Saturday, 10 October 2015

Suppose there is therapy for MS that is effective, safe, convenient and cheap...



Readers of this blog have come across this drug many times. 

The problem is, after spending a day in the sun it keeps vanishing in oblivion until the next surfacing of this U-boat drug. Why? 

Quite simply because Cladribine is a scary drug.

(a) Cladribine is highly effective:

The level of efficacy appears to be as good or notably better than any current MS drug available.



(b) Cladribine is as safe as any DMT:

In comparison to highly active MS drugs, it is notably safer! 


Cladribine does not cause secondary autoimmunities like Alemtuzimab or Daclizumab, which may occur 
in up to 50% of people.

Cladribine has not been shown to cause PML, unlike fingolimod, Dimethyl fumarate or anti-CD20 and notably natalizumab, where there is up to greater than 1 in 100 chance of this developing. Mitoxantrone has a 1 in 25 risk of causing leukaemia.

But the cancer risk...?

We have undertaken a meta-analysis of all pivotal trials and found that the occurrence of cancer is no higher on Cladribine than any other drug. What was unusual about the CLARITY trial is that there were no malignancies in the placebo arm, but three in the drug-treated arms. In subsequent studies of Cladribine the lack of a cancer signal was confirmed in ORACLE MS (see above) and the ONWARD study. Nevertheless, the MHRA (the regulatory equivalent of the EMA/FDA in the UK) informed us that another trial, and then post-marketing surveillance, would be required to convince them to award Cladribine a license. That was in 2013, so may be their views have changed since Alemtuzumab has been licensed in the meantime despite significant safety issues?

Putting the cancer scare further into perspective one should remember that in 2010/11 Merck Serono was in a race with Novartis to bring the first oral DMT to market. Merck were the hare and took a risk on one large phase III trial plus supportive evidence from previous studies. The tortoise won and got there first and made it difficult for the hare to survive. The regulators were not happy with one trial and wanted another to show safety, however patents have a limited lifetime, and thus rather than doing another study that would take years, Merck dropped their Cladribine program.

It was not the cancer risk as such that scared them off, 
it was a commercial decision: Subsequent trials did not confirm the suspicions about cancer, and we know that Merck are trying to resurrect the programme and are going back to the European Regulators. If what the EMA tells them is in line with what the MHRA told us (and why should they disagree?) then they will need another trial, completion of which will see the life of their patent - shaky as it is already - expired.


(c) Cladribine is convenient:

Cladribine only needs about 5-6 doses/year, and possibly for no longer than two years. This is as easy as alemtuzumab and even easier because you don't have to go to hospital for the infusions and it doesn't cause adverse reactions (reactivation of old lesions and problems associated with steroid use).

After being given the drug, it is out of the system within 24h from the last dose until the next year so maybe time to get drug-free pregnant. 

It won't be there to interact with any other drugs to stop them working in their function as a neuroprotection and or repair drug that RRMSers and PPMSer/SPMSer will need to take and will work better if the inflammation is dealt with.

(d) Cladribine gets in the brain:

Most DMTs act by blocking the immune system and stopping it getting into the brain. So does Cladribine (by depleting B and T cells), however it also works in the brain. The only other drug that penetrates into the brain without blood brain barrier dysfunction is currently fingolimod though it won't exert its immunosuppressive mode of action there as it primarily works by blocking egress from lymphnodes. Cladribine does get in, and can kill lymphocytes in the brain; this should be neuroprotective and thus potentially slow progression.

You may say the 
Rice et al. 2000 was negative, however it lasted only one year, which we know is too short for a clinical progression study; nevertheless it was clear that some people with SPMS had some benefit from taking the drug.

Now the really scary bits...

(e) Cladribine is cheap:

MS drugs make over $20,000,000,000 a year and pay shareholders and CEOs a lot of money. For that you get innovation.

Cladribine is a generic drug (e.g. Litak, Lipomed) that needs subcutaneous injection, so for people who have been injecting Interferons and Copaxone a dawdle (but remember, only 5-6 injections PER YEAR given Cladribine is an induction treatment, and no nasty injection site reactions), and it is scary that Merck Serono reportedly spent between $600,000,000-$800,000,000 developing Movectro, the oral (pro-drug) version, which becomes Cladribine after being ingested that cost €20,000 a year when it was licensed in Russia and Australia. All the while generic versions of Cladribine have been sitting on the shelf given it has been licensed for people with hairy cell leukaemia since 1993!

