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.

Sipe, et al. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet 1994
Beutler, et al. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Nat Acad Sci USA 1996
Stelmasiak, et al. Effect of parenteral cladribine on relapse rates in patients with relapsing forms of multiple sclerosis: results of a 2-year, double-blind, placebo-controlled, crossover study. Mult Scler J 2009
Giovannoni, et al. A Placebo-Controlled Trial of Oral Cladribine for Relapsing Multiple Sclerosis. NEJM 2010

Giovannnoni, et al. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis. Lancet Neurol 2011

Leist, et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet 2014

(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. 

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.


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...