Wednesday, 1 November 2017

News: daclizumab handcuffed by the EMA

After a second person with early RRMS died from fulminant liver failure whilst being treated with daclizumab the EMA are restricting daclizumab's use. 


The following statement was released last Friday on the EMA's website. It is reassuring that the EMA has decided not to withdraw daclizumab product from the market. I still think there will be a group of pwMS who will benefit from the therapy. For example, patients at (1) high-risk of PML transitioning from natalizumab, those with (2) PML post-natalizumab and (3) patients with high-disease activity who don't want an irreversible therapy nor therapies that cause continuous immunosuppression. The elephant in the room is that in both fatal cases, those who died of liver failure on daclizumab also received concomitant tizanidine. Could tizanidine, or other hepatotoxic drugs, when used in combination with daclizumab, be the problem? I suspect the use of daclizumab will now be so low we won't be able to answer this question with post-marketing surveillance. 


EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) recommends further restrictions for multiple sclerosis medicine Zinbryta due to risk of serious liver damage. 27 July 2017.

Zinbryta to be used only in a restricted patient group, with strict liver monitoring

PRAC is recommending further restrictions on the use of the multiple sclerosis medicine Zinbryta (daclizumab) following a review of the medicine’s effects on the liver.

The review found that unpredictable and potentially fatal immune-mediated liver injury can occur during treatment with Zinbryta and for up to 6 months after stopping treatment. In clinical trials, 1.7% of patients receiving Zinbryta had a serious liver reaction.

In order to reduce the risks, doctors should now only prescribe Zinbryta for relapsing forms of multiple sclerosis in patients who have had an inadequate response to at least two disease-modifying therapies (DMTs) and cannot be treated with other DMTs.

In addition, doctors should monitor patients’ liver function (ALT, AST and bilirubin) at least once a month as closely as possible before each treatment and continue monitoring them for up to 6 months after treatments have stopped.

If the patient does not comply with monitoring requirements or the response to treatment is inadequate, doctors should consider stopping treatment.

It is recommended that the doctor should stop treatment if a patient has liver enzyme levels over 3 times the normal limit and refer any patients with signs and symptoms of liver damage to a liver specialist.

Patients who test positive for hepatitis B or C infection should also be referred to a specialist.

Zinbryta must not be used in patients with pre-existing liver disease and should not be started in new patients with over 2 times the normal limit of liver enzymes. It is recommended that doctors do not use Zinbryta in patients with other autoimmune conditions.

The PRAC is also recommending that in addition to the current educational material, patients and healthcare professionals in the EU should be given an acknowledgement form. The form will be used to confirm that doctors have discussed the risk with their patients and that the patients understand the importance of monitoring and checking for signs of liver damage.

These recommendations, which strengthen provisional measures introduced in July 2017, will now be sent to EMA’s Committee for Medicinal Products for Human Use (CHMP), which will adopt the Agency’s final opinion.

ProfG    

10 comments:

  1. What do you mean with "2nd patient'?
    There was one death in May. Was there another since? Please provide a press brief.

    Thanks

    ReplyDelete
    Replies
    1. The death in May was the second patient. The first death occurred in one of the clinical trials.

      Delete
    2. Do you think that Biogen will still make an effort to identify the root cause of these incidents?

      I truly hope so for those who switched last year and are actually doing very well on Zinbryta.

      Your observation of usefulness for long term Tysabri patients with elevated PML risk is spot on: many Neuros waited several years for Daclizumab approval in order to then move their elevated risk patients. A full withdrawl woud create a serious quagmire for some..

      Delete
  2. Prof G would you prescribe daclizumab?

    ReplyDelete
    Replies
    1. Yes I would. There will some patients who don't want an immunosuppressive therapy that may need an agent such as daclizumab.

      Delete
  3. Don't you feel sorry for your colleagues at the NIH who spent so much of their time on daclizumab to only see it sidelined as a 3rd or 4th line drug?

    ReplyDelete
    Replies
    1. I suspect he feels more sorry for the two families involved :-(

      Delete
    2. Re: "Don't you feel sorry for your colleagues at the NIH who spent so much of their time on daclizumab to only see it sidelined as a 3rd or 4th line drug?"

      This is the reality of drug discovery and development. It comes with risks even in the late stages. This is why Pharma are the only game in town with big enough pockets to take the hit.

      Delete
    3. Re: "I suspect he feels more sorry for the two families involved :-"

      Yes, you are right any preventable death is a tragedy.

      Delete

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