Friday, 2 March 2018

Urgent News Update: daclizumab is withdrawn from the market

The EMA has just announced that Biogen and Abbvie are pulling daclizumab from the market. Why?



On a recent trip to Goettingen in Germany, I was shown a handful of cases with eosinophilic encephalitis occurring shortly after starting daclizumab. The number of cases at that time was just 5, but it was sufficient for me to state that this must be the final nail in the coffin for daclizumab. Daclizumab has taught us a tremendous amount about the pathogenesis of MS, but with a large number of other DMTs on the market, it would be difficult to justify its use with its current, and emerging, safety profile. What daclizumab has taught us is the T-regs are probably not involved in the pathogenesis of MS and that the memory B cell is king. 



ProfG    

24 comments:

  1. Bad news for MSers, maybe worse news for Biogen. Their MS franchise is under pressure. Not that I'm shedding any tears…

    Any more news on the Ocrevus rumors (deaths due to opportunistic infections)? I believe I first saw that reported here, and then saw some follow-up articles elsewhere on the Internet. Haven't heard a word in a few months, though… False alarm, or reason for concern?

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    1. At least Biogen has Barts who wants to give Tysabri to all undiagnosed patients to save them from certain death from acute multiple sclerosis #ThinkBiogenChariot

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    2. CharcotwouldbefuminginhisgraveSaturday, March 03, 2018 2:34:00 pm

      Lol so so true

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    3. it is #BrainAttack. it is not about death from MS but saving brain

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  2. In regards to my last comment, of course very insensitive of me to downplay the human tragedy in this. But Biogen has built a business around its MS franchise, which is showing major cracks. Tecfidera sales are way off, Tysabri is under pressure from Ocrevus, and this news takes out another pillar in their MS platform.

    Would be nice if they started directing some research at finding the cause and then cure of this disease, but that's not a moneymaking business model. Better to keep patients shackled to obscenely expensive drugs that profoundly impact the immune system, with long-term consequences completely unknown…

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    1. When daclizumab was initially licensed I was unsure when I would use it. It didn't seem to have an obvious place when put up against fingolimod, tysabyri or alemtuzumab.

      With the initial reports of deaths from hepatic failure I decided that I wouldn't want to use it unless I had to (especially with cladrabine and ocrelizumab just around the corner) and now I'm glad of my decision.

      I'll be interested to read about these cases if and when they are written up and published

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    2. Re: "....Would be nice if they started directing some research at finding the cause..."


      Good news is we made a substantive appointment last week in our Preventive Neurology Unit to do just this, i.e. focus on the cause(s) of MS and how we can prevent the disease.

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  3. By now, someone should have found the memo outlining this scheme to to shackle patients to extremely expensive drugs, rather than look for a cure. A vaccine is being developed, as well as therapies to regrow the myelin that has been lost.

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  4. "What daclizumab has taught us is the T-regs are probably not involved in the pathogenesis of MS and that the memory B cell is king."

    Classic autopsy studies have repeatedly yielded much more useful observations. Do you think that all the health, money and time wasted on daclizumab were worth of your (probable) assumption?

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  5. TGIF! Could you please explain how a medcation that’s been on the market for nearly 20 years would suddenly develop such a drastic risk profile?

    What’s the usefulness of clinical studies if they couldn’t uncover some apparently obvious life threatening side effects?

    Finally, what therapy advice would you have those who did well with Zinbryta?

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    1. Re: "What’s the usefulness of clinical studies if they couldn’t uncover some apparently obvious life threatening side effects?"

      It is a numbers game. Too few patients treated in the phase 2 & 3 trials to see rare events. That is why we have phase 4 programmes to look for events after the drug is launched.

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    2. Re: "Finally, what therapy advice would you have those who did well with Zinbryta?"

      They would need to stop daclizumab and transition onto one of the other DMTs. I can't think of a single DMT that would be contraindicated post-daclizumab. However, most patients will probably need a high-efficacy DMT post-daclizumab as it was generally used 2nd or 3rd line.

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  6. Strange Daclzumab is withdrawn when Natlizumab has killed over 600 and yet it's still licenced!

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    1. The deaths due to natalizumab are mainly in patients who JCV+ve.

