Risk and benefits
The major issues before the ODAC included the validity of clinical outcome assessment given the large chunks of missing data and the major adverse event of liver injury, with a majority of patients on pexidartinib experiencing transaminase elevations. The potential for liver injury may be exacerbated by chronic use of the drug or by drugs used to treat comorbidities such as diabetes or cardiovascular disease, several panel members noted.
During the clinical development program for the drug, 2 of 768 patients who received the drug developed irreversible liver injury leading to liver transplant in 1 patient and death in the other.
Many of the panelists who voted to support approval did so with some reluctance about the adverse events. For example, Karin Anton Calis, PharmD, of the National Institutes of Health voted yes because of the efficacy of the drug in a disabling condition.
“Hopefully it will be used in a restricted system so that there can be adequate monitoring, but I’m still concerned about those patients that may have this unpredictable liver toxicity, “ he said.
Victor M. Villalobos MD, PhD, from the University of Colorado at Denver, Aurora, also voted yes.
“This is an ultra-rare disease with no good therapies available to patients and it can be highly morbid, and I feel that getting real-world data on how we can use this drug in a safe and effective manner will be really important to the academic community going forward,” he said.
Other panel members who also voted to support approval expressed concerns about the hepatotoxicity, but noted that the drug has the potential to change lives, as attested by TCGT patients who spoke during the public comment portion of the meeting.
However, panelist Doris Strader, MD, from the University of Vermont, Burlington, said that she voted no because, while she was sensitive to the potential benefits of the drug for some patients, “I was concerned about the missing data and was not convinced that there was clinically meaningful benefit. Likewise, while I understand that the hepatic injury is not liver failure, I am concerned that this may be persistent for a long time, and I worry that there is not enough to suggest that there is going to be rigorous monitoring of patients over their lifetimes.”