Friday, 3 August 2018

Oral Cladribine works better than Beta Interferon

Cladribine inhibts MS, as was shown in the CLARITY trials, but it was also indicated in other trials.

The ORACLE trial was at the first demyelinating event, and the ONWARD trial was comparing cladribine with interferon beta. 

These trials were terminated when the manufacturers decided to can the development of oral cladribine.

Guess what the ONWARD trial showed?


Montalban X, Leist TP, Cohen BA, Moses H, Campbell J, Hicking C, Dangond F. Cladribine tablets added to IFN-β in active relapsing MS: The ONWARD study. Neurol Neuroimmunol Neuroinflamm. 2018 Jul 11;5(5):e477. 

OBJECTIVE:To evaluate the safety and efficacy of cladribine tablets in patients still experiencing active relapsing MS despite interferon (IFN)-β treatment.
METHODS: A 96-week phase II study, randomizing patients treated with IFN-β to cladribine tablets 3.5 mg/kg/IFN-β or placebo/IFN-β. Patients were to receive cladribine tablets 3.5 mg/kg/IFN-β or placebo/IFN-β in a 2:1 ratio (n = 172) with safety and exploratory efficacy outcomes being assessed.
RESULTS: Adverse events (AEs) and serious AEs were similar across treatment groups, except lymphopenia. Fifty of 124 (40.3%) cladribine/IFN-β recipients vs 0% of placebo/IFN-β recipients reported lymphopenia as an AE, with grade 3/4 lymphopenia (laboratory lymphocyte count < 500 cells/mm3) experienced by 79/124 (63.7%) vs 1 (2.1%), respectively. Patients treated with cladribine tablets 3.5 mg/kg/IFN-β were 63% less likely to have a qualifying relapse than placebo/IFN-β recipients, and cladribine tablets 3.5 mg/kg/IFN-β reduced most MRI measures of disease activity.
CONCLUSIONS: In patients with active relapsing MS despite IFN-β treatment, cladribine tablets 3.5 mg/kg/IFN-β reduced relapses and MRI lesion activity over 96 weeks compared with placebo/IFN-β but led to an increased incidence of lymphopenia.
CLASSIFICATION OF EVIDENCE:This study provides Class I evidence that for patients with active relapsing MS despite IFN-β treatment, cladribine tablets added to IFN-β reduced relapses and MRI lesion activity over 96 weeks and increased the incidence of lymphopenia.

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This study perhaps shows why cladribine has such a hard time  getting approved. Cladribine had some serious adverse effects. The one still mentioned by the European Medicines Agency in the approval documentation was lymphopenia.

Which "numbnut" allowed this to be even considered as a adverse event? 

It is not a "side-effect" but an "effect" and the mechanism of action of the drug. 

Severe lymphopenia (grade 3/4) occurred in about 85% of our cohort of people treated with alemtuzumab, verses  1.5% treated with generic cladribine in our does-adjusted study and 6% in the first year of the oral cladribine CLARITY study. Even after the first year of treatmet cladribine only occurred in about 25% of people after 3.5mg/kg. 

In this study there was 88.2% of people who had grade 3/4  (<500 cells/microlitre) lymphopenia following 5mg/kg cladrine and beta interferon), this dose was discontinued but about 65% of people got severe lymphopenia following delivery of 3.5mg/kg cladribine and beta interferon, so much more than with cladribine alone.

The annualised relapse rate was 0.12 on cladribine/beta interferon verses 0.32 with beta interferon alone. So the cladribine relapse rate was similar to that observed in the CLARITY study.
                           
There were no malignancies reported in the patients, so supporting our idea that the cancer reported in the CLARITY study was, in part, a statistical fluke. 

COI: Have received consultancy from Merck.

20 comments:

  1. "Adverse events (AEs) and serious AEs were similar across treatment groups, except lymphopenia."

    but in full text:
    "Seven patients who were treated according to the amended protocol had herpes zoster, with all occurrences seen in patients treated with cladribine "

    Apparently herpes zoster does not count as adverse event.

    ReplyDelete
    Replies
    1. Yet7 cases of Herpes zoster is listed in Table 2 of the paper as an adverse event. Lymphopaenia was more common (50 cases).

