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
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
(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
(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
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...
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
- 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
- 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!
It is scary that people in power can't see the cost saving potential for the
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
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
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?