Browne L, Lidster K, Al-Izki S, Clutterbuck L, Posada C, Chan AE, Riddall D, Garthwaite J, Baker D, Selwood DL. Imidazol-1-ylethylindazole voltage gated sodium (Nav) channel ligands are neuroprotective during optic neuritis in a mouse model of multiple sclerosis. J Med Chem. 2014 Mar 6. [Epub ahead of print]
A series of imidazol-1-ylethyl)indazole sodium channel ligands were developed and optimized for sodium channel inhibition and in vitro neuroprotective activity. The molecules exhibited displacement of the radiolabelled sodium channel ligand and selectivity for blockade of the inactivated state of cloned neuronal Nav channels. A metabolically stable analogue 6 (CFM6104) was able to protect retinal ganglion cells during optic neuritis in a mouse model of multiple sclerosis.
This is the second is instalment of the same story we reported earlier this year. The first below was for biologists and this new one was the the chemistry behind the drug.
Targeting drugs to lesions. Animal studies help inform clinical trials 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 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.
The lamotrigine trial failed in progressive MS Trial. Why?
The wrong idea…..maybe, The wrong drug….possibly
The wrong trial design…….definitely.
We showed that half of the people in the trial were not taking the drug in the prescribed manner so the trial was doomed. Furthermore there was a suggestion of efficacy in people actually taking the drug.
However, this message is lost by the take home message that the Lamotrigine trial failed. Therefore, lamotrigine has been chucked in the bin because of ineffective trial design and implementation and the basic science that underpinned the trial has been rubbished along with the animal models that underpinned the trials.
Whilst you may say I am biased, there are a large number of other examples where clinical trial design and implementation are killing off MS drugs. This is why it is critical that an effective trial design is found to spot useful candidates. Since the interferons were found to work in MS, imaging modalities notably gadolinium enhancing lesions can be used to predict activity, trial design has rapidly evolved so there are more hits than misses in RRMS. Before this time there were just misses because they used to test their best candidates in SPMS, which does not respond to such drugs. In progressive MS we are in that miss phase and unfortunately some of the misses may be hits if only we knew how best to show it.
However, one needs to ask the question, why did people not take their meds, one possibility is that they thought their meds were not working. Another possibility was that the drug was causing unacceptable side effects.
We know side-effects happened because there were movement problems in most people on the drug. They could not tolerate the drug such that they did not reach the intended maximum dose as used in epilepsy and many people dropped out of the study. Why?
Because you need sodium channels for your nerves to function properly. They selected people for the trials who probably had less tolerance in the system to accommodate a diminution of nerve impulse conduction, because they have less circuitry because of their Progression and so side effects predominated.
Was it a duff idea? Well we do not think so.
In our animal models we tested a number of different targets with different drugs and found that sodium channel blockers were indeed a good candidate drug to try.
They were not all created equal and some were better than others in saving nerves. But some were found to save nerves as a consequence of the inflammatory attack.
In the early stages of EAE we found that nerve damage happened and that this occurred as the lesion was forming, but once it was resolving treatment did not have any extra benefit over the natural regulatory/repair mechanisms. This suggested we should deliver such drugs when the lesions were evolving during the formation of the “Inflammatory Penumbra”.
This occurs over a few days in animals but probably for a couple of weeks to a month in humans. It seems that there is damage as a consequence of the inflammatory attack and we called this the “inflammatory penumbra” to reflect the similarities pathways with stroke. In stroke the blood clot stops oxygen to the nerves and kills them, but then the ischemic penumbra occurs and grows outside this region of damage and particularly once there is a return to oxygen supply, nerves start to fire excessively and commit suicide by exciting themselves to death. During MS/EAE the inflammatory insult will cause damage around the blood vessels but will cause additional damage, within the penumbra including this excitotoxicity. We showed that sodium channel blocking drugs could limit this and we showed that drugs could inhibit damage that occurs during optic neuritis in the optic nerve and save neurons in the eye.
The upshot of this is that we (ProfG) are trying this approach in optic neuritis to see if it saves nerves..The drug selected for that clinical study was not my favoured candidate, but it is being tried as you can ramp the dose up quickly because the idea is to give the drug whilst the lesions would be evolving. Once we know it works in this paradigm, we can think about whether we can then target PPMS and SPMS, where the disease process may be a bit different, and nerve damage during RRMS.
So far all pre-clinical studies have investigated the effects of sodium channel blockers during the inflammatory penumbra and it remains to be seen if they can also halt non-relapsing progressive disease in both animals and humans.
There is a logic of why there can be benefit for progressive MS. However, in our studies there was no evidence that it was stopping the processes that drive that attacks and so suggested that optimal response may require co-administration with something that will deal with the immune problem.
Next thing we found was that the sodium channel blockers could slow the loss of nerve content in the spinal cord and the upshot of this is that we aim to to try a more effective (in our hands) sodium channel blocker in MS in the PROXIMUS trial, when there is an inflammatory penumbra present.
However, we realised and found that these types of drugs can cause side effects, when they get into the brain.
Now we know that drugs can be excluded from the brain by drug-exclusion pumps on the blood vessels. Therefore for drugs we want to get into the brain we have to design chemicals to by-pass these molecules, which is difficult. One of these pumps is called p-glycoprotein and is upregulated in cancers to stop anti-cancer drugs working. This forms part of the blood brain barrier.
Imagine p glycoprotein as a cloths peg. When a chemical enters the cell membrane it gets sucked into the area near the spring and with energy the peg is opened and the drug gets pushed out from the teeth of the peg.
Now we know that MS is associated with blood brain barrier breakdown, and during a student project we found out that some of these drug pumps are lost in lesions in EAE. We then also showed that this occurs in MS. Importantly this not only occurred in the active lesions but also the pump was lost in chronic lesions too.
This, therefore contributes to blood brain barrier breakdown and could even contribute to nerve toxicity as it may let in things from the blood that should not be there. Importantly it gave us a way to target therapy to lesions,where therapy is needed most.
What does that mean?
Well if we could make a drug that is normally pumped out of the brain by p glycoprotein then it would not be able to enter the brain to cause too many side-effects. However, in the lesions the drug should be able to enter the brain/spinal cord as the pumps are missing. So we could target drugs to sites where they are needed.
So how could we show this?
Well we know a good chemist (See the new paper) and they made some new sodium channel blocking drugs. Based on their chemical structure we could predict that they would not get into the brain probably, because they would be pumped out by p-glycoprotein.
We showed that this would be the case and showed that a drug (CFM6104) did not get into the healthy brain. Interestingly even when EAE was occurring we could not even pick it up in the CNS by some techniques. However because of a bit of chemistry magic the drug glowed-in-the-dark under ultra violet light and we could trace it and we could show that it did indeed leak into lesions and this stopped nerve loss to a similar extent that could be found with global sodium channel blockage.
Therefore you do not need much if you can get it to the right place (which is the hope for anti-LINGO antibody that was 99.95% excluded.In contrast our drug was about 95% excluded).
This study makes the point of lesion targeting of neuroprotection . We recently showed that this could be exploited for symptom control Whilst our work it is a neat bit of applied science, it is not the finished article and we need more work to get a useful clinical drug. However, this could be applied to whole host of other treatments and drug classes as any drug that interferes with nerve signalling will cause unwanted side-effects. This is a way to avoid them.
CoI. This work from Team G