Author Topic: FDA rejects MS drug Lemtrada (alemtuzumab, Campath)  (Read 253 times)

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Offline agate

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FDA rejects MS drug Lemtrada (alemtuzumab, Campath)
« on: January 03, 2014, 11:26:26 am »
From WebMD, January 3, 2014:

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FDA Rejects MS Drug Lemtrada

By Kathleen Doheny
WebMD Health News

Reviewed by Michael W. Smith, MD

Dec. 30, 2013 -- The FDA has rejected the new multiple sclerosis drug Lemtrada, saying the drugmaker didn’t show the drug's benefits outweigh some serious risks.

The agency asked the maker, Genzyme, to test the drug in more clinical trials.

The drug was to be used for relapsing-remitting MS, the most common type.

...

Genzyme says in a news release it plans to appeal the FDA’s decision on Lemtrada (alemtuzumab).

The drug has been approved in Canada, the European Union, and Australia. In the U.S. it received a mixed review from an FDA advisory committee in November. At that time, several members raised concerns about its safety.


The FDA had earlier approved the drug to treat leukemia, marketed as Campath.

Lemtrada is given as an infusion. It was expected to be used in MS patients who did not respond to other treatments.


Lemtrada's Side Effects a Concern

"We're disappointed by the decision," says Timothy Coetzee, PhD, chief advocacy, services, and research officer for the National Multiple Sclerosis Society. He says he's concerned about what this means for U.S. patients with MS.

In two clinical trials, Lemtrada reduced relapse rates over 2 years by about half compared to patients on another MS drug, Rebif (interferon beta-1a), Coetzee says. That reduction in relapses, he says, "is a pretty big deal."

A patient who relapses must go to the doctor and take time off work. Recovering from a relapse can also take some time, Coetzee says.

But the powerful impact of Lemtrada also can have downsides.

One potential side effect is called immune thrombocytopenic purpura, or ITP. This causes low platelet counts in the blood and can lead to dangerous bleeding. In the clinical trials, one patient died of ITP.

Genzyme put a special patient safety monitoring program in place after the death.

In the later research studies, most patients treated with the drug had mild to moderate infusion-related reactions, Coetzee says, including headache, rash, nausea, and fever. He says about 30% of those on Lemtrada developed thyroid-related problems. But those conditions, if caught early, can often be treated, he says.

Infections are another potential side effect, including shingles and upper respiratory, urinary tract, and sinus infections.

Coetzee says the National Multiple Sclerosis Society will continue to monitor the situation and to gather more information about the FDA's decision.

The entire article can be seen here.
MS Speaks--online for 13 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.

Offline agate

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Re: FDA rejects MS drug Lemtrada (alemtuzumab, Campath)
« Reply #1 on: January 20, 2014, 07:25:40 pm »
The FDA has come in for some criticism about its rejection of alemtuzumab, as outlined in this blogpost from the MS Discovery Forum (January 7, 2014).
MS Speaks--online for 13 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.

Offline agate

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Re: FDA rejects MS drug Lemtrada (alemtuzumab, Campath)
« Reply #2 on: January 31, 2014, 04:21:36 pm »
The FDA's rejection of Lemtrada has surprised and angered MS doctors and patients, according to this blog article in MedPage Today, January 23, 2014.
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Offline agate

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Re: FDA rejects MS drug Lemtrada (alemtuzumab, Campath)
« Reply #3 on: February 18, 2014, 08:42:35 am »
More reaction to the alemtuzumab situation in a Lancet editorial, February 18, 2014:

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The Lancet Neurology, Volume 13, Issue 3, Page 233, March 2014

Alemtuzumab and the value of neurological research


The announcement by the US Food and Drug Administration (FDA) on Dec 27, 2013, to reject an application for the use of alemtuzumab in relapsing-remitting multiple sclerosis (MS) has caused a stir within the neurological community. Investigators involved in two large phase 3 trials that tested its safety and efficacy expressed discontent; patients' organisations protested the decision; the drug makers announced their intention to appeal this initial ruling (which is subject to further regulatory review); and even an opinion piece in the Wall Street Journal called for FDA reform, given such “vivid example of the serious problems besetting US drug regulation”. Friction among these stakeholders is common, and reflects the difficulties of the ever more complex process of moving experimental therapies into clinical practice. However, the process will not be streamlined solely by reforming the regulatory agencies.

The CARE-MS I and CARE-MS II randomised trials compared intravenous alemtuzumab with subcutanous interferon beta in more than 500 and 800 patients, respectively. In both studies, alemtuzumab was more efficacious than interferon beta in reducing relapse rates, and patients treated with the antibody had fewer brain lesions and less brain atrophy. In CARE-MS II, in which participants had ongoing disease activity, alemtuzumab also had a beneficial effect on accumulation of disability; this improvement was not detected in patients with early MS who formed the study population in CARE-MS I. In both trials, the safety profile of alemtuzumab was as anticipated for an anti-CD52 antibody with lymphocyte-depleting effects: infusion reactions, infections, and autoimmnunity. In light of these findings, the benefits were deemed greater than the risks by Canadian and Australian regulators, and by the European Medicines Agency, which approved the use of alemtuzumab in patients with active disease. But the FDA concluded that, because of their open-label design, the CARE-MS trials did not provide robust evidence to substantiate safety and efficacy claims.

Weighing up the risks and benefits of new treatments for chronic neurological disorders is a balancing act, but inconsistencies among regulators are becoming habitual. The recent regulatory discrepancies on the approval of new oral drugs for the treatment of MS (ie, cladribine and fampridine) raised similar questions to those now elicited by the alemtuzumab affair: how robust do results have to be in one study so that a second one is not needed? How long does a study need to be to assess safety? What is the most unbiased trial design? These issues refer to the uncertainties inherent to the scientific endeavour, but a more fundamental question is poised to the neurological research community after these incidents: why are the aims of the stakeholders in this long and complex process seemingly so misaligned?