This is likely to stay there. 

In comparison to Movectro, where only 42% of what is eaten gets into the body (bioavailability), 100% of what is injected gets into the blood stream.

The oral version was priced at €20,000/year, but the current UK list price for subcutaneous Cladribine is £165/10mg vial, and as little as $34 in USA. Given the total annual dose of about 60mg an effective induction treatment would be available at a cost of less than £1,000, so about £2,000 for a 2 year course, to achieve NEDA in 45% of people taking Cladribine.

The nearest equivalent is Alemtuzumab. 
  • Cost of drug for 2 years are 8 x ~£7030, 
  • 8 in-patient infusions, 
  • 2 x course of steroids to stop infusion related reactions, 
  • 24 trips to hospital/doctors/home visits for monthly blood collection to check you have not got autoimmunity-reminding you that you have MS every month. 
  • 8 times urine collection. Cost of analysis of the blood and urine samples. 
  • Cost of dealing with secondary autoimmunities that will eventually appear in 20-50% of people. 1% platelet autoimmunity treated with intravenous immunoglobulins; 30% thyroid problems possibly meaning destruction of thyroid (3% need thyroid operations at £4,000) and thyroid hormone replacement for the rest of their lifes, 1% Goodpasture's syndrome that may need a kidney transplant.
  • 50% of people need a re-treatment, so a real cost of about £80-£100,000 per person.

In the USA the costs of the cheapest MS drugs are about $50,000 a year so $100,000 for 2 years or $158,000 for Alemtuzumab excluding other extra costs verses as little as $400 with generic Cladribine. That is scary!

(f) Cladribine could help end the Post Code Lottery:

It is scary
 that people in power can't see the cost saving potential for the NHS.

THEY ARE NOT INTERESTED ! 

We have asked enough people with the power to do something about this.

6,000 new people diagnosed each year in UK.

On cheapest MS drug that is 6,000 x ~£8,000 per year = £56,000,000 a year, £112,000,000 for 2 years and £280,000,000 for 5 years.

For Alemtuzumab that could be 6,000 x ~£80,000 = £560,000,000 for 2 years or about £670,000,000 for 3 years

For generic cladribine that is 6,000 x ~£1500 = £9,000,000 for 2 years, £10,500,000 for 3 years

N.B. NHS England is going to ask local NHS Trusts to foot 30% of drug costs... Hence, there is a very real concern they are going to support a drug that costs £20,000 against the backdrop of an intended reduction in spending on the NHS. Your drugs could get rationed... That is scary too.

(g) Treatment for All, really:

Just imagine for a moment if generic Cladribine was licensed, maybe it would be more than 2% of people with MS in India, able to have any form of DMT, so 98,000 people treated. 

All the countries in EU that can't afford current DMT could have one, indeed a very good one.

People in ProfG's South Africa could get a drug !

Generic Cladribine cannot fail to be of value to people with MS. Although people with RRMS will particularly benefit, Cladribine could also be anti-inflammatory "platform drug", on which neuroprotective molecules for people with PPMS and SPMS could be layered (which people with RRMS need too, given our knowledge about progressive changes from day 1). 

(h) Yes we mean treatment for all people with MS including people with Progressive MS. Everybody with MS has inflammatory activity that needs treating. This is greater in RRMS than in progressive MS, but with a cost-effective option everyone could have this benefit. Cladribine could be a platform on which to layer other drugs for neuroprotection and repair in progressive MS and RRMS. As it is an induction treatment requiring a few doses a year, and after being given, the drug is out of the system within 24h from the last dose it not interact with other drugs, and thus will be safer. 

So why on Earth should all the above be scary you might ask, and I agree it is not, except for the fact that it is not available, and that has to do with Big Pharma and the processes that they and the regulators have put in place.

Pharma dropped the ball in the first place (missing out on a drug which is placed on a par or even better than the best available MS drugs), and has established a well oiled system that will leave no stone unturned to avoid making generic Cladribine (or any other academically repurposed drug for that matter) a licensed disease modifying therapy for people with MS.

