Does the EMA/Merck need a rethink about letting Cladribine fail


#MSresearch: Do the EMA/Merck Serono need a rethink 

Julia Pakpoor,Giulio Disanto,Daniel Altmann, Sue Pavitt, Benjamin Turner, Monica Marta, Gunnar Juliusson, David Baker, Jeremy Chataway, Klaus Schmierer Cancer Risk is Not Increased in People with Relapsing Multiple Sclerosis Taking Cladribine
AAN, April 23, 2015

BACKGROUND: CLARITY (phase III trial of movectro) reported significant efficacy of cladribine in pwRMS. However, concerns over its safety were raised and a suspected increased risk of cancer was important for the rejection of cladribine by the European Medicines Agency in 2011.
DESIGN/METHODS: Meta-analysis of all phase III trials of licensed DMDs for pwRMS, and CLARITY.
RESULTS: Eleven trials were selected for inclusion. Study heterogeneity was not significant. Investigated treatments included cladribine, dimethyl fumarate, fingolimod, teriflunomide, natalizumab, alemtuzumab and glatiramer acetate. The cancer rate in the CLARITY treatment group (0.34%) was not increased compared to all other treatment groups, whether including placebo-controlled trials only (0.6%, p= 0.4631) or all trials, i.e. including those with an active comparator arm (0.67%, p=0.3669). No cancer was detected in the CLARITY placebo group whilst the combined cancer rate of all other placebo groups was 1.19% (p=0.0159).
The cancer rate of zero in the CLARITY placebo group is also lower than in the recent phase III trial of cladribine in people with clinically isolated syndrome (ORACLE, 2.91% p=0.0012). In contrast, no difference was detected between cancer rates in the treatment groups of CLARITY (0.34%) and ORACLE (0.49%) (p=0.6546).
CONCLUSIONS: Our study suggests that cladribine in doses used in CLARITY and ORACLE does not increase cancer risk in pwRMS. The perception was due to an unusually low cancer rate in the placebo group of CLARITY. Long term follow-up will determine the cancer risk of all DMDs. Given its efficacy, tolerability and convenience cladribine should be reconsidered for treatment of pwRMS.

The fate of Moveco rested on on one not the usual phase III trial and the EMA questioned the safety of oral cladribine and wanted another trial. Merck Serono did not want to do this and despite being licenced in Australia and Russia they ceased production of the drug

The EMA may be made a mistake in rejecting Movectro (oral cladribine) and Merck Serono may have made a mistake on pulling the plug on the programme, because had they not done this and waited for the other trials to report they could of had a different story to tell.

Having witnessed the logic of the certain regulators that 10 tumours in 10,000 people on drug would be 9 more than 1 tumour in 1,000 people in a placebo group. I can see why some people despair about the drug licencing process (N.B. 10 tumours in 10,000 people is the same risk as 1 tumour in 1,000 people).

There were some cancers in the Movectro group compared to the placebo group, where there were none. What was unusual was not that there were cancers in the oral Cladribine group, which remember contained twice as many people as the placebo group, but the lack of cancers in the placebo arm. Cancers are a fact of life and they occur whether you are on drug or not. In this analysis the cancer rate in the cladribine group was no higher than found for the other DMT in the other pivotal phase III trials of other MS drugs.

However, Mud sticks

So that’s it……Movectro gone (unless this data helps them to reconsider)

If the producers had persisted and done the trial requested then, Movectro would probably be available now. They did do more trials (presented in abstracts) after the plug was pulled, which did not show that there were more cancers and now have follow-up data from Australia/Russia where the drug was licensed and perhaps EMA/Merck should rethink.

It must be said that the CLARITY trial was randomised and this
difference occurred, so regulators may want more studies still.
Based on the data as it stands we don’t know if cancer risk is increased.

However, the only way to assess the real risk is post-marketing surveillance as 2 years is not long enough for such risks to really show themselves, as is notably following high dose mitoxantrone, which does have a cancer risk. Any drug that removes large proportions of the immune system (which protects against cancer and infections)is liable to this risk.
Movectro could have been a useful drug and compares well or better than many other MS drugs and it could be argued it is better than all current MS drugs based on CES: Convenience; Efficacy; and Safety. Shame it ended in a bottomless CES pit

Also if you went generic, as movectro production was stopped, it could also include Cost.

Movectro is a pro drug and becomes the active drug cladribine and was sold in Russia and Australia at €20,000 per year. It apparently cost the company about $800,000,000, according to some sources on the web, to develop the drug. (If they had a charitable arm they could have treated nearly half the world’s MS for that;-)

The oral drug is 40% bioavailable compared to 100% bioavailable for the injected generic version, which must and does work also, costing about £165 per 10mg vial or $32 in US so about£1500/$350 a two yearly course.

No wonder ProfG thinks it could be useful for cash strapped countries (e.g. UK 😉 see his posts)

Generic companies can make loads of money and this is profitable as shown by the size of some recent take over bids

Perhaps at such a low cost and as an induction therapy, it could be readily available to everyone and notably even in Progressive MSers with gadolinium enhancing lesions, where no treatment may be offered and who would benefit, based on what we know.
They could get access to such an drug, as it would not be competing with any licensed drug and it would not break the NHS bank .

