Surprise, surprise: AstraZeneca and FibroGen's once-hyped anemia drug roxadustat hits an FDA wall

After an overwhelmingly negative opinion from an external FDA advisory panel, AstraZeneca and FibroGen’s potential first-in-class anemia drug roxadustat looked unlikely to pass muster with the U.S. regulators. Now, the second shoe has dropped. As one analyst sees it, a restructuring at FibroGen could be next.

The FDA has issued a complete response letter for roxadustat’s application in anemia associated with chronic kidney disease, FibroGen said Wednesday. The rejection covers both patients who require dialysis and less sick, nondialysis-dependent individuals.

The FDA has requested additional clinical studies if FibroGen wants to shoot for an approval ever again. But as SVB Leerink analyst Geoffrey Porges observed in a note last month after the advisory committee vote, AZ’s and FibroGen’s investors likely won’t be willing to fund an additional phase 3 trial for the ill-fated med. Without revenue contributions from roxa in the U.S., FibroGen will need an overhaul to keep the business afloat, Porges has said.

It’s not immediately clear whether FibroGen and its partner AZ plan to run additional trials to support a potential U.S. refiling. In their statements Wednesday, both companies said they’re working to evaluate the next steps.

An expected FDA snub

The FDA's complete response letter wraps up a roller-coaster clinical and regulatory path for roxa in the U.S. As the first member of the HIF-PHI drug class to win an approval anywhere in the world, roxa once bore blockbuster expectations based on the notion that it was at least as effective as and safer than Amgen and Johnson & Johnson’s standard-of-care erythropoietin therapies Epogen and Procrit.

But safety concerns came to the fore in April, when FibroGen revealed that its data on the med incorporated different analytical criteria than were specified before the trial. An analysis based on the prespecified criteria practically erased roxa’s presumed safety advantage.

RELATED: AstraZeneca, FibroGen hit another roxadustat setback as FDA panel calls for more safety data

Then, an FDA internal review document outlined a slew of new safety problems previously unknown to investors. After digging into clinical trial data, the FDA reviewers linked roxa to increased risk of death, blood clots, serious infections and more compared with erythropoietin therapy in the dialysis-dependent population and with placebo in the nondialysis-dependent group.

Concurring with the FDA staffers’ concerns, panelists at an advisory committee voted 13-1 against roxa’s approval in non-dialysis patients and 12-2 against for dialysis-dependent patients during a July meeting.

Is a restructuring next?

Once the votes came through, SVB Leerink’s Porges immediately suggested that FibroGen investors should demand a restructuring. The company “should become at least one-third smaller,” he wrote in a note to clients on July 16. The analyst went as far as flagging the “perils of trusting FibroGen’s data, management and board.”

During a Monday conference call centered on FibroGen’s second-quarter performance, CEO Enrique Conterno said that those “directly responsible” for the safety data error were no longer with the company.

“Management is taking steps to ensure the company's processes are consistent with best practices in all respects,” Conterno said. The company plans to install independent quality oversight of clinical data management, programming, analysis and reporting, the CEO added.

As an FDA rejection looked almost inevitable by the time of the conference call, FibroGen’s focus had clearly shifted to ex-U.S. opportunities.

In China, roxa sales reached $96.3 million in the first half of 2021 and the business has become profitable, Conterno said. FibroGen’s commercial partner AZ—a powerful marketing presence in China—is expanding the drug’s reach, he said. By the end of June, roxa was listed at hospitals that cover about 81% of the entire chronic kidney disease anemia market opportunity in China, Conterno said.

RELATED: Can AstraZeneca sustain rapid growth in China amid price-cutting scheme and local competition? It'll probably be slower, execs say

In Europe, where FibroGen partners with Astellas, roxa in June received a positive opinion from the European Medicines Agency’s drug reviewers. The company expects a final go-ahead from the European Commission this month. 

Still, in the case of an FDA rejection, Conterno acknowledged on the call that FibroGen would have to “basically reassess our priorities and reallocate our resources and significantly decrease expenses.”

As Porges sees it, a major restructuring should happen in the next six months to preserve capital and allocate funding to pivotal trials of its pancreatic cancer candidate pamrevlumab, a potential first-in-class antibody against connective tissue growth factor, or CTGF. The company recently modified the drug’s phase 3 trial design to enable a potential accelerated approval pathway with the FDA.