The prestigious New England Journal of Medicine retracted an article about results from a study used to win regulatory approval of a controversial drug at the center of a small Bay Area company's multibillion-dollar acquisition by Amgen Inc.
The withdrawal, at the request of the article's two academic authors, sets the stage for an upcoming hearing between Amgen and the Food and Drug Administration, which has been trying to force Amgen to take the drug off the market. The agency has said results of the drug's late-stage clinical trial were manipulated.
The twice-a-day oral drug — called avacopan and branded as Tavneos after ChemoCentryx Inc. of San Carlos won FDA approval for it in 2021 — was designed to treat people with a set of rare autoimmune conditions known as ANCA-associated vasculitis. The disease causes inflammation and damages blood vessels, leading to problems with the kidneys, lungs and other organs.
Amgen (Nasdaq: AMGN) bought ChemoCentryx in fall 2022 for $3.7 billion. Tavneos had sales last year of $459 million — a 62% year-over-year increase — according to Thousand Oaks-based Amgen, which has a large research center in South San Francisco. The drug sells for about $19,000 for a 30-day supply.
Troubled history
The FDA has claimed that ChemoCentryx, which was led by CEO Thomas Schall, manipulated results of the late-stage study that was the basis of the drug's hard-fought approval. The retraction Monday of the New England Journal of Medicine paper brings more weight to those charges.
An Amgen spokesperson told Fierce Pharma that it "takes scientific integrity seriously and respects the role of journals in upholding the peer review process." The company launched an independent, fully blinded relook at ChemoCentryx's study and promised to share that with the FDA as part of an upcoming hearing.
The request for the retraction came from two authors of the 2021 article, David R.W. Jayne of Addenbrooke's Hospital in the United Kingdom and Peter A. Merkel of the University of Pennsylania. The other main authors of the paper were Schall and Pirow Bekker, who was chief medical officer at ChemoCentryx from 2014 until he retired in 2017.
The New England Journal of Medicine said endpoints of nine patients in the key late-stage clinical trial were "readjudicated" after the database was locked and the study unblinded. That was not disclosed in the article, the journal's editors said, "and is inconsistent with proper research conduct."
The FDA sent Amgen a request to withdraw Tavneos in January, but Amgen has resisted; in a March alert from FDA, the agency said eight deaths as well as liver injuries have been associated with Tavneos.
In an April proposal with the Federal Registry to kill approval of Tavneos, the FDA claimed unblinded datasets and topline tables, listings and figures were transferred to Bekker in early November 2019. Those documents indicated ChemoCentryx's study failed to show statistical significance on its primary endpoint of sustained remission of ANCA-associated vasculitis after 52 weeks of treatment with avacopan. But the drug-approval application to the FDA did not include those results, the agency said.
The request to the Federal Registry does not explain Bekker's retirement two years after his involvement with the data in 2019.
'Readjudication'
After an independent statistical consultant brought in by ChemoCentryx and Huibin Yue, director of biostatistics for the company, verified the results, Bekker and Yue "looked for cases that could alter the study results to indicate Tavneos achieved a statistically superior outcome on the primary endpoint of sustained remission," according to the Federal Registry filing. They identified nine subjects — three who had been given the powerful immune-suppressing glucocorticoid prednisone and six who had received avacopan — for readjudication.
Later that November, ChemoCentryx said in a press release that the trial met its primary endpoints showing it wasn't inferior to glucocorticoids after 26 weeks and was superior to that standard of care at 52 weeks.
Dr. Catherine "Cass" Kelleher, ChemoCentryx's chief medical officer from April 2019 to March 2021, "repeatedly raised red flags" about "liver events," according to a 2022 class-action lawsuit filed in U.S. District Court in Oakland against ChemoCentryx and Schall by shareholders, including the Indiana Public Retirement System. Schall "chastised" Kelleher for raising concerns about the drug's safety signal, according to the suit.
The drug was narrowly recommended for approval by an FDA advisory committee and was approved with a more restrictive label that includes a warning about liver toxicity.