Overcoming an initial rejection by the FDA, alemtuzumab (Lemtrada) was given marketing approval late Friday for treatment of relapsing-remitting multiple sclerosis but "generally" as a third-line treatment, its manufacturer said.
The approval also comes with a requirement for a boxed warning about "serious, sometimes fatal autoimmune conditions," severe infusion reactions, and the possibility of increased risk of certain cancers, according to .
And alemtuzumab will only be available through a restricted distribution program that will require prescribers, pharmacies, and patients to be certified. The intent is to "educate healthcare providers and patients on the serious risks associated with Lemtrada and the appropriate periodic monitoring required to support the detection of these risks for 48 months after the last infusion," the statement said.
Alemtuzumab is unusual among MS drugs in several respects. It was sold for many years as Campath for treating certain leukemias. In MS, it is administered by IV infusion in two annual cycles, the first lasting 5 days and the second 3 days. Its target is the CD52 protein on the surfaces of T and B cells. The two treatment cycles temporarily deplete these cells. Their subsequent repopulation is marked by a transformation in immune responsiveness, such that the autoimmune attack on myelin fibers in the nervous system is shut down or at least reduced in most patients.
In the drug's pivotal trials, which included the standard MS drug interferon-beta-1a as a control, most patients showed marked declines in annualized relapse rates that persisted long after the final infusion.
But when Genzyme first applied for marketing approval, the FDA was concerned that the trials' open-label designs -- Genzyme believed a double-blind, double-dummy design would be impractical since patients assigned to alemtuzumab would have to receive hundreds of sham injections -- detracted from the results.
Alemtuzumab's safety was also a major question mark. As the boxed warnings indicate, small but worrisome minorities of patients developed new autoimmune conditions affecting the thyroid and other organs, with some cases fatal.
These concerns led the agency last December to turn down the company's marketing application, although authorities in Europe, Canada, and Australia had approved it. It told the company to conduct new active-comparator trials with different designs. However, Genzyme was able to persuade the FDA that these would not be needed.
On the other hand, Genzyme was unable to win approval for the drug as first-line treatment. The states prominently that, "[b]ecause of its safety profile, the use of Lemtrada should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS."
Besides the risks of autoimmune disorders and malignancies, the label also lists a host of other adverse effects: rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral infection, urticaria, pruritus, thyroid gland disorder, fungal infection, arthralgia, pain in extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting. Some of the infections were severe, as were some cases of pneumonitis.