“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|
drug may help multiple sclerosis patients
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 …
|News 17 April 2015|
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 …
“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.”
Relevant papers underpinning this work from our PROMISE 2010 Programme:
The inflammatory penumbra
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.
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.
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.”