We (MD & MD2) have taken quite a bit of flak recently about being excited but gagged and friday we will find out the results, which we have not seen! (Honest).
Dr Raj Kapoor will present “Phenytoin is neuroprotective in acute optic neuritis: Results of a phase 2 randomized controlled trial” at the American Academy of Neurology in Washington.
However, the press embargos have been lifted and it is clear that nerves were saved. This was supposed to be launched on friday but as the whole world has blabbed, we may as well post.
We believe this good news for RR and Progressive MSers, as we are cracking that progressive nut. we have tested a hypothesis in animals and now we have done this in humans and it works!
We knew the take home message and this has been on the web (on the AAN website) for weeks and you haven’t spotted it.
As a scientist it is incredibly frustrating when neurologists do not translate our ideas as it can be years of our lives wasted, as the case with the CUPID trial. If they succeed you will get limited or no credit….. I guess there is no i in team:-)
However, it is incredibly rewarding when your ideas come to fruition and shows some value to humans and we are incredibly proud of the MD Team. TeamG and UCLP and this story has taken many years of hard work.
The idea and concept of today’s (partial) breakthrough have their roots firmly in animal studies. TeamG can take credit for reviving this phoenix.
The first failure for sodium channel blockers was that of Prof Waxman from Yale. He had pioneered the idea with Ken Smith & Raj Kapoor in London.
Watch the video of Marija and the Bouncers that explain this
(CLICK). (Sodium channel blockers are the locks) and how it relates to nerve energy.
We had helped ProfWaxman find the sodium channel problem in EAE that he had been looking for and helped them get the EAE going and off they went doing their own thing.
After showing that phenytonin was (somehow?) immunosuppressive in acute EAE. Prof Waxman had lined up a phenytonin trial in progressive MS.
However, this was bottled after it was found (as should have been expected-if they were used to EAE research) that EAE mice get EAE after one withdraws an immunosuppressive drug. This can take a couple of days to a few weeks dependent on the drug…but decent EAE comes back!
TeamG saves the Class
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.
We (NeuroDocG/ProfG) with Dr Kapoor did two things:
(2) We looked to see who had neurofilaments as a marker of nerve damage and it was found that people who took the drug had less neurofilament in their blood than the people who where not taking their drugs. Therefore this strongly suggested that sodium channel blockade can be neuroprotective.
This information has also been ignored and lamotrigine has been tarred as a failure probably never to be used again.
At the same time, as part of Promise 2010….the MD’s (MD1-MD4) were looking for neuroprotective drugs and we tested a number of different classes of drugs. We had also decided that optic neuritis was going to be one of the better ways to test things in humans.
However, the original planned human testing arm was cut from the original Promise 2010 grant budget.
So we were tasked by ProfG with reverse engineering MS to produce an optic neuritis model in animals to get the evidence needed for the human studies. This is what we did.
We tested a number of different types of agent and showed that sodium channel blockers were one of the better classes of drugs, (There are a number of others) that could save nerves in the eye following the onset of optic neuritis.
The blue dots are nerves within the retina of the EAE seen at low magnification (Left) and higher magnification (centre & right). We
caused optic neuritis (centre & right) and nerves got damaged and died and the sodium channel blocker (centre) could save them despite the optic neuritis in the optic nerve.
We also showed that the optimal response was time dependent and you only have so long to start treatment of get the best response. In animals this was a few days to treat the inflammatory penumbra and we predicted it would be about a few 2-4 weeks in optic neuritis. Also steroids are not much use after this time point.
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;137:92-108
Therefore it was decided that people should be put on drug within to weeks of onset if possible. This makes sense when you see how nerves are lost in optic neuritis in humans.
Dr Raj Kapoor was recruited to the Promise 2010 team as sodium channels blockers were his baby. He has done a really fantastic job in recruiting about 100 people with optic neuritis (a common problem in pwMS), within two weeks of their first symptom, in a quick time. This is aided in London by a large population and having specialist eye hospitals with neurologists embedded in them so they can pick up optic neuritis quickly.
It was decided that phenytoin would be used as it could be loaded/dosed quickly our preferred other options needed the dose to titrated up slowly and time was of the essence.
The study was funded by the NMSS in the USA…so they and their US donors are the stars too! A big thank you!
All we can say that from the title it is clear that the results are Positive and this is fantastic news and translates our animal work and shows that we are on the right track, in targeting Progressive MS. This is great news for 2015.
The Doom & Gloomers will be saying chunter, chunter,chunter:-)
as the have been doing (But please don’t bother commenting!)
Yes you have a point because mores studies will indeed be needed before phenytoin could become available for progressive MSers. It has to be said in our hands pheytonin was not the best, so there is room for improvement, with a more neuroprotective sodium channel blocker and development of other drugs with better side effect profiles.
Phenytonin is a generic and it will be difficult to develop but pharma have plenty of new molecules up their sleeve and could do an accelerated drug development process. Maybe this is why Biogen splashed out over $600 million to buy a sodium channel company. Maybe Novartis that makes Oxcarbazeppine have more compounds in their closet.
However it says we can indeed use animals to find drugs to treat MS .
So well done to Dr Kapoor and the UCLP (ProfG & DrK) team.
How can you get your hands on a sodium channel blocker right now?
Disclaimer: please note Barts-MS can’t recruit subjects for clinical trials via this blog.
If you are interested in participating in the PROXIMUS trial you need to be referred to Barts-MS via your GP or treating neurologist.
- A diagnosis of definite multiple sclerosis
- Treatment with DMDs for at least 6 months
- EDSS score between 3.5 and 6.0
- No history of relapses in the preceding 6 months
- A history of slow progression of disability, objective or subjective, over a period of at least 6 months
- Age 18-60 years
- Pregnant or breastfeeding or unwilling to use adequate contraception.
- Participants who do not take a DMDs for MS.
- A clinical relapse or pulsed intravenous or oral steroids in the 6 months preceding the baseline assessment.
- Participants presenting with medical disorder deemed severe or unstable by the CI such as poorly controlled diabetes or arterial hypertension, severe cardiac insufficiency, unstable ischemic heart disease, abnormal liver function tests (>2.5 times ULN) and abnormal complete blood count (in particular leukopenia, as defined by a lymphocyte count <500, neutrophil count <1.5 or platelet count <100, or thrombocytopenia <1.5 LLN), or any medical condition which, in the opinion of the chief investigator, would pose additional risk to the participant.
- Infection with hepatitis B or hepatitis C or human immunodeficiency virus.
- Participants receiving other sodium or calcium channel blockers in the previous 12 weeks
- Exposure to any other investigational drug within 30 days of enrolment in the study.
- Judged clinically to have a suicidal risk in the opinion of the investigator based upon a clinical interview and the Columbia Suicide-Severity Rating Scale (CSSRS).
- Prior history of malignancy unless an exception is granted by the Chief Investigator.
- History of uncontrolled drug or alcohol abuse within 6 months prior to enrolment into the study.
- Past untoward reactions to Oxcarbazepine or carbamazepine.
ProfG is at the AAN and hopefully will post more details on this and MD1003 once the work is presented.