Monday, 16 June 2014

Statins is CNS penetration important. What are Neuros doing to get them made available?

Yesterday the research talk by ProfB was about getting drugs to where they are needed and the slow speed of developing drugs. 

He used two examples from the lab of one targeting into the brain and the other kept out of the brain to improve the efficacy: to side effect profile.

However, the main question asked after the talk was what is happening to statins? This was a recurrent feature of the day. However it has nothing to do with the talk.  

OK whilst we were part of the group that showed that statins could work in EAE, the clinical development of statins for MS has nothing to do with us. Sir Jeremy chairing the session (PI of the Simvastatin Trial in MS) however avoided answering the question....so one can only suspects the answer was not positive.

Academics do one study and if it works they then have to wait to get finance to do the follow-on study, whereas pharma would be geared up to start the next study straight after the success of the first.  So academics do things slowly

However, in the case of statins, which appeared to slow the progression in a trial in a trial of high dose statin, What have the academics and neuros and the MS Society that supported the study, done next.................seemingly nothing! 

It is years since the study ended

We (neuros) are embarking on a period of trials of repurposed (developed for other disease applications then tried in MS. This is case for most current MS drugs) for progressive MS and repair, supported by MS Societies, etc. 

However, what is being done to ensure that "nothing" does not happen after positive results. If there is no way of getting drugs available to people is it ethical to even start?

We only have a few years to sort this out. The MS Smart trial is starting, Proximus is starting, other trials are starting in Europe and US. 

There are many in the establishment that think that Neuros will just start prescribing. Will they? 

Do the people in the establishment need to stop dreaming and start thinking, so that there is a concrete published pathway and plan to do this. Having seen so grant forms this pathway is not part of the funding application and surely is the most critical piece of any award.

Do we need phase III data, two phase III or just start after a phase II. Pharma would cry foul if there are double standards being applied...Should we care what Pharma think?.

Is the process that we should do study of cheap generic drug and then hope that pharma will repurpose it? They will make a pro-drug so that you take a drug and when it is broken down it turns into the cheap generic drug. Pharma spends a billion dollars doing this so that can charge $50,000 p.a. in US for this, rather than  $100 p.a. for the parent drug (just as they have done for Movectro, famprydine, Tecfidera, laquinimod etc.). Or in the case of statins about $50p.a. 

If they made a new statin however could pharma charge much more than statins currently cost....It may be difficult to justify a big hike. 

Likewise, if we have generic statins at £2.30 a month being prescribed will pharma be bothered doing trials in progressive MS any more. While there is no alternative pharma will be in the hunt to charge as much as possible. 

Should the PI be made to follow their studies through before moving onto new ones?

Can we incentivise pharma to do the statin study we need to know if there is a dose-response as a minimum. If pharma did the study, we should get governments to either only sanction purchase from the company doing the study or provide a new patent for a number of years, allow some price adjustment so they can recoupe costs and make profit. 

Can we get progressive MS as an orphan disease so only one phase III need to be done and so make it academically more attractive. This is part of the Big pharma alternative. 

Something needs to happen. It is a political solution..the MS community needs to make it happen..We need some champions. 

We have talked about this issue before


How do statins work...I'm not definitively sure in terms of neurodegeneration. The cholesterol pathway is however important in Altzheimer's disease as shown by the genetic susceptibility and statins have been implicated as a neuroprotective in that disease, so why not in MS? The data implicated in Altzheimers disease is based on people taking statins as for co-morbitiy i.e. High cholesterol and are probably not crazy high doses as used in MS trials. But how does the data in altzheimers disease have relevance to my talk?

Corrao G, Ibrahim B, Nicotra F, Zambon A, Merlino L, Pasini TS, Catapano AL, Mancia G.Long-term use of statins reduces the risk of hospitalization for dementia. Atherosclerosis. 2013; 230:171-6

BACKGROUND: Dementia is a major public health problem because of its high prevalence in elderly individuals, particularly in the growing category of subjects aged 80 years or more. There is accumulating evidence that cholesterol may be implicated in the pathogenesis of dementia, and this has led us to assess the relationship between time spent with statins available and the risk of hospitalization for dementia.
METHODS: A population-based, nested case-control study was carried out by including the cohort of 152,729 patients from Lombardy (Italy) aged 40 years or older who were newly treated with statins between 2003 and 2004. Cases were the 1380 patients who experienced hospitalization for dementia disease from initial prescription until 2010. Up to twenty controls were randomly selected for each case. Logistic regression was used to model the risk of dementia associated with the cumulative time during which statins were available. Monte-Carlo and rule-out sensitivity analyses were performed to account for unmeasured confounders.
RESULTS: Compared with patients who had very short statins coverage (less than 6 months), those on 7-24, 25-48, and >48 months of coverage respectively had risk reductions of 15% (OR: 0.85; 95% CI: 0.74 to 0.98), 28% (OR: 0.72; 95% CI: 0.61 to 0.85), and 25% (OR: 0.75; 95% CI: 0.61 to 0.94). Simvastatin and atorvastatin were both associated with a reduced risk of dementia, while no similar evidence was observed for fluvastatin and pravastatin.
CONCLUSIONS: Long-term use of statins seems effective for the prevention of dementia
.
This is interesting because pravastatin and fluvastatin are relatively CNS-exclued statins whereas Simvastatin and Atorvastatin are relatively CNS-penetrant statins. 


CNS penetration is not going to be important in controlling blood levels of cholestrol but would be important if an action is going to be by neuroprotection where it is saving nerves. 

This is why is is good to know how and where your drugs work

4 comments:

  1. If a drug with a well documented safety record shows positive results at Phase ii then neuros should prescribe if there are no other treatments available. Simvastin is a good example. Otherwise patients will order them online - it's better to be under the supervision of a medical professional. Prof G bangs on about time is brain so cannot expect patients to wait 10 years for formal trials.

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  2. Good point..But there is still a question about dose. Does it need to be so high. Some will question if it works. In the original study it involved 70 people in each group differences were seen in a year.

    Can they afford to do it can they afford not to do it.

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  3. The majority of people with dementia are over 50 and various people have suggested all over 50's have statins, so I don't suppose most doctors would mind prescribing it. However, would they prescribe it to someone in their 20s? Especially as the simvastatin trial was on a very high dose (80mg) I think and one of the side effects of high dose statins can be muscle wasting. re cholesterol, atorvastatin gives the same effect as simvastatin at a lower dose, but are all statins that can cross into the CNS's action on MS the same?

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    Replies
    1. Are they all the same?

      I don't know there is not the evidence and there is no evidence in SPMS for atorvastatin

      Delete

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