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FDA's AMDAC supports Merck's bezlotoxumab – with reservations

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By Mari Serebrov
Regulatory Editor

Although the FDA's Antimicrobial Drugs Advisory Committee (AMDAC) voted 10-5, with one abstention, that Merck & Co. Inc.'s bezlotoxumab showed substantial evidence of safety and efficacy in preventing the recurrence of Clostridium difficile infection (CDI), Thursday's vote was far from a slam dunk victory.

Whether they voted yes or no, the panelists expressed several concerns about the first-in-class drug designed to neutralize C. difficile toxin B. Most of them stemmed from a desire for more data and questions about which patients would benefit from the fully human monoclonal IgG1/kappa antibody.

"This is not a rare disease," AMDAC Chairman Lindsey Baden, director of the clinical research division of infectious diseases at Brigham and Women's Hospital, said as he explained his no vote. Thus, it shouldn't have been difficult to conduct studies in large populations to determine who would best benefit from the drug, he added. Baden was uncomfortable that a novel drug for what could be a large, new indication was tested in only 800 patients in the two phase III trials.

While the data Merck served up were intriguing, Baden said the sponsor "was not there yet." He suggested the phase III trials were more like phase IIb trials.

Ellen Andrews, executive director of the CT Health Policy Project, cast her first no vote as the panel's consumer representative. While she's happy that Merck is tackling CDI, she said she felt the sponsor needed to sort out whether the drug, which is intended to be given with standard-of-care antibiotics when a patient is first treated for an infection, could adversely affect the cure – a possibility the FDA raised in its presentation.

The lone abstention came from Amanda Corbett, a clinical associate professor and global pharmacology coordinator at the University of North Carolina's Institute for Global Health and Infectious Diseases. She said she had never abstained before, but her biggest challenge in voting was a lack of information.

Michael Green, a professor of pediatrics and surgery in the division of infectious diseases at the University of Pittsburgh School of Medicine, voted yes, but he said he feared that, if approved now, bezlotoxumab would be freely used by doctors who think more is better, which would increase the cost of treating CDI and perhaps harm some patients.

His colleague, Juan Gea-Banacloche, chief of the infectious diseases section at the National Cancer Institute, expressed similar thoughts. While recognizing the high cost of treating CDI, he said he couldn't help but wonder how much it would cost to prevent one case of CDI if bezlotoxumab were added to the initial treatment regimen for all patients.

Several panelists who voted yes encouraged the FDA to restrict the drug's use to patients who were most at risk of a recurrence and to warn about a potential for cardiovascular risks. A few questioned whether "recurrence" was the right word to use in labeling, as many patients would interpret that to mean "cured." A "sustained response" would be a better definition of what the drug appears to do, said Joan Hilton, an epidemiology and biostatistics professor in residence at the University of California, San Francisco School of Medicine.

MRSA Survivors Network founder and President Jeanine Thomas, the patient representative, was the only one on the panel who saw no way forward for the drug.

"We need superior therapies," she said. Bezlotoxumab is not significantly better than placebo, and further studies wouldn't make it better, she added.

STATISTICALLY SIGNIFICANT

According to the data presented at the meeting, bezlotoxumab demonstrated a 10 percent reduction in recurrence over placebo, a figure the FDA acknowledged as statistically significant. That translates into a 40 percent relative risk reduction, Merck officials said, noting that if the number held in real-world use, the drug could prevent nearly 50,000 incidents of CDI in the U.S. each year.

Panelist concerns reflected the dire need for new drugs in the space, the fragility of the patients, the societal and economic cost of CDI, and how little is known about the infectious disease. In its ongoing development of the antibody as a non-antibiotic approach to dealing with harmful bacteria, Merck is generating a wealth of data about CDI. If successful, the Kenilworth, N.J.-based drug company could help develop new strategies against drug-resistant bugs.

To date, the FDA has approved 50 monoclonal antibodies. If approved, bezlotoxumab would be only the second one to take on an infectious disease. Because the drug targets a toxin rather than the organism itself, there's been no evidence of the bug building a resistance to it, according to Merck.

The PDUFA date for the drug, which was granted priority review, is July 23. Merck licensed the drug in 2009 from Medarex, now part of Bristol-Myers Squibb Co. (See BioWorld Today, April 22, 2009.)