Pharma says they know academic neuros can't deliver this treatment, unless they restart the Movectro Development Programme. 

They are probably right as the system put in place costs too much money for tax-
funded organisations, such as the NIHR, to justify spending. Governments could make things happen but they won't unless there is a strong lobby to finally take note and make it happen.

If we can not deliver generic Cladribine as a repurposed drug, which we know works and everything is in place (bar cash) to do this, then what is the hope of repurposing something with marginal efficacy?

You lobbied your MS Societies to spend millions on stem cell therapies that have yet to deliver in over a decade. You lobbied your MS Societies to spend millions on CCSVI that has delivered nothing but bad news.

For a study costing £3-4 million (if the comparator drug arm is paid for) could have the ammunition to "make generic Cladribine happen" as a DMT, even doing it the pharma way.

Generic Cladribine cannot fail to be of value to people with MS. This includes both people with PPMS and SPMS as well as RRMS. 

Somewhere in the World it needs to be shown that generic Cladribine is as good as anything currently out there for the benefit of the international community.

Maybe this should be a priority, think about doing something positive for the World of MS, not just the Markets of Western Europe and North America.

Will this scare Pharma off MS? Patents are running out and generic chemicals will eventually arrive (maybe as soon as 2016 in Australia) and costs will fall, but why settle for second-best? Pharma can switch focus to get better treatments for progressive MS, be really inventive.

CoI: We have (i) Advice from regulators and are one trial short, (ii) Supply of drug sorted, (iii) pwMS-friendly trial design sorted, (iv) 30 UK centres on board, (v) Licencing arrangement sorted.

What could go wrong? No money for a trial, or that Merck Serono come back in the game - as recently suggested - to kill this pipe dream?

42 comments:

  1. Why don't you guys do something radical and take the drug for a few years and show you don't get cancer?

    ReplyDelete
    Replies
    1. Why don't you read this.

      http://multiple-sclerosis-research.blogspot.com/2015/10/cladribine-and-risk-of-cancer-in-people.html

      This is an induction therapy and two courses of treatment is enough. Any immunomodulatory therapy has a cancer riask, life has a cancer risk.

      In the anti-CD20 trial it was evident there were more cancers in the treatment arm and breast cancers at that, will the same type of mud stick to this drug.

      Delete
    2. MD,

      This is what I don't understand. With the anti B cell therapies, surely people will be spending a lot of their lives B cell deficient. Does that not raise the very real possibility of long term problems with anti B cell treatments that aren't shown in shorter term studies?

      It seems that we know a lot of the side effects that alemtuzumab causes, and simply saying that anti-CD20 is safer than this isn't possible given that some may get away with 2 doses of alemtuzumab? Surely once someone gets say 5 years out from last alem dose their risk are decreasing substantially while those on continuous anti-CD20 will still be facing risks?

      The same would potentially follow with cladribine if used as induction.

      I'm just struggling to understand how near continuous B cell suppression would be a good thing over 10 to 20 years.

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    3. In the case of both alemtuzumab and ocrelizumab the stem cells remain unaffected, and only the intermediate cell types are affected. This means that there is a constant pool of cells regenerating themselves after the infusions. Therefore we're not talking about long term suppression. The latter would be very bad...

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    4. So MD, please be lucid - are you saying that Cladribine has a lower cancer risk than Ocrelizumab? Or the same risk, or higher risk? Or do you not know?

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    5. Doc Gnananapavan,

      That's what I don't understand about alemtuzumab - all drug supposed to be gone in 30 days, but very long term suppression of some cell lines. What's the process behind this?

      Delete
    6. @MD you guys have been advertising anti-CD20 as being very safe and a game changer. Now you are saying that it increases the risk of various cancers!

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    7. "So MD, please be lucid - are you saying that Cladribine has a lower cancer risk than Ocrelizumab? Or the same risk, or higher risk? Or do you not know?"

      Simple answer is I do not know,

      I don't know the data for ocreluzimab as I did not photograph the results from today or the results in RRMS presented yesterday. The cancer risk is probably chance, and can probably countered by the two OPERA trials. Maybe someone can comment. As the results were being presented on the PPMS a neuro.

      Yes ant-CD20 is a game changer however the point was cladribine failed for what was a spurious cancer risk and only one trial.

