AstraZeneca and partner FibroGen's new data dispelled most doubts about their first-in-class anemia drug's heart safety profile, clearing the path for an FDA filing in chronic kidney disease. But how the agency will review some of the data remains an open question.
Industry watchers never doubted roxadustat’s ability to boost red blood cell levels. But they were spooked by confused wording on cardiovascular events in a May announcement.
So, all eyes were on a pooled safety analysis presented over the weekend at the American Society of Nephrology meeting.
The pair showed cardiac risks associated with roxadustat are comparable to placebo in nondialysis-dependent patients with anemia caused by chronic kidney disease. And in patients already on dialysis, the med measured up to Amgen and Johnson & Johnson’s standard-of-care med, Epogen/Procrit.
“The drug is doing what we’re hoping it does,” AstraZeneca’s biopharmaceuticals commercial chief Ruud Dobber told FiercePharma.
In China, where the drug has nabbed go-aheads in both dialysis and nondialysis patients, AZ is negotiating national reimbursement and will decide on a launch plan according to that outcome, he said. With the new data, the pair is now eyeing an FDA filing by year-end. If approved, the drug will be managed by the sales staffers currently handling the hyperkalemia drug Lokelma as a dedicated renal team, Dobber said.
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Compared to Epogen, which is given under the skin, roxa is a more convenient oral treatment, Dobber argued. Besides, anemia patients are often treated with iron.
“Data show the use of roxa diminishes very substantially the need for iron,” which could be a key marketing message, he said. According to results from the phase 3 Rockies trial on dialysis-dependent patients, roxadustat patients used a mean of 59 mg iron, compared with 91 mg for Epogen from week 36 to the end of the study.
The obvious priority now is to get FDA approval, and despite the overall win, there are some lingering questions about the drug.
First, roxadustat nailed it in what’s known as the incident dialysis population—these are patients who have been on dialysis for less than four months and are considered very unstable. In this subgroup, those taking roxadustat had a 30% lower risk of major adverse CV events (MACE)—a marker the FDA uses—compared with those on Epogen.
When angina and congestive heart failure hospitalizations were added in the MACE+ marker for European regulators, the benefit expands to 34%.
But when it comes to all dialysis-dependent patients—among whom about 40% were incident in the trials—the MACE risk profile is dialed back. In those patients, the risk-reduction is comparable to that delivered by Epogen, with a hazard ratio of 0.96. That means it's just about as likely for roxadustat patients to suffer a MACE event as those on Epogen.
It begs the question: Is incident dialysis driving the entire benefit? That’s the question raised by Wolfe Pharma analyst Tim Anderson and bear investors cited by Jefferies analyst Michael Yee.
During an investor call Sunday, AstraZeneca management said a separate analysis of the stable pool would be problematic because the studies were not powered to do so, according to Anderson. On top of the statistical problem, FibroGen management also told Yee that taking patients off existing Epogen and disrupting them to a new drug that needs titration naturally “disadvantages” roxadustat, the Jefferies analyst noted in a Saturday report.
RELATED: AstraZeneca and FibroGen's roxadustat, not yet filed in U.S., nabs 2nd anemia nod in China
As SVB Leerink analyst Geoffrey Porges sees it, the entire dialysis group shouldn’t be a problem for roxa. “It is clear to us that the company will get approval for incident dialysis (where roxa was superior to Epogen) for MACE and MACE+, and for stable dialysis, where roxa was noninferior to Epogen for MACE and mortality and superior for MACE+,” he wrote in a Friday note to clients.
But the larger nondialysis indication might be the most controversial, he said. Because of its cardiovascular risks, Epogen is not approved for nondialysis patients, so getting an approval there could mean a huge market for the AstraZeneca drug.
While roxadustat's risk of MACE was comparable to placebo for nondialysis, the hazard ratio hit 1.08, which indicates a numerical trend against the drug.
During the Sunday call, AZ management explained that the studies included many very sick patients with less than 15% of normal kidney function, which complicates the evaluation of active treatment versus placebo. For example, about 40% placebo participants converted to dialysis and got Epogen, while roxadustat patients largely stayed put.
As Jefferies’ Yee also noted, the principal investigator said the numeric difference that has met classic non-inferiority is more of a Wall Street obsession that won’t matter to doctors who are treating patients.
Nevertheless, how the FDA views the data is another story. “Overall, in our view, a commercial case in favor of roxa can reasonably be made, but still outstanding is how FDA and other regulatory agencies treat this data set that AstraZeneca and its KOL speakers admit is very complex,” Wolfe’s Anderson wrote in a Sunday note. “When these agencies run the data through their own filters, what will they conclude and what will they allow in the label? This will partly determine how payers subsequently treat the product.”