FibroGen and AstraZeneca's blood-boosting pill roxadustat has been used since 2018 to treat anemia in kidney disease patients in China, and appears on track to gain approval within weeks in Europe. In the U.S., however, its chances of reaching market have dimmed significantly.
Citing concerns over safety, advisers to the Food and Drug Administration on Thursday voted against approval of the pill, which mimics the effects of lower oxygen environments to stimulate production of red blood cells. Shares in the San Francisco-based company slumped by more than 40%, subtracting even further from a market valuation already depressed after revelations that initial safety data were misleading.
Roxadustat was developed to be a safer, more convenient alternative to Epogen and other biologic drugs that stimulate a hormone key to red blood cell production. Anemia is a common side effect in kidney disease patients, caused in part by lowered levels of the hormone Epogen boosts — erythropoietin — and physicians prescribe those drugs to bring red blood cell counts back to normal.
However, the erythropoietin-stimulating agents have been linked to heart attacks and strokes, prompting the FDA to recommend lowering target levels of hemoglobin, the red blood cell protein that carries oxygen, in order to prevent side effects.
Researchers and regulators have therefore been interested in safer alternatives. The oral delivery of roxadustat was an attractive bonus because it would save patients, especially those not yet needing invasive dialysis treatments, the need to visit a hospital for an infusion of Epogen.
Roxadustat, which blocks a protein called "hypoxia inducible factor", or HIF, doesn't appear to have lived up to the promise of a safer alternative, though. An analysis of the studies in dialysis patients showed a greater risk of major adverse cardiovascular events than Epogen and similar drugs. Some experts on the panel said the data suggest that HIF inhibition may itself create a major risk for blood clots.
"It's uncertain to me whether [red blood cell increases] really is the cause, and whether it really is HIF inhibition that is," said Leslie Cho, a professor at Case Western Reserve Medical School.
Those statements didn't discourage Wall Street analysts covering Akebia Therapeutics, which has a rival HIF drug called vadadustat the FDA is currently reviewing. Alethia Young, of Cantor Fitzgerald, said roxadustat's setback "creates a first-in-class opportunity" for Akebia.
GlaxoSmithKline on Friday, meanwhile, announced positive data for its HIF drug, called daprodustat.
FibroGen had sought approval in kidney disease patients both on dialysis and those not yet needing such treatment. In its clinical program, the company compared roxadustat against placebo for the non-dialysis patients and against erythropoietin-stimulating agents in the dialysis population.
To address safety concerns, FibroGen proposed the FDA approve a lower dose and hemoglobin target than was used in clinical trials. However, many of the panelists said they didn't want to support the new dosing regimen without it first being tested in a trial setting.
Moreover, many panelists were reluctant to approve it for non-dialysis patients, who, because they don't need to regularly go to medical facilities for procedures, might have less frequent hemoglobin monitoring.
Panelists voted 13-1 against approval in the non-dialysis population and 12-2 against in dialysis patients. Some, however, suggested that a potential acceptable use might be in those patients whose red blood cell counts don't rise even with use of Epogen.
The FDA isn't required to follow the recommendations of its advisory committees, but does most of the time.
AstraZeneca, which since 2015 has paid all development costs for the U.S. and would be responsible for commercializing roxadustat, said it wants to continue discussing the drug's path forward with the FDA.
But Geoffrey Porges, an analyst at SVB Leerink, said he expects AstraZeneca to hand back U.S. rights in two to three months.
"We do not believe that AstraZeneca, or Fibrogen’s investors, will be willing to fund an additional Phase 3 trial," he wrote in a July 16 note to clients. "When reviewed in the cold harsh light of day, the drug has a positive dose association with mortality, and has signals for severe infection risk, seizures and major cardiovascular events. These signals were unknown from the company’s disclosure to us and to investors before this week."
AstraZeneca is also partnered with Fibrogen in China.