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    8. If I read this correctly 2 courses of treatment with Cladribine leads to 50% of people needing no further treatment. This, to me, indicates you are killing the cause of MS not just suppressing the immune system.

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    9. I am not saying it increases cancers i am also not saying it is very safe either. based on data presented today there was no safety signal mentioned. However based on infections seen in lupus and arthritis which caused serious problems , that terminated development in those conditions

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    10. In reply to Anon 1:53pm Doc Gnananapavan,

      That's what I don't understand about alemtuzumab - all drug supposed to be gone in 30 days, but very long term suppression of some cell lines. What's the process behind this?

      Alemtuzumab depletes CD4 and CD8 lympho up to 12 months with selective delayed reconstitution of the CD4 pool. The reconstitution starts at 1month after the infusion with the lowest levels at day 7 after alemtuzumab. So as the circulating pool of cells in the blood are removed, there is a slow homeostatic proliferation of the immune cells induced by the lymphopenia to re-establish the steady state levels. The CD4 cells in particular do not seem to be good at this and they also seem to be more susceptible to a mechanism called apoptosis (cell destruction) which explains the delay in reconstitution.

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  2. OK. Tell me what I need to do here in Australia to make this happen.
    (RRMS 2 years post diagnosis)

    ReplyDelete
    Replies
    1. You are in Australia where Movectro is licensed however not available as Merck decided to suspend it. I don't think there is currently a manufacturer actually producing their pill. Thus, there's no quick fix unless off label prescription, which is always a niche solution only in a highly regulated environment. In line with the instructions we received from the MHRA we aim for a head to head trial of generic Cladribine against a licensed DMT as comparator. Should Merck recycle their license in Australia, a trial could explore the generic version vs Movectro (there should be absolutely no difference).

      Delete
    2. DrK, you haven't really said what he can do about it.

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    3. Thanks for the quick reply Dr K. Am currently on Tecfidera, I guess I have to play the wait and see?

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    4. As long as you remain NEDA there's probably little reason to change unless adverse effects prevent that.

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  3. How do you know two courses of treatment is enough?

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    Replies
    1. Published data...... NEDA is about 50% so 50% will need new course and maybe in time retreatment maybe needed but if you have your annual MRI scans one could see if your MS comes active and then have another course.

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    2. Agree MD, the treatment strategy would be very similar to Alemtuzumab. This is also in line with the license in Australia.

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  4. I'm in the UK. I too want to know what I can do to make this happen.

    What are the MS charities saying? Are you at barts talking to them? This blog is the only real platform where msers have a voice, how can individuals make a difference?

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  5. In Barcelona in transit atm. I'll get back with more later. The short answer is we will need your help big time to make this happen. It requires a movement (and money). More soon.

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  6. All,

    How much cash would we need to start a pharma, run a trial and then go open source once the cash was paid back?

    ReplyDelete
    Replies
    1. your wildest estimate multiplied by 10

      Much easier to convince a large generic maker to Sponsor a trial for marketing purposes.

      Tony Fonda

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    2. I agree it is difficult to imagine changing well trodden pathways everybody has learned to live with more or less comfortably; the researchers in the labs of industry or industry-sponsored academia, the regulators (for example, the branch of the MHRA dealing with submissions for licensing is funded 100% by industry, which in turn means they are 100% dependent on wealthy companies paying their fees), NICE (a bargain like generic Cladribine wouldn't require any of their sophisticated modelling to underpin cost-effectiveness!), and politicians who believe supporting overpriced drugs are important to keep the stock market happy (and the shareholders with whom they spend their afternoons on the golf course:-). We need a movement to change this, and I believe MS Society and MS Trust should be involved in a leading role, and not give up even if the pharma lobby should succeed once again in preventing MPs from turning up in sufficient numbers to vote for the repurposing bill (6 Nov).

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    3. I am understand that this would be very difficult to do; but not impossible. Am trying to present a alternative approach, rather than being beholden to others could we do something for ourselves? How could we do a feasibility study on this?

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  7. I have seen that Mercksubmitted Cladribine (oral version) to EMA in September, do you know if this is Movectro? How much time does it need to be accepted? Also you mentioned that injected version is much more efficient, would it cause a problem in "creating and licensing" of this injection if they got the license for the oral version?