A Series in The Lancet (Research: increasing value, reducing waste) provides the conceptual framework to initiate a discussion of this question. Participants and investigators in the CARE-MS trials will probably agree with the authors of this Series that the “present situation is ethically, scientifically, and economically indefensible” and back their call for a new research governance strategy. Regulatory requirements directly influence researchers' choice of study design and methods; hence, regulatory agencies ought to be transparent about their rules, ensure that guidance on those rules reaches all stakeholders, and monitor delays and inconsistencies in their procedures. Yet, they are not the only stakeholders that should take any opportunity to minimise waste: all those involved must be accountable for the integrity of the process and its effectiveness. The decision about what study to do is primarily driven by research funders, who should also be more transparent and engage the potential end-users of research in their priority-setting procedures. Awareness of all relevant information and previous knowledge is crucial; however, selective or biased reporting and dissemination of findings are insidious problems for which researchers and journal editors share responsibility.

Neurologists have reasons to celebrate their embracing of rigour in research and evidence-based clinical practice. Notably, they have been instrumental in establishing the Cochrane Collaboration and are driving CAMARADES, an initiative to use systematic reviews of animal studies to speed up translation of preclinical findings. Regulatory inconsistencies show that big challenges remain. As The Lancet Neurology went to press, the final ruling on alemtuzumab by the FDA was still unknown. Even if that changes, it is time to pause and reflect on how to prevent other research endeavours from facing similar troubles.

The editorial can be seen here.
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Offline agate

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Excerpted from the Lancet, March 7, 2014:

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FDA's rejection of alemtuzumab divides neurologists

Asher Mullard

...

Alemtuzumab's backers have had a rocky ride trying to get their drug to patients with multiple sclerosis (MS). Although they succeeded in convincing European regulators to give the antibody the green light in June, 2013, they continue to face an uphill battle in the USA. The US Food and Drug Administration (FDA)rejected Genzyme's antibody therapy in December, 2013. Neurologists are weighing in on both sides of the FDA's decision.

“I think it was a very disappointing decision”, says Richard Rudick, director of the Cleveland Clinic Mellen Center for Multiple Sclerosis. Rudick advocated for alemtuzumab on behalf of Genzyme at an advisory committee meeting in November, but says he donated his consulting fee to a charity. 70 clinicians, both with and without ties to the drug, have also signed an open letter to the FDA calling on the agency to reverse their decision. They argue that the CD52-targeting antibody—which depletes the lymphocytes that may drive the autoimmune disease—offers compelling efficacy and manageable toxicity for patients with few therapeutic options. Two pivotal trials in treatment-naive and in treatment-experienced patients with MS met their primary endpoints, relapse rate, and time to 6 month sustained accumulation of disability, against an interferon β1a comparator.

But not everyone is convinced, and longstanding clinical trial design issues lie at the heart of the FDA's rejection. FDA reviewers argue that the pivotal trials were vulnerable to bias because Genzyme ran open-label trials in which patients knew which drug they were on while neurologist raters were blinded. The setup, said FDA officials at the advisory meeting, could have skewed the baseline characteristics of the control and active groups (dropout in one trial was 12·6% in the control group and 2·3% in the active group). Clinical outcomes in multiple sclerosis are “highly subjective”, they added, and are susceptible to inadvertent or deliberate distortion from unblinded patients. If 6% of the interferon-treated control patients over-reported their symptoms (inadvertently, or because they had previously failed on interferon and wanted to be switched to a new drug) and 10% of alemtuzumab-treated patients under-reported their symptoms (perhaps because they had high hopes for alemtuzumab and didn't want to be taken off the drug), the treatment-experienced pivotal trial can be written off as a false-positive result, showed one FDA analysis.

“I personally support the FDA's decision”, Dennis Bourdette, director of the Multiple Sclerosis and Neuroimmunology Center at Oregon Health & Science University, tells The Lancet. “The considerable toxicity of alemtuzumab renders it inappropropriate for treating most patients with MS.” The drug's risks include the potentially fatal immune thrombocytopenia, Graves disease, and opportunistic infections. Alemtuzumab was nevertheless approved for the treatment of chronic lymphocytic leukaemia (until 2012, when Genzyme controversially withdrew it to pursue the more profitable development of the drug for MS). However, the adverse events pose a different benefit—risk dilemma in the context of MS, especially if the benefit data are questionable.
Genzyme plans to meet with the FDA to discuss the agency's concerns and a possible resubmission. In the interim, say some neurologists, patients with MS, the financial means, and clinical need might travel to Europe or Canada to access alemtuzumab, which will be problematic if they don't get safety monitoring upon their return.

...

Without some resolution, however, the community remains stuck in a bind. “The single-blinded design has its downsides, there is no question about it”, says neurologist Olaf Stüve of VA North Texas Health Care Systems. “But while you can design a double-blind study on paper, it's not feasible to run it.” Alemtuzumab and interferon have different dosing schedules and different adverse event profiles, he explains, which would effectively unmask blinded patients. Even if trials were run only against a placebo comparator, or against an active comparator with placebo injections to make up the differences in dosing regimens, injection-site reactions could unmask participants. So what do you do when the FDA's need for reliable data conflicts with the practicalities of running trials? With the MS specialty moving towards embracing active-comparator trials, the difficult question is particularly pressing. “It was a very complex decision”, says Stüve. “It's hard to say whether they made the right or the wrong choice.”

The entire article can be seen here.
MS Speaks--online for 13 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.