Data From 3 Roxadustat Trials Lead Off Kidney Week Sessions Ahead of Efficacy, Safety News

Investigators presented data about 3 global phase 3 trials of roxadustat at a national nephrology meeting Thursday to a standing-room only crowd, but the information they are really waiting to hear will have to wait until early Friday afternoon.

The trials showed the drug increasing hemoglobin levels, but day 2 will see the release of highly anticipated efficacy and pooled cardiovascular safety data about the first-in-class oral drug. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) and works by restoring production of the hormone erythropoietin and improving iron regulation in patients with chronic kidney disease who are anemic. Weeks before American Society of Nephrology's (ASN) Kidney Week 2019, 3 scientists won the 2019 Nobel Prize in Physiology or Medicine for their discoveries behind the basic science of the drug, with work regarding the molecular mechanism of cells in response to oxygen.

The drug, made by biotech firm FibroGen and marketed by AstraZeneca, is approved in China and Japan; the companies expect to submit a new drug application to the FDA by the end of the year. The 3 trials—HIMALAYAS, ROCKIES, AND OLYMPUS—will be part of the submission to the FDA.

Robert Provenzano, MD, associate professor of medicine, Wayne State University, Detroit, Michigan, the lead investigator on HIMALAYAS, said he was excited about the prospects for the drug, because it isn’t very often that one sees the development of a therapy from bench to bedside.

Unlike the other trials, HIMALAYAS focused on patients with incident dialysis, meaning those who had least 2 weeks of dialysis but fewer than 4 months, and no exposure to erythropoiesis-stimulating agents (ESAs), which include epoetin alfa (sold as Procrit and Epogen).¹ In the multicenter trial, 1043 patients were randomized 1:1 to receive roxadustat or epoetin alfa for up to 4.4 years, with mean treatment duration of 1.8 years. Roxadustat reached the US primary efficacy end point of mean change in hemoglobin (Hb) levels from baseline to the average over 28 to 52 weeks. The mean Hb increased from 8.4 g/dL to 11.0 g/dL in roxadustat-treated patients vs. 8.4 g/dL to 10.8 g/dL in epoetin alfa-treated patients.

Roxadustat was noninferior to epoetin alfa in the EU primary efficacy endpoint of proportion of patients achieving a Hb response (defined as Hb ≥11.0 g/dL and Hb increased by ≥1 g/dL from baseline) during the first 24 weeks of treatment: 88.2% in the roxadustat arm versus 84.4% in the epoetin alfa arm. In addition, patients on roxadustat needed lower average monthly intravenous iron than those treated with epoetin alfa.

Asked to explain some of the workings of the drug during a Q&A with the audience, Provenzano said, "My opinion is that this is a physiological response rather rather than a pharmacological response.​" Later, he explained that roxadustat works by stabilizing the HIF alpha subunit from being degraded. The body responds by thinking it is in an oxygen-poor environment, such as one seen when at high elevations, which naturally stimulates the processes behind the production of erythropoietin and red blood cells. Compare that, he said, with the administration of erythropietin, which may cause spikes and has been linked to some cardiovascular issues.

"It's a suggestion, we don't know, but the data tomorrow will answer that question," he told The American Journal of Managed Care^®.

Meanwhile, the ROCKIES trial compared roxadustat to epoetin alfa in patients with ESRD and anemia receiving dialysis²; the OLYMPUS trial compared roxadustat to placebo in patients with chronic kidney disease who were not on dialysis.³ Steven Fishbane, MD, Zucker School of Medicine at Hofstra/Northwell, Great Neck, New York, led both of these trials.

Results from ROCKIES showed that roxadustat effectively increased Hb overall and in patients with elevated inflammation levels, and reduced intravenous iron use in patients with dialysis-dependent CKD.

