Sunday, 5 August 2018

Daclizumab, The Final Nail

If the answer was daclizumab, I often wondered "What was the question"
I guess we don't need to contemplate this anymore

To me, it was always hard to think how the use of the agent would be staged within the treatment ladder. But as a non clinician I didn't worry myself with that

Furthermore, I don't need to contemplate about this any more as, daclizumab has been withdrawn from use. This occurred following  the development of autoimmune hepatitits and the occurrence of encephalitis

Daclizumab was a drug that threw a spanner into the works, as it depletes T regulatory cells but made MS better.  Surely if T regulatory cells were critically controlling MS, as the dogma tells us, then it should have got worse. So it was always interesting seeing how the clinical response viewed and explained, for most EAEers this was simply ignored. However it was the fact that B memory cells expressed CD25, got me thinking about B cells.

Anyway

The History, By Tom Williams and Sir Jeremy.
Immune-mediated encephalitis with daclizumab: The final nail. https://doi.org/10.1177/1352458518791374

"Clinical trials identify many safety concerns, but can only provide limited exposure of the drug to a highly selected and controlled cohort. Most MS treatments carry a black triangle status from the European Medicines Agency (EMA), requiring additional monitoring during the initial period of real-world, post-marketing experience. Greater patient exposure occurs in a more diverse patient group, with more potential for drug–drug and drug–other condition interactions. The MS community is all too familiar with this following the initial Food and Drug Administration (FDA) approval and subsequent temporary suspension of natalizumab as progressive multifocal leukoencephalopathy cases were recognised.

Daclizumab was authorised in 2016, following consideration of clinical trial data from 2236 exposed patients. Elevated liver enzymes were common, and there was one death due to autoimmune hepatitis, but no cases of encephalitis were identified in any studies. Post-marketing surveillance, however, has critically swung the risk–benefit balance in favour of product withdrawal. Despite risk minimisation approaches, a further case of fatal autoimmune hepatitis was reported to the EMA pharmacovigilance committee in June 2017, resulting in a licencing restriction to those who have tried two previous disease-modifying therapies and are unsuitable for any others. In March 2018, however, the EMA recommended the immediate suspension of daclizumab following 12 reports of meningoencephalitis, 3 of which were fatal.

Daclizumab was known to cause skin reactions but in this study the encephalitis was not associated with skin lesions, so maybe some of the relapses on daclizumab may not have been relapses

Devlin M, Swayne A, Newman M A case of immune-mediated encephalitis related to daclizumab therapy. https://doi.org/10.1177/1352458518792403


5 comments:

  1. "Clinical trials identify many safety concerns, but can only provide limited exposure of the drug to a highly selected and controlled cohort."

    I (rhetorically) wonder if the same holds for presumed efficacy.

    ReplyDelete
    Replies
    1. Biology shows us there is always variety, some respond well some very well. However withh regard to side effects you are looking for rare events. Wirth regard to efficacy it is already known to be effective across a broad cohort of people

      Delete
  2. I know nothing about daclizumab except what I've read on this blog. And I wasn't at all surprised by the withdrawal.

    Because every time the blog had a post about daclizumab, it reminded me of these accounts from the clinical trial (one is really harrowing).

    See the comments on this old post -
    http://multiple-sclerosis-research.blogspot.com/2011/10/ectrims-daclizumab-results.html

    Were the researchers too eager to get the drug approved? Did they ignore negative signals?

    ReplyDelete
  3. Replies
    1. Thanks it has been deleted. I dont know how it slipped through.Maybe it was so long that we could read it all.

      Delete

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