Friday, 15 January 2016

Suppose there was Therapy for All

This is a repost from last year to end *Cladribine week*. 






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

The problem is, after spending a day (or week?) 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 = £48,000,000 a year, £96,000,000 for 2 years and £240,000,000 for 5 years.

For Alemtuzumab that could be 6,000 x ~£80,000 = £480,000,000 for 2 years or about £570,000,000 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) Licensing arrangement sorted.

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


This seems to have happened...

23 comments:

  1. "6,000 x ~£8,000 per year = £56,000,000 a year"

    Are you sure about this? ;)

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    1. These are model calculations - perhaps not every new diagnosis would be eligible for treatment, but it really depends on how far you want to push your luck. We know early treatment is most effective, and if the benefit-risk is agreeable, and drugs are affordable, why not consider *treating-2-target-4-all*?

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    2. Ha Ha 6 x 8 = 48. We threw in an extra £8,000,000 for good measure.

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  2. I should say that trying to get Clabridine approved is a valiant effort but in reality is it really needed? There are over 12 approved drugs for RRMS. Since I think it has become clear to you that you are spinning your wheels maybe you should focus on something that academics may be able to contribute.

    Instead of focusing on immunosuppression as a therapy (this has been done to death) focus on what is causing MS. Why is the body attacking itself? This has been the focus for decades but if Team G is as clever as they are portraying themselves they should be able to make a contribution in this area.

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    1. "I should say that trying to get Clabridine approved is a valiant effort but in reality is it really needed? There are over 12 approved drugs for RRMS."
      In an ideal World we want MS to be diagnosed as early as possible so it can be treated as early and effective as possible. We all need to take on board the trial evidence that clearly shows early treatment is the most effective approach, for some it may even be curative. Leaving aside some fundamental insights such as any neurodegenerative disease becomes more difficult to stop or revert as it progresses.
      Unless this is the first time you visit this blog, you know we are not focussing on immunosuppression only. Look at ProfG's summary of the 2nd week 2016!
      This blog is for everyone to read, not only for the posh Western Europeans/North Americans with their 11-12 drugs on the shelf, but for people living in places where the last thing they can afford is a shot of beta-interferon. And whilst we tell people in resource-poor healthcare settings the story of Cladribine, we realise our own healthcare system is not so resource-rich after all; daily headlines remind us of that, in the UK anyway.
      So here is what we want: Drugs that are highly effective, safe, convenient, and all that at a price that virtually every pwMS – or the healthcare setting where they live in – can afford. Because this is what we want: a World free of MS. Do you agree?
      We know for the majority of pwMS Cladribine will not be a cure, just like none of the other drugs is. But the evidence suggests it is as good as any of the drugs currently around, it is as safe (or safer) as most of them, it may offer new opportunities for pwMS currently not eligible for DMTs (CNS penetrance), it is very convenient (6 jabs/year, few blood tests), and – call it a stroke of serendipity – it is cheap.
      Obviously, we won’t stop at immunosuppression, but rest assured we won’t stop trying to get effective treatment to as many pwMS as possible either.

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    2. "Because this is what we want: a World free of MS. Do you agree?"

      I think this is the goal of everyone, but if academia cannot get a drug approved because of the system that currently exists in wealthy countries and you know this will never happen maybe you should be focusing on something that academics do have a chance to contribute to the cure of MS.

      For poor countries Clabridine seems like a solution. Maybe you should get on board with these governments (maybe shift location if you are that committed to helping poor countries).

      But it seems that your health care system does not want anyone but Pharma developing drugs and conducting trials.

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    3. We made it clear enough over this week (and before) there are licensed and off-label drugs for pwMS, and the decision which drug to pick way is between the pwMS and the team (doctors, nurses). We're not talking some fancy molecules nobody has ever tried before, with magic properties, or some CCSVI non-sense, but solid evidence. Most of the time, one of the licensed medications will be the way to go (provided eligibility is confirmed), sometimes not. I sense you'd rather not me saying this by suggesting I should relocate, but I’m planning to stay, thank you.

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    4. So, Clabradine is not licensed in the UK, you want to help poor countries, you think it is the best drug available.

      Since Clabradine can only be prescribed off label and it was made clear this is not the way your health care system was designed to operate what is your goal?

      Are you going to be the Clabridine cheerleader for poor countries with headquarters in London? What do you plan to do to get the leaders of poor countries to adopt it?

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    5. Klausy you forget the costs of monitoring for and treating cancer

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    6. Cladribine is licenced in the UK but for treatment of hairy cell leukaemia.