    ReplyDelete
    Replies
    1. Usually it takes about one year between submission and licensing unless special circumstances (which can mean faster or delayed). A bioequivalent dose of injected Cladribine should be just as effective as the oral version. Given only 42% of the oral dose is available in the blood compared to 100% after injection, a relatively higher dose needs to the taken when using oral. Whether licensing of Movectro would be detrimental to getting the generic version licensed will depend on a number of circumstances including political decisions (e.g. repurposing bill).

      Delete
  8. "In the anti-CD20 trial it was evident there were more cancers in the treatment arm and breast cancers at that..."

    Scaremongering to help promote Cladribine, which has not yet been shown to have efficacy for PPMS? How many more years before it could be shown to have any effect? I hope that you are not going to be trampling on the one drug with which someone has shown effictiveness for PPMS (Ocrelizumab) in order to promote another because there's something in it for you. Under the guise of something else.

    Just playing devil's advocate.

    ReplyDelete
    Replies
    1. No scaremongering, we're very positive about the Ocrelizumab data (see prior comments on this blog and the Daily Mail:-). Having said that, the fact Cladribine penetrates into the CSF should be beneficial for people with PPMS. To be demonstrated in a trial though.

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    2. no scaremongering it is an observation made by a neuro

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    3. Why say "breast cancers at that"? This is one of the most common cancers. So what was your point?

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    4. The neuro who spotted that I was writing a blog post as the data was presented, picked up the occurrence of cancers and the breast cancers.and suggested that this was mentioned as it was not by the speaker...as females are the likely recipient of the drug it was thought that this should be mentioned.

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  9. Imagine how the Pro HSCT community feel about this post. A treatment that is proven to be MORE effective than Alemtuzumab and Cladribine but you refuse to give it the light of day. The irony is that if Ocrelizumab is proven to be effective in progressive MS it means that HSCT would also be effective in treating progressive MS which again you have often said was not the case.

    Imagine a world where neuros would actually consider giving patients the MOST EFFECTIVE treatment rather than pushing drugs which just aren't as effective...

    ReplyDelete
    Replies
    1. "The irony is that if Ocrelizumab is proven to be effective in progressive MS it means that HSCT would also be effective in treating progressive MS"

      That sounds like a massive leap in faith.

      Delete
    2. wrong ..... HSCT should stop active progressive MS we have said this many times and is supportedData was pres by evidence, this was presented by Prof Muraro at ECTRIMS, I wasn't in that session as i cant be in two places at once. maybe NDG can comment. We currently do not do HSCT but it is the ultimate immune replacenent

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    3. "it is the ultimate immune replacenent"

      And very scary. Unless you're kept in a very sterile place. I don't think the NHS will ever be capable of that. Mind you, they didn't do a bad job of containing Ebola.

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    4. I would predict that HSCT is as least as good as ocrelizumab, the side effects differences will be important

      Delete
  10. 'And very scary'
    1000's of patients treated yearly with various chemo regiments for cancer and survive. The risk is now down to 0.5% mortality in proper clinics, is that any more scary or much more risky than PML in natalizumab, or ITP in Alemtuzumab?? The problem is people don't read the published data and believe what is said by various MS Societies. Come on we still have neuros who believe the wait and see approach is best.. Experts?? Hmmm..
    I just wish this blog with its 5 mil hits would give the treatment as much air play as it does to Clabridine which is less effective, anyone who argues that is being biased to their own product.

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    Replies
    1. We reported the HSCT data when it was published but 0.5% is 1 in 200 people dead!

      Delete
  11. What about herpes zoster? Could it be considered as a serious side effect? Also cladribine is causing leucopenia (like Tecfidera). For this reason it would not be surprising that it causes PML, too, no? If not, why would it not cause PML?

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    Replies
    1. PML is a result of persistent leucopaenia e.g. giving an immunosuppressive drug every day and you have not chance to make cells to fight infection, with an an induction therapy the drug is not present for long. In the case of cladribine it is gone in 24hours so if you have an infection shortly after immune depletion it can be a problem because you have few cells but your immune cells are free to come back and so can expand a to get rid of the JC virus and this is why the risk is low.

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