Friday, 8 November 2013

Is alemtuzumab too risky?

Is alemtuzumab being misunderstood by the FDA? MSBlog #MSResearch

Anna Edney & Simeon Bennett. Sanofi’s Lemtrada Drug May Be Too Risky, FDA Staff Says. Bloomberg Nov 8, 2013 4:47 PM GMT

Excerpts:


.... Alemtuzumab may not offer enough benefit to patients to outweigh risks including cancer, U.S. regulators said. Securities linked to the drug’s success plummeted......

.... Alemtuzumab’s “serious and potentially fatal safety issues,” which include the risk of autoimmune and thyroid diseases, may make the medicine too dangerous to approve unless there is substantial clinical benefit shown, Food and Drug Administration staff said in a report today. Agency reviewers also questioned whether Genzyme conducted adequate trials to prove the annual infusion works....

..... “The certainty of the risks of potentially lifelong hypothyroidism, serious infusion reactions, melanoma and other malignancies, Graves’s ophthalmopathy and other autoimmune disorders, and prolonged increased susceptibility to infection may not be balanced by the uncertainty that exists in the limited evidence of the potential clinical benefits from clinical trials that were not well-controlled,” FDA drug reviewer John Marler wrote in the report. ....

Click here to read the full article

22 comments:

  1. The FDA staff is doing their job in preparing for next week’s advisory committee meeting. This is what they do with advisory committees. Sanofi’s management is all in favor of a strong REMS program. That would not bother them. They have been meeting with the FDA in preparation for the FDA decision to approve or reject Lemtrada. The decision remains scheduled for the latter half of December 2013. The FDA is going through the data – including the consistent results in Genzyme’s 5-year follow up. The staff raised questions on trial design. Sanofi believes that they have answers. For one specific example, it was clear that a double blind study was not feasible. The companies are preparing for the panel and can now do so with the staff’s questions. All of the questions have answers. Sanofi is not backing off of their support for this drug and does not appear to be discouraged by the staff’s background package.

    Lemtrada is twice as good as what most people take today. There are real risks. Safety issues need to be discussed, but also need to be put into perspective. What is the magnitude of the risks and – importantly – how do they compare to MS? The FDA decision centers around safety and how risk can be mitigated. Staff concerns are fairly reasonable. They want an in depth discussion and will get one. For more on FDA advisory committees:

    http://bit.ly/1aw5YKu.

    What would a robust REMS program look like? It would probably look like the program devised for Tysabri after it was pulled from the market. The FDA is concerned with designing an effective REMS and ensuring compliance with the monitoring requirements. Doctors administering the drug will register with Genzyme in order to track patients for complications. Next week, the advisory committee with probably make recommendations for further strengthening the REMS program as well as enforcing compliance. Biogen is tracking all serious adverse events associated with Tysabri. According to the most currently available data, there have been 401 cases of Tysabri-induced progressive multifocal leukoencephalopathy (PML) as well as 88 deaths. A REMS works for Tysabri and a REMS would work for Lemtrada, which is the safer of the two drugs.

    - http://seekingalpha.com/instablog/957061-chris-demuth-jr/2323182-gcvrz-forum

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    1. "Lemtrada is twice as good as what most people take today"? The FDA's point is that the trials don't give us reliable evidence of any effectiveness whatsoever. There's only been a lot of optimism from a lot of people, all predicated on the same questionable data.

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  2. Thank God I'm in the UK and got Alemtuzumab in a trial. Not sure what the FDA are looking at to question the benefits of Lemtrada. Hopefully, NICE will approve its use in the UK. As the drug is used throughout Europe the impressive results seen in the trials should be replicated. As noted above, FDA approved Tysabri with the risk of PML. Thyroid problems are hardly in the same league. Hopefully a robust monitoring programme will satisfy the FDA.

