment was well tolerated, with five (12%) of 42 patients having a serious adverse event in the phenytoin group (only one, severe rash, was attributable to phenytoin) compared with two (5%) of 44 in the placebo group.

INTERPRETATION: These findings support the concept of neuroprotection with phenytoin in patients with acute optic neuritis at concentrations at which it blocks voltage-gated sodium channels selectively. Further investigation in larger clinical trials in optic neuritis and in relapsing multiple sclerosis is warranted.

FUNDING: US National Multiple Sclerosis Society, Multiple Sclerosis Society of Great Britain and Northern Ireland, Novartis, UK National Institute for Health Research (NIHR), and NIHR UCLH/UCL Biomedical Research Centre.

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Relevant papers underpinning this work from our PROMISE 2010 Programme:

The inflammatory penumbra:

Al-Izki et al. 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 et al. 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 et al. 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 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.

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:

"I still 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. Until we have a licensed add-on drug to slow down, stop or prevent progressive MS we have promises to keep and many miles to go before we sleep. If you have MS and are on a DMT and think you are progressing you may be eligible for the PROXIMUS trial. To be screened for this trial you will need to ask your GP or neurologist to refer you to our centre for screening. Without people with MS volunteering for this trial we can't take the field forward. Thank you."

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, Team G was part of this trial

7 comments:

  1. Very interesting and exciting, though I note that phenytoin is not without side effects? How would that be in a cocktail with a DMT? Cure potentially worse than the disease? Roll on Charcot - here's to a simple anti-viral to cure the lot.

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    1. Point taken but these are first (baby) steps. The aim is to find the best neuroprotectant. Phenytoin certainly wasn't in the mice so the fact it has shown efficacy in the above study is significant. The reason it was used in this study is stated in the post.
      We need to find the most effective, with the least side-effects and hopefully this study will provide the impetus to achieve that.

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    2. Okay - thanks for the explanation. [Sorry, forgot to add my "call sign" - was in rush + grumpy.]

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  2. I am very happy with all this news, although still linger a while to actually reach us pwMs on a daily basis.
    But it's the beginning, and I've heard some of my colleagues here in Brazil reporting that their neutologistas are already citing the work of the Team G and Dr. Taj Kapoor on Phenytoin.

    And left me even happier the effects of CFM6104 ...

    The PROXIMUS trial is still recruiting participants?

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    1. Yes still recruiting, which has been very slow. Hope it happens.

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  3. Will/should the next stage be crowd-funded?

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