      The question you ask of us what do we do? Wait and see.

      The question I ask of you is what do you do?, because we can't do everything.

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    7. Dear Anon 7.22
      It is DrK please, not Klausy and do you not read?

      This is becoming a stuck record and frankly very, very, very tiresome. If you cannot assimilate data then this is your issue as there will never be any pleasing you. You have said you piece.

      Our position on this one is clear and based on available data the risk of cancer is no higher for cladribine than other highly effective DMT.

      However, if you want to start speading dirt what about the extra cost of alemtuzumab... infusion time, steroids to limit the adverse events of the infusion, anti-virals whilst immunosuppressed, monthly blood tests, urine test, dealing with thyroid autoimunity 30%, removal of thyroid gland 3%, dealing with problems of good pasteurs syndrome, maybe steroids, maybe i.v.IG maybe even kidney transplant.

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    8. "The question I ask of you is what do you do?, because we can't do everything."

      Team G are the ones pushing for Clabridine. I live in a posh country where I am on a medication I am satisfied with and would not consider switching to Clabridine either off label or even if it was approved.

      "This blog is for everyone to read, not only for the posh Western Europeans/North Americans with their 11-12 drugs on the shelf, but for people living in places where the last thing they can afford is a shot of beta-interferon."

      It seems Team G is proposing Clabridine is an optimum choice for poor countries whose people that suffer from MS would be of benefit. I agree just as I agree many of these countries have inadequacy in other areas such as food, other diseases, etc.

      So, as a person living his life that has no aspect in academia and is not involved with Clabridine or its effects on MS there is little a I can do to get this in the hands of people in poor countries.

      This seems to be an agenda for Team G. So I think it is only fair for you to explain how you are going to attempt to make Clabridine available for people in poor countries.

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    9. "This seems to be an agenda for Team G. So I think it is only fair for you to explain how you are going to attempt to make Clabridine available for people in poor countries."

      Part of the initiative is to explain why Cladribine has the potential to make a difference for pwMS anywhere, whether they live in an affluent area of the World, or in less advantageous conditions (and we don't ignore there are many other "inadequacies", but that is not the point). This serves one of the issues we want to address: Effective treatment for a large majority of pwMS, wherever they live, is not a pipe dream. We have further plans, but it's too early to discuss publicly. We won't be long.

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  3. If you were diagnosed with RRMS and there was no financial or political constraints, which drug would you take and why?

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    1. Always difficult to anticipate what comes after the day X, but I guess I'd sit down with my MS Nurse Specialist and discuss all options out there and make an informed decison.

      If you're asking me for my *Desert Island Drug* (for MS) it be Cladribine, hands down. Why? - Please click on "Projects" above.

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  4. For myself with normally low lymphocytes (0.8 to 1.0 say) DMF stopped as fell to 0.3, fingo c/i, Rebif ineffective, alemtuzumab ruled out, MS now secondary progressive; cladribine sounds like my last remaining option?
    Thanks might print the off-label info and discuss with neuro. Nothing to lose.

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  5. Perhaps we need some Walter White Knights to start producing this good stuff? How hard could it be to produce in a half decent hobby laboratory?

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    1. Absolutlely not...For human use requires very strict standards

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  6. This thread faded away, and has only just been brought to light on the MS Society Forum.
    There is a simple question~: is Cladribine effective for for those who are SPMS? Next question~:
    If it is, then why are we not getting it?
    As was referred to above, there have been pressure groups for LDN, CCSVI, stem-cells; so why not cladribine?
    Personally, I see my MS Nurse in six weeks and intend to raise the subject with her.

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    1. Re: ".... is Cladribine effective for for those who are SPMS?"

      Possibly. However, we would need to do a properly designed trial to see if was effective in SPMS. However, based on the natalizumab in SPMS trial (ASCEND Trial) we are confident that if powered and designed properly all highly-effective anti-inflammatory therapies would be effective in SPMS. I will be important to manage expectations. Anti-inflammatory therapies are unlikely to reverse disability in the SPMS phase, only slow its rate of progression down and hopefully over time prevent worsening (flat-lining). The delay in seeing this effect is due to therapeutic lag.

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  7. I agree with Geoff, my Neuro just told me I am SPMS with relapse (from RRMS) and see's Aubagio (my current treatment) as the best treatment and suggested Simvastatin as an additional drug to help reduce brain shrinkage, to me if feels like it is all delaying with no forward steps as I slowly see myself becoming less mobile year after year, frustrating to say the least.

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