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Safety will be the main point of contention when the reviews roxadustat, a chronic kidney disease (CKD)-related anemia drug, on Thursday.

Developer FibroGen is seeking an indication for the treatment of anemia due to CKD in adult patients on and off dialysis.

If approved, roxadustat would be the first-in-class oral anemia treatment, as the only other available treatment options for anemia include iron, erythropoiesis stimulating agents (ESAs), and red blood cell transfusions.

Branded as a "safer" alternative to ESAs, which include epoetin alfa, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, and epoetin alfa-epbx, roxadustat works as a reversible inhibitor of hypoxia inducible factor-prolyl hydroxylases, orally administered and titrated up to achieve a target hemoglobin level.

The agent is proposed to be formulated as a film-coated tablet at 20, 50, 70, 100, or 150 mg doses of roxadustat. A recommended starting dose for patients on dialysis or patients who are not on dialysis and not on an ESA is 70 mg three times per week in patients weighing under 100 kg (220 lb), or 100 mg three times per week for patients weighing 100 kg (220 lb) or more.

Roxadustat already demonstrated efficacy in six phase III studies, three in a non-dialysis dependent population and another three in a dialysis-dependent population. According to , "roxadustat's efficacy is not in question" as all phase III studies in both the dialysis-dependent and non-dialysis dependent groups showed a significant increase in hemoglobin.

In a pooled analysis of non-dialysis dependent patients, roxadustat showed an increase in hemoglobin by only week 2 of treatment, maintaining a sustained increase in hemoglobin through week 52 (9.10 g/dL at baseline versus 10.95 g/dL).

Efficacy was similar in patients on dialysis, who maintained a significant improvement in hemoglobin levels throughout the trial (9.63 g/dL at baseline versus 10.85 g/dL).

Instead, FDA briefing documents highlighted that the "principal issue" here is the drug's safety -- particularly in regards to thrombotic events.

When compared with placebo, roxadustat showed an estimated risk difference for serious thrombotic events of 1.1 events per 100 patient-years, with a relative risk of 1.45. This increased risk was mainly driven by risks for myocardial infarction and stroke, while deep vein thrombosis and pulmonary embolism weren't as common.

Looking only at the non-dialysis population, the risk for a major adverse cardiovascular event -- including myocardial infarction (MI), stroke, or all-cause mortality -- was comparable to placebo (HR 1.10, 95% CI 0.96-1.27). However, there was a slight increase in risk of major adverse cardiac events (MACE) when looking at a sensitivity analysis that included a window of 7 days post-treatment (HR 1.38, 95% CI 1.11-1.70), mainly driven by all-cause death in the roxadustat group.

On the other hand, the dialysis-dependent group had a comparable MACE safety profile to darbepoetin alfa (Aranesp) (HR 0.89, 95% CI 0.60-1.33), including in an analysis that incorporated the 7-day post-treatment window (HR 0.70, 95% CI 0.44-1.12).

Other notable adverse events included seizures, acute kidney injury, hyperkalemia, fracture, gastrointestinal hemorrhage, and hyponatremia.

However, not all of these risks are unique to roxadustat, as ESAs are also known to carry an increased risk of death, MI, stroke, congestive heart failure, thrombosis of vascular access, as well as other thrombotic events.

In order to offset some of this increased thrombotic risk, FDA briefing documents suggested "less aggressive dosing schemes," and strategies such as lower starting doses, smaller dose increments during titration and lower hemoglobin targets. However, they also noted these strategies haven't yet been proven effective in a clinical trial setting.

When looking closer into the associations with thromboembolic events, the FDA found in an exploratory analysis that an increase as well as a decline in hemoglobin rates were both found to be tied with higher rates of thromboembolic events.

"In light of these findings, the applicant speculates that thromboembolic risks might be reduced through use of a lower roxadustat starting dose," the document said. "Their prediction seems plausible, but is unproven."

Roxadustat is already approved in China and Japan for dialysis-dependent and non-dialysis dependent patients. China's label includes safety information about cardiovascular events, vascular access thrombosis, deep vein thrombosis, seizures, and serious infections, while the Japanese label carries a boxed warning for serious thromboembolism including cerebral infarction, myocardial infarction, and pulmonary embolism.

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