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    1. I am in the US and just received my final Tysabri (50). I am choosing to stop receiving it due to the risks of PML. I am JCV positive, have been receiving Tysabri for more that 4 years so my chances of developing PML are 1-164! The neurologists are not coming out and telling us this which is ridiculous. I will be receiving IV solumedrol 1000 for 3 days in hopes of controlling the rebound effect. I will step down to 2000 and then 1000. I will be starting tecfadera in late December. If I can not tolerate this medication or if I relapse, I have no other recourse. I will be speaking at the hearing on November, 13th. I am hoping that the FDA approves Lemtrada or I may wind up flying to Europe later next year for treatment. I would gladly trade hypothyroidism for MS any day!

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  3. Would Prof. G have anything to say on this post? How can EMA and FDA have so heterogeneous opinions on Alemtuzumab? Is it a UK-MSologists lobbying consequence?

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    1. A French drug verses American Drugs? Only joking.. I am sure ProfG is proud of his part in the EMA decision and helping people to get choice of their treatments

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    2. Remember the FDA killed movectro, it was was given just as often as Alemtuzumab,based on phase III results probably as efficacious and ral and had a better safety profile than Alemtuzumab, with a similar cancer risk to other drugs.

      There is therefore a history

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  4. I think there's a chance that MS could be being misunderstood by the FDA.

    Cancer risk? I though there wasn't one in the phase III trials? Given the 1 in 3 lifetime risk of cancer, I can't imagine that it could ever be high enough to push it much over that. Though there was some risk with the higher dose used for CLL. It's a risk I'd absolutely take. Better getting cancer at 70 (with potential for CURE, not a word you hear bandied about with MS) than spending the previous 20 years in a wheelchair, tired and cognitively impaired.

    Fatal side effects? Will they compare this with the suicide risk and the early death associated with MS? MS is actually therefore a fatal disease. Will they factor this in? Of course not.

    Lifelong thyroid problems? I'd gladly swap this for MS. Thyroid eye disease less so and it is vision threatening in its more extreme forms... but again so is MS. MS seems to be one of the most under treated forms of visual loss out there. Visual problems in your 80s (ARMD)? Someone will be there injecting a monoclonal antibody into your eye.. not so with visual problems with MS in your 20s, 30s or 40s.

    Throbocytopaenia and Goodpastures - not good, but thankfully much rarer. And also risk of death from these in the trials very very small.

    So we have a quote from a director of MS at the Cleveland Clinic saying that alemtuzumab should be a second line drug for those that have failed first line. I think due to their lack of effect, by any measure the majority will FAIL his proposed first line medications (is 30% disability reduction or less really any measure of success for sufferers? It's better than 0%, but hardly a success). I thought doctors were supposed to be steering clear of paternalism, but here we have it in full flow. "I'll tell patients what risks they should be willing to take... I know best". This, to me, is unacceptable and extremely arrogant and conservative. Simply because he watches most people get disabled over the course of his career, and not overnight, he probably feels that he can sleep comfortably, but my gut feeling tells me he's doing people with MS a tremendous disservice with this extremely conservative attitude.

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  5. Another view on the subject is that the FDA isn't confident about the fantastic effect that has been marketed on this blog regardinging this drug. I read the October 16 Memorandum ( linked in the post we are commenting ) and would like to have some more fact based objections to what Dr. Mentari, Dr Marler and Dr Yan say. To me it was quite surprising to read their opposition and I hope some or any of the professors can comment on especially the issues that are pointed out on page 6 in the "report" attached.

    How can they have the opinions I quote below if they are totally wrong? ( page 6 in above mentioned "report" )

    *" As these concerns are serious and potentially fatal, Dr. Mentari does not recommend approval of alemtuzumab unless substantial clinical benefit exists. "

    * "Because of these issues, Dr. Marler finds that the applicant has not submitted evidence from adequate and well-controlled studies to support the effectiveness of alemtuzumab for treating multiple sclerosis. "

    * " Dr. Yan finds, like Dr. Marler, that the applicant has not provided evidence from adequate and well-controlled studies in this application and that such studies still need to be conducted to establish the effectiveness of alemtuzumab for the treatment of patients with multiple sclerosis. "

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  6. First line treatments inhibit up to 30% of RELAPSES and have no or minimal effect on disability. Just in case anybody thought otherwise.

