#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 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.