Lemtrada hits speed bump on road to approval
Lemtrada (alemtuzumab) is the latest medication seeking approval for use as a treatment for multiple sclerosis, but reviewers at the U.S. Food and Drug Administration (FDA) have not given it a glowing endorsement.
The Peripheral and Central Nervous System Drugs Advisory Committee voted that the clinical trials weren’t done well enough to be able to assess Lemtrada. But in a seemingly contradictory move, the Committee also voted that there was substantial evidence that Lemtrada was effective for the treatment of relapsing MS. In addition, the Committee voted unanimously that any safety concerns with Lemtrada should not stop it from being approved in the U.S. (Bennett S, Tirrell M. Bloomberg, November 14, 2013; www.bloomberg.com/news/2013-11-14/sanofi-ms-drug-s-mixed-verdict-from-fda-panel-puzzles-analysts.html).
Lemtrada is a monoclonal antibody that targets a protein, called CD52, on the surface of various immune cells, which leads to a rapid depletion of the T cells and B cells that drive inflammation in MS. The drug (then called Campath-1H) was first tested in MS in 1991 (Moreau and colleagues. Lancet 1994;344:298-301). It was initially approved by the FDA to treat a type of blood cancer in 2001.
A unique feature of Lemtrada in MS is its dosing schedule. The drug is administered as a slow IV drip on five consecutive days, then three more doses are given a year later (so eight treatment days over two years). But this small amount of drug is enough to induce a profound and long-lasting suppression of immune function.
The European Union approved Lemtrada as an MS treatment in September 2013 based on the results of two phase III studies. In CARE MS-I, people with relapsing-remitting MS (RRMS) who had not previously been on therapy received either Lemtrada or Rebif for two years (Cohen and colleagues. Lancet 2012;380:1819-1828). People were less likely to have a relapse on Lemtrada compared to Rebif (22% vs. 40%), however, neither drug was shown to significantly reduce the risk of disability progression. In CARE MS-II, people who had experienced at least one relapse while being treated with an interferon or Copaxone received either Lemtrada or Rebif for two years (Coles and colleagues. Lancet 2012;380:1829-1839). Here the results were somewhat better: relapses were less common with Lemtrada compared to Rebif (35% vs. 51%), and there was also a lower risk of disability progression (13% vs. 20%).
The 18-person FDA committee was composed of physicians, academics and members of the public, with only one having expertise in MS. In voting in favour of approving Lemtrada, the committee largely ignored the FDA’s internal review, which was highly critical of the Lemtrada application. One FDA reviewer did not recommend approval due to “serious and potentially fatal” concerns about the drug. The other two reviewers found that the evidence from clinical studies was not adequate to support the effectiveness of Lemtrada, and that additional studies were needed.
At issue were fundamental problems with the two phase III studies. Neither compared active treatment to placebo, and doctors and participants knew which treatment was being given (which can bias the results). In addition, the CARE MS-II trial may have overestimated the benefits of Lemtrada since some participants taking Rebif had previously failed treatment with Rebif. (Click here for the free full text of the FDA briefing document).
The FDA safety review raised numerous concerns about side effects that may occur with Lemtrada, such as the development of a range of other autoimmune diseases, thyroid cancer and melanoma. For example, the estimated incidence of immune thrombocytopenia (ITP), which can result in fatal bleeding complications, is 200-fold higher in people treated with Lemtrada compared to the general population; in clinical trials, ITP was reported in about 1%. The incidence of thyroid cancer in people treated with Lemtrada was low (0.4%), but this is about seven times higher than what is seen in the general population. The FDA also estimated that the rate of melanoma during Lemtrada treatment was about 3-5 times higher than normal.
The Committee voting is expected to lead to FDA approval of Lemtrada in late December, although the agency may require additional clinical testing to better establish the benefits and risks. The likely indication is as a third-line treatment in people who have not responded to at least two prior treatments. Alternatively, it could be used as a short induction drug to induce a profound response in people with highly aggressive MS, followed by a medication with a more favourable risk-benefit profile for longer term treatment. While much discussed as a treatment approach, there are no published trials of induction therapy with alemtuzumab.
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