Although one-year results of Campath in treating multiple sclerosis showed strong efficacy, Genzyme Corp. and partner Schering AG suspended dosing in a Phase II trial in response to three confirmed cases of severe idiopathic thrombocytopenic purpura (ITP).
Nevertheless, the companies plan to collect efficacy and safety data from the trial in preparation for a Phase III study to begin in the first half of next year. In the meantime, they will try to find ways to better manage patient safety.
"Until we complete these investigations regarding the ITP and determine whether we can improve the risk management strategy, we have decided that it would be most responsible and appropriate to suspend further dosing with Campath," said Richard Moscicki, Genzyme's senior vice president of medical, clinical and regulatory affairs, and chief medical officer.
The Phase II randomized trial divided 334 patients with active relapsing-remitting multiple sclerosis into one of three groups: a low-dose Campath (alemtuzumab) group at 12 mg per day for five days, a high-dose group at 24 mg per day for five days in once-a-year intravenous infusion regimens, and a 44 mcg of Rebif (interferon beta-1a) group for three times per week, as indicated in its label.
At one-year follow-up, an independent data safety monitoring board found that patients taking high and low doses of Campath experienced at least a 75 percent reduction in the risk for relapse when compared to patients treated with Rebif. While that difference was statistically significant (p=0.00267), results of a second primary endpoint - the time to progression of clinically significant disability - missed the assigned statistical significance figure for the interim analysis, but still showed a benefit. Patients receiving high- and low-dose Campath experienced at least a 60 percent reduction in the risk for progression of clinically significant disability when compared to Rebif-treated patients.
"In my experience, I must say, over many years and many clinical trials, this large treatment effect is rarely observed in therapeutic trials, especially in comparison with a known active agent," Moscicki said, "and, to my knowledge, has not been observed in MS trials."
Of the three patients diagnosed with ITP, two occurred in the high-dose Campath group, and one in the low-dose group. ITP is a condition in which patients experience a low platelet count that can result in abnormal bleeding. One ITP case, in a patient who did not seek treatment, resulted in a fatality. The two other patients have responded to treatment and are being monitored by their physicians.
Non-serious adverse events included infusion reaction in the Campath patients, and flu-like symptoms in patients using Rebif.
According to analyst Jennifer Chao, of New York-based Deutsche Bank Securities Inc., Campath, now on the market for B-cell chronic lymphocytic leukemia (CLL), might never gain approval for MS because "a chronic autoimmune disease involving loss of cognitive and ambulatory function does not warrant severe side effects to the extent of what is marginally accepted" for cancer therapies. Still, she kept her "buy" rating of the stock.
The MS therapy Tysabri, developed by Cambridge, Mass.-based Biogen Idec Inc. and Dublin, Ireland-based Elan Corp. plc, was pulled from the market in February - just three months after FDA approval - when two patients came down with progressive multifocal leukoencephalopathy. There have been two reported cases since. The drug was approved based on only one-year data because of high efficacy results.
Genzyme's Phase II MS trial with Campath is expected to last three years. Patients were to receive treatment for five days in the first year, three days in the second year, and as determined by an investigator in the third year. ITP is in the current label for Campath as a recognized complication of its use.
Henri Termeer, Genzyme's president, chairman and CEO, said the "remarkable efficacy" of Campath in MS and the serious adverse event of ITP is "clearly a trade-off."
"Campath is a very active compound. It is used currently in oncology, and we expect the oncology programs that we have ongoing will be in no way affected by this complication," Termeer said in a conference call. "We know a lot about this drug in clinical settings, but MS is different from oncology."
Campath was approved in 2001 and became a Genzyme product in 2004 when the company acquired San Antonio-based Ilex Oncology Inc. for $1 billion. Chao expects Campath revenues to Genzyme to be about $21.4 million in 2005 and $23.5 million in 2006.
To address concerns of ITP, Cambridge, Mass.-based Genzyme and Berlin-based Schering have notified regulatory authorities, trial sites and patients, and they are consulting with the FDA and a panel of hematologists with expertise in the condition. The companies plan to conduct more frequent hematological monitoring, and to educate patients about the signs and symptoms of ITP. And they are updating informed consent forms, reviewing patient laboratory data and seeking indicators that might help identify those at risk for developing ITP.
Almost all Campath patients in the trial have received their second year's dose, and Genzyme and Schering are evaluating the necessity and timing of the third planned dose. The companies are dropping the higher dose for Campath because it does not appear to show an efficacy advantage to the lower dose.
Genzyme and Schering, concerned that disclosing the ITP adverse event would cause patients to drop out of the trial, sought the permission of the FDA to also disclose the efficacy results.
"The FDA agreed with us that we should indeed move forward in planning this [upcoming Phase III] study in order to obtain regulatory approval for the product," said Alison Lawton, Genzyme's senior vice president of regulatory affairs and corporate quality systems.
Genzyme's stock (NASDAQ:GENZ) rose $1.17 Friday to close at $72.83.