      Please note that Biogen have provided clinicians with a JCV assay for free and the data about PML risk linked to the results of this assay. You need to ask the question why do neurologists start MSers on natalizumab, or continue natalizumab, in JCV+ve patients? Is that EMA's, Biogen's, the neurologist or the patient's fault?

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  7. So to get this right: Prof. Cohen presents preliminary results of the EXTEND long-term safety study (through 9.2016) at the ACTIMS 2017 where everything is going fine for the 1300 Paticipants - except for a „few hepatic issues” and merely 5 Months later the company says “sorry” and withdraws their therapy altogether?

    In the meanwhile, cases of encephalitis are openly discussed among those administering the therapy while the “Early Warning Database”of the EMA isn’t apparently updated until 23.2.18 where in some big upload not only encephalitis cases but also other hepatitis cases are recorded?

    This is begging for someone at Biogen to come clear on “Who knew what and when..?”

    And to put this into perspective: this was initially considered one those “moderate risk” therapies were the Antibody had previously been on the Market as Zanapax with a nearly flawless safety record..

    So looking forward: how does Pharma want to maintain patient trust at a time where three chemotherapies - with a much spottier track record - are now marketed as escallation therapies?

    Or is Biogen now simply the “Bad Apple” ?

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    1. It is all about timing. The EMA and Pharma can't act on hearsay. They need hard data; this takes time to get. Each case has to be investigated and once there is a clear signal then it triggers and investigation

      After the cluster of encephalitides were reported from patients treated with daclizumab the EMA triggered a second Article 20 procedure to re-evaluate the benefit:risk of daclizumab as a treatment for MS. At this stage Biogen and Abbvie decided that based on this new data that it would difficult to justify using daclizumab in the current DMT environment; i.e. there is not really an unmet need that justifies the risk of daclizumab. That is when Biogen and Abbvie decided to withdraw daclizumab from the market.

      Please note it is not that uncommon for a drug to be withdrawn from the market when a safety signal emerges after a drug has been launched. This tells us that the EMAs pharmacovigilance systems are working. Please note encephalitis post-daclizumab was not seen in the clinical development programme.

      In my opinion the actions the EMA, Biogen & Abbvie have taken are proportionate and appropriate. What do you expect them to have done? They completed an Article 20 review late last year and at that time new safety issues had not emerged yet. It is easy to make a judgement call in hindsight, but the safety profile of daclizumab has taken months to emerge and become clear.

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    2. Thank you for your detailed response. All actions post EMA Article 20 are understandable. It’s obvious that the manufacturer would have not been able to recruit a sufficiently large patient group for further safety studies with this medication any longer and called it quits.

      The timeline for reporting of this “cluster of encephalides” still doesn’t seem right. The initial case of fulminant hepatic failure presumably related to Zinbryta occurred in late May 2017. The EMA Warning was out in early July. If that timeline remained valid, then there must have been half a dozen severe cases of encephalitis occurring at once in mid February 2018 triggering the 2nd Article 20 review.

      Half a dozen cases all at once? Seems more like they were collected over a period of time during which very positive results of the EXTEND safety study were communicated to practitioners at ACTRMIS...

      I understand that any incident warants a correct vetting before declaring it to be part of a signal. It should be however clearly communicated in the interest of transparency and it was my understanding that this was the precise purpose of the EMA Early Warning Database. Therefore my bewilderment that presumably all and any Zinbryta related incidents were “reported” in some mass upload on Feb. 23. or merely a few days before the drug was taken off the market...

      A concerning MS Patient on some escalation therapy is left to wonder how many incidents - some of which could well be lethal - are sitting somewhere for review before the get uploaded into the EMA DB. This is not transparent.

      Maybe you can offer some perfectly logical explanation for the time lag on Zinbryta. I’m currently not seeing one.

      Thanks.

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  8. What about NK cells pof g? What does this mean for charcot project?

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    1. what do it mean...not alot I suspect

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    2. Re: "What about NK cells pof g? What does this mean for charcot project?"

      Not a lot. I am not sure daclizumab was working via NK cells. It was likely working via memory B cells that also relied on IL2 to survive. The NK cells were important for PML prevention post-natalizumab.

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  9. MS Patient said

    "This is why daclizumab is such an interesting drug. If we can work out how NK cells are doing their job in daclizumab-treated patients we will have a clearer idea about what is causing and driving MS.
    Gavin Giovannoni 7th February 2016
    No wonder JK Rowling calls your b*******

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