COI: This is work by members of TeamG. ProfG (conflicted) and Merck Serono had no involvement in the planning or performance of the study.

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    • Yes…… neuros are like drums…… you have to beat the info into them:-). People that attend AAN do not necessarily go to ECTRIMS

      We'll remind everyone again when the paper comes out.

    • Q: What's the difference between a neurologist and a computer?
      A: it's a lot easier to punch information into a computer!
      Boom tish…………………………………………..

    • I'm sure if you had a million dollar stand and some lavish goodie bags, distributed by some scantily dressed hotties (of either sex, equal opportunities here!) I'm sure the message would sink in a lot quicker!

  • On a serious note, if ever there was a case for a rethink by the regulators on Cladribine, this is it.
    I suspect they'll be too pig-headed to listen but as ever I'm more than willing (and hopeful) to be proved wrong.

    • The above study provides some CLARITY (I'll get me coat). I'm sure MD and DrK will elucidate further but the abstract is pretty clear in it's conclusions.

    • The number 22 includes non-controlled trials. Hence, the denominator for this figure is unknown and likely to be far bigger than for the 2! Following revisions of our original submission our wording will nevertheless be more cautious, along the lines of: Whereas current evidence cannot rule out an increased risk of cancer, it also cannot say there is such a risk. Only longer term follow-up will resolve this issue – as it will for all other disease modifying drugs. As far as I’m aware, no haematological malignancies, such as lymphoma or leukaemia, have been detected in cladribine treated patients. This is of interest given haematological malignancies may result from longstanding immunosuppression.

    • Evidence lacking. Occurrence of all three cancers in CLARITY with a short latency (10 – 18 months after first exposure), and their 'non-systematic' nature – one each of ovarian, pancreatic and skin cancer (melanoma) – argue against a causal relationship with the drug. Only long term follow up will tell, among them Merck Serono's PREMIERE study ( due to complete in Nov 2018…

    • I'd rather not wait, but do another trial to (i) confirm the efficacy already demonstrated in CLARITY & ORACLE, (ii) address the issue of lymphopenia highlighted by the EMA in 2011 when they rejected cladribine, and (iii) further evaluate the cancer risk. That's what the regulators are asking for before considering a license.

    • There are posts on the blog about cancer risks and MS, it depends on the cancer in some cases MS appears to be protective

    • DrK how do get one each of ovarian pancreatic and skin cancer which is 3 when in the paper there were 10 in 728 people against none in 319 placebo

    • if you don't like the placebo group for safety outcomes then you can't use the efficacy outcomes. you can't pick and choose data klausy.

    • Barts MS Blog 3:45 Does anyone do much research on cancer and MS? I;ve been trying to find out for the last 10 years if my cancers were a result of a compromised immune system.

    • Cancers are controlled by the immune system and so if you have a compromised immune system cans are a risk

    • AnonymousFriday, April 24, 2015 4:28:00 pm
      Apart from the 3 cancers, there were 5 uterine leiomyoma (benign tumors), one cervix carcinoma stage 0 (a precancerosis, i.e. not cancer), and a "myelodysplastic syndrome" which was later revised to be tuberculosis.

    • AnonymousFriday, April 24, 2015 8:16:00 pm
      The standardised incidence ratio (SIR) for cancer matched for country, gender and age Merck Serono reported to the EMA in 2011 was 0.99 (95% confidence interval: 0.25, 2.7). It's simply too early to make a definitive call for rare events (such as cancer). Unlike the efficacy outcomes where results are unequivocal.

  • MD + MD2, a couple of questions; when you classify Cladribine as induction therapy, is this information verified with various trials outcomes? Seen that in Russia and Australia Cladribine was used in MS for some time, are these patients still doing well with their MS?

    • As the programme of oral cladribine programme was terminated by Merck Serono alot of data has yet to see the light of day. In addition to ORACLE the abstracts of the extension of CLARITY and another trial have been published but the papers have not. As to the Russia/Australia data I am aware that Merck Serono has to follow-up people for years but they will have the data and not us. Maybe we can do a freedom of Information request.

    • Oral cladribine is not available and generic cladribine is not licensed for this indication and so in Europe doctors should not be prescribing off label. So to get it to a state where it can be prescribed and insuranced I suspect and believe it needs to be licensed….Catch 22.

      If the MS community wanted it to get licensed there surely has to be a way, if you cannot get generic cladribine repurposed when you know it works then when it comes to the other drugs what chance is there.

    • Agree MD. Perhaps the MS Societies of the world could join forces with crowdsourcing and government to raise £10Mill for a second phase III trial of cladribine which, if successful, would enable application for a license? Now it's probabvly me dreaming!

    • Not sure how off label prescribing works here (UAE) I'd reckon its less regulated then Europe , but the injections are available cheap .. but good luck fining a neurologist that would support this treatment strategy !

    • Perhaps a study could be conducted in UAE? To satisfy regulators, and reassure pwMS taking the drug, further phase III evidence is required. The key is bringing pwMS, clinicians keen to move cladribine forward, and funding together – any suggestions?

  • The next era is that of induction therapies, Alemtuzumab has been presented twice at the AAN 2015. Maybe Cladrabine still has a window.

  • You Docs knows pharmaceutical companies better than us (I suppose)
    Do you see any chance that Merck Serono rethink about Cladribine development although they have just pulled the plug ?

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