"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
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