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    1. That's an old statistic. It's no longer accurate and it's a statistic. In that 30% there will be people who have had no relapses since starting treatment and also non-responders.
      If you have a terrible relapse and can't walk for several months afterwards, it will be counted as disability.
      If you slowly progress and after 20 years can't walk, then that's progression. The two aren't the same.

      Lemtrada is different. The chance to have no relapses for 10 years is very appealing. I'd go for it.

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    2. Nataluzimab can be a first line treatment and inhibits relapse at rate a lot better than 30%

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  7. There isn't much debate on safety. The problem is that there isn't sufficient proof that Lemtrada works better than Interferon. And its not just the structure of the trials (which the FDA repeatedly told them wasn't adequate). There's pervasive evidence of enormous bias and a not-so-subtle suggestion that the baseline EDSS evaluations and the relapse calculations based on them were rigged. The only arguments that have any merit at this point are statistical ones on the trial data. The European agencies clearly didn't slice and dice the figures as well as the FDA. And what doctor in his right mind would prescribe Lemtrada over other treatments if the evidence of its efficacy is sorely lacking. Unfortunately, it seems like everyone has been had.

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    1. Anon,

      are you in a position to tell us that you're coming at this from a neutral perspective? Do you have any involvement or connection with any of the drug companies? Your conclusion that everyone has been 'had' suggests that you believe fraud is involved. If so, are you willing to come out from behind your anonymous tag and stand up for what you believe?

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    2. Yes you have to realise that pharma read the blogand can coments so be warned

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    3. To suggest that the efficacy of lemtrada is no better than beta interferon, then I think you need to throw those rose-tinted glasses away to read the papers

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    4. You mean the FDA's rose-tinted glasses? Read the report for yourself:

      http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM374186.pdf

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    5. Why then has the EMA taken a different stance?

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    6. Because the EMA largely took the trial results at face value, while the FDA tested for anomalies and bias. The EMA document is below, which do you think has more statistical rigor?

      http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003718/WC500150522.pdf

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    7. In reply to Anon, you were not at the hearing on November 13th so you did not see or hear the patients speak that have received Lemtrada! Their stories are amazing and remarkable. Lemtrada saved them from wheelchairs or worse. I was there and I spoke with them. I submitted a presentation and also was one of the OPH speakers in favor of approving Lemtrada. Where do you come off being so self-righteous about this drug? I have been living with MS for 13 years now and have suffered from the horrible symptoms of MS. I have tried and failed all of the other drugs out there. I have stopped Tysabri due to the concern of developing PML, which at the point I am at, is 1-164!!! I will be starting Tecfidara the first of the year. I also have to go one large amounts of IV solumedral to hopefully offset the rebound effect which happens to patients when they go off of Tysabri. The decision to take Lemtrada should be made between the patient and his or her neurologist after discussing all of the potential side effects. We as MS patients are well schooled about our disease and should be treated as such and be allowed to make an informed consent. Not people like you!!! Get off your high horse and speak to people suffering from this disease and allow yourself another perspective.

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    8. Melissa - how can patients make an informed risk-reward decision without reliable studies quantifying how effective it is? Success stories are wonderful, but there are also several patient testimonials you didn't hear because Lemtrada killed them! Sanofi could easily make the drug available for MS patients off-label by putting it back on the market for CLL patients. Of course, they wouldn't be able to charge 10x the price as they are trying to do now. Perhaps you should reconsider who is the bad guy here. Hint: it isn't the FDA.

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    9. Sanofi have put in place a monthly monitoring process to de risk some of the known but treatable problems of Lemtrada and the unfortunate death of people in trials is not unknown for many MS drugs currently being used including beta interferons that are considered to be a safer option. Whilst Alemtuzumab studies are not without their problem due to the unblinded design this drug was tested against an active comparator unlike many others, and succeeded.

      The European Experiment now begins, unless it gets pulled due to safety issues. This could be like the human experiment with rimonabant approved by the FDA/EMA and then pulled for safety issues, so Sanofi have already been there.

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