      Delete
    2. They were not similar across treatment groups. I'm spotting the contradiction between two parts of the same paper. Applies to the malignancies too.

      Delete
    3. Why don't you contact Xavier Montalban directly with your concerns? His email is in the paper and I'm sure he'd love to hear from you ;-)

      Delete
    4. Good idea. I might also ask him to explain in plain Greek the meaning of the following phrase taken from the caption of the graphic above:

      "p-Value based on Wald Chi-square from the number of qualifying relapses using a Poisson regression model with fixed effects for treatment group and IFN-β treatment and with log of time on study during the double-blind period as an offset."

      Those dedicated pharma-ghost-writers are light years ahead!

      Delete
  2. "Which "numbnut" allowed this to be even considered as a adverse event?
    It is not a "side-effect" but an "effect" and the mechanism of action of the drug."

    Maybe it is unsafe to walk around with minimal WBC counts + MS...

    ReplyDelete
    Replies
    1. Maybe it is unsafe...maybe and that is why Merck has a monitoring strategy to reduce this.

      Lymphopenia was not listed as an adverse effect in the alemtuzumab trials

      Delete
    2. "Lymphopenia was not listed as an adverse effect in the alemtuzumab trials"

      A divine intervention, probably.

      Delete
  3. your title is misleading...you still have to take interferon with cladribine???

    ReplyDelete
    Replies
    1. No you don't....The CLARITY trial gave essentially the same result for the relapse rate.

      Delete
  4. I do not understand MD why researchers even are allowed publish comparison studies with any of these CRAB drugs which have zero effect on progression or outcome of MS.

    Why are journals publishing this garbage? Why are acceptable endpoints of trials gadolinium MRI activity and relapses when they both have very little to do with progression or outcome of disease?

    Also, why are we not comparing cladribine to ocrezulimab or alemtuzumab? How is this forwarding research?

    ReplyDelete
    Replies
    1. I agree it is marketing dressed up as rubbish pseudo research.

      Trialling a strong DMT (known from phase II trials) against a CRAB drug is a no contest...well generally it is. Laquinimod was worse than the CRAB.
      Putting your drug against low hanging fruit, means tthat many peoples disease will not be under control.

      Again you have to question the ethical review panels and the regulators who approve it. The comapanies will say they are doing it in countries where people dont get access to drugs...dubious ethics

      However there is an issue of cost do a trial. They company has to purchase the comparator, which cost more.

      Journals are desperate to publish stuff and if it has been done it should be published, if not to save someone dpoing it again

      Delete
  5. Just the same old drugs, the same old stuff. Comparison with a real dinosaur of a drug? Come on! And relapse rate says nothing about the
    real deal - progression: https://www.youtube.com/watch?v=OqY-_K1fYJY

    ReplyDelete
    Replies
    1. These studies were planned an performed years ago and were terminated in 2011 when cladribine was pulled form the market. They are being reported now because it is marketing. The CLARITY extension has only just surfaced but again done years ago.

      Says nothing about the real deal...not everyone aggress with George Ebers

      Delete
  6. When you do hsct for cancer or ms or scleroderma or lupus etc

    You get most times severe lymphopenia ,neutropenia ,very low red blood

    cells counts ,low plateles (needing a transfusion)etc

    And that is a good thing

    It happen to me... ;)

    Do you thing they´re gonna stop doing Hsct for those disease because of

    those side efects?

    Those side efects are consequence of the treatmment

    In 2013

    WBMT
    Worldwide Network for Blood & Marrow Transplantation (WBMT)

    Report

    1 millionth blood stem cell transplant marks
    major medical milestone

    Half of them in europe

    https://www.wbmt.org/fileadmin/pdf/01_General/Distribution_1_Mio_transplants.pdf

    https://www.wbmt.org/fileadmin/pdf/01_General/Press_release_final.pdf

    Obrigado

    ReplyDelete
  7. So adding IFN-b to Cladribine is dangerous. Ok. Got it.

    ReplyDelete
    Replies
    1. There is little biological sense to do do such a thing:-(

      Delete

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