When Takeda’s gout drug Uloric (febuxostat) was approved by the FDA, it was with a requirement for postmarketing studies to further assess its safety. Now a nonprofit consumer advocacy group says the FDA should remove the drug from the U.S. market after findings released this March show significant deadly heart risks.
In a petition (PDF) sent to the FDA on Thursday, Public Citizen stated there is “overwhelming evidence that the serious cardiovascular harms of [Uloric] outweigh any purported clinical benefit,” and that leaving it on the market would only cause “further preventable harm” to patients.
The Japanese pharma submitted results from a postmarketing cardiovascular safety study previously required by the FDA in January, and it is “working with the agency to conduct a comprehensive review of this data,” a Takeda spokeswoman told FiercePharma.
A spokesman for the FDA told FiercePharma the agency will review Public Citizen’s letter and will respond directly to the organization.
The 2009 approval allowed Uloric to be used as a treatment of hyperuricemia—instead of for the direct reduction in gout flares—in gout patients. But it followed two failed attempts in 2005 and 2006 under TAP Pharmaceutical.
The FDA had rejected the medication out of concerns for increased cardiovascular risks observed in clinical trials. At the time of the second NDA submission, FDA reviewers noted 9 of the total 12 deaths among subjects on Uloric were attributable to CV causes, whereas no serious adverse CV events were linked to comparator allopurinol or placebo.
In response to the FDA’s concern, Takeda conducted another trial that ultimately didn’t find the same CV safety signal. But after putting data from all three phase 3 studies and two long-term extension studies together, the FDA reviewers couldn’t determine “with much confidence” whether Uloric poses greater risk. So, when they did approve the drug, they slapped a warning on the drug’s label and asked Takeda to run a large, postmakreting study to further examine Uloric’s CV safety profile.
Concerns flared up on Nov. 15, 2017, when the FDA issued a drug safety communication alerting the public of increased cardiovascular events with Uloric, compared to allopurinol. The agency at that time said it will “conduct a comprehensive review and will update the public with any new information,” once it has the full final results.
Findings from the 6,190-subject study were then published this March in The New England Journal of Medicine. In that study, researchers noted that after 32 months, overall adverse CV events were similar in both arms, but “[a]ll-cause mortality and cardiovascular mortality were higher with [Uloric] than with allopurinol.”
Following the release of the study, Takeda said in a statement that the reason for the imbalance in cardiovascular deaths has not been identified.
“The agency should have demanded that an appropriately designed clinical trial to assess febuxostat’s cardiovascular risks be conducted before, not after approval,” said Michael Carome, M.D., director of Public Citizen’s Health Research Group, in a statement. “The FDA almost certainly would have denied approval of febuxostat if data from this post-market trial had been available at the time of the initial submission.”
Besides higher risks of cardiovascular risks, the organization also argued there’s not enough data showing Uloric is more effective in the actual prevention of gout flares, other than that it’s able to lower serum uric acid levels, which can cause acute painful gout episodes.
Uloric returned Takeda $1.9 billion in U.S. sales from fiscal years 2012 through 2017, Public Citizen noted in its petition.