The study enrolled patients with baseline Hb of <12 g/dL if treated with an erythropoietin analog or <10 g/dL if not; 2133 patients were randomized 1:1 to receive roxadustat (n = 1068) or epoetin alfa (n = 1065). There was a statistically significant improvement in Hb levels from baseline with a mean increase of 0.77g/dL averaged over weeks 28 to 52, compared to 0.68g/dL with epoetin alfa. Roxadustat also improved Hb levels from baseline in a subgroup of patients with elevated high-sensitivity C-reactive protein (hsCRP) levels of greater than 5 mg/L, demonstrating a statistically significant improvement with a mean increase of 0.80g/dL compared to 0.59g/dL with epoetin alfa, a secondary endpoint.

"Historically, this has been a difficult population to treat with epo drugs," Fishbane said of patients with CKD and elevated inflammation levels.

In ROCKIES, adverse events (AEs) "run slightly higher" in the roxadustat group, he said, and mortality was about the same for both the roxadustat group and the epoetin alfa group. In addition, more patients discontinued the study drug than epoetin alpha.

In the OLYMPUS trial, patients with moderate to severe CKD anemia (Hb <10.0 g/dL) were randomized 1:1 to receive 70 mg roxadustat or placebo 3 times a week. Of the 2781 patients, 1393 received roxadustat and 1388 received placebo. Roxadustat demonstrated a statistically significant improvement in Hb levels from baseline, with a mean increase of 1.75g/dL averaged over weeks 28 to 52, compared to 0.40g/dL with placebo.

The primary efficacy end point (for the FDA) was mean change from baseline Hb to average Hb over weeks 28 to 52; for the EU submission, it was the proportion of patients with Hb response at 2 consecutive visits during the first 24 weeks of treatment without anemia rescue therapy.

The mean change in Hb from baseline to the average over weeks 28 to 52 was +1.75 g/dL with roxadustat versus +0.40 g/dL with placebo (P <.001). As with the other trial, patients with elevated inflammation (n = 411) saw baseline Hb of +1.75 g/dL with roxadustat and +0.62 g/dL with placebo (P <.001). The proportion of patients achieving Hb response at 2 consecutive visits without rescue during the first 24 weeks was 77.0% with roxadustat vs 8.5% with placebo (P <.001).

Mortality rates were about the same in the 2 groups, Fishbane said.

In the ROCKIES trial, in patients treated with roxadustat, the most frequently reported AEs were diarrhea, hypertension, pneumonia, headache, and arteriovenous fistula thrombosis, as well as sepsis and acute myocardial infarction.

In the OLYMPUS trial, the most frequently reported AEs in the intent to treat analysis set were ESRD, pneumonia, urinary tract infection, and hypertension, as well as azotemia, sepsis, acute kidney injury, and hyperkalemia. Both OLYMPUS AND ROCKIES were funded by AstraZeneca.

In the HIMALAYAS trial, funded by FibroGen, the most frequently observed AEs included hypertension, diarrhea, and muscle spasms.

The investigators said that AEs with roxadustat were generally similar to those seen in patients treated with epoetin alfa and commonly found in patients with CKD.

References

1. Provenzano R, Evgeny S, Liubov E, et al. HIMALAYAS: A phase 3, randomized, open-label, active-controlled study of the efficacy and safety of roxadustat in the treatment of anemia in incident-dialysis patients. Presented at: American Society of Nephrology Kidney Week 2019, Washington, DC; November 5-10, 2019.

2. Fishbane S, Pollock, CA, El-Shahawy MA, et al. ROCKIES: An international, phase 3, randomized, open-label, active-controlled study of roxadustat for anemia in dialysis-dependent CKD patients. Presented at: American Society of Nephrology Kidney Week 2019, Washington, DC; November 5-10, 2019.

3. Fishbane S, El-Shahawy MA, Pecoits-Filho R, et al. OLYMPUS: A phase 3, randomized, double-blind, placebo-controlled, international study of roxadustat efficacy in patients with non-dialysis-dependent (NDD) CKD and anemia. Fishbane S, El-Shahawy MA, Pecoits-Filho R, et al. Presented at: American Society of Nephrology Kidney Week 2019, Washington, DC; November 5-10, 2019.