GlaxoSmithKline's novel anemia drug succeeds where AstraZeneca-FibroGen, Akebia failed

After the FDA’s resounding rejection for AstraZeneca and FibroGen’s roxadustat, attention on novel oral anemia therapies has shifted to later players. Now, third-in-line GlaxoSmithKline has notched up a first-in-class success.

For both dialysis-dependent and nondialysis patients with anemia from chronic kidney disease, GSK’s daprodustat matched up to traditional erythropoiesis-stimulating agents (ESAs) in terms of heart safety, as measured by a composite marker of time to first major adverse cardiovascular event (MACE). The detailed data from two phase 3 trials, ASCEND-D and ASCEND-ND, were unveiled at American Society of Nephrology Kidney Week 2021.

Armed with the two trial wins, GSK plans to file daprodustat with the FDA in the first half of 2022, teeing up what could be the company’s first new drug launch after its planned consumer health spinoff. GSK has recently pegged the drug’s peak sales potential at between 500 million pounds and 1 billion pounds. GSK partner Kyowa Kirin has been selling the drug in Japan since last year under the brand name Duvroq.

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

The trials make dapro the first hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) to succeed in anemia caused by kidney disease regardless of a patient’s dialysis status. The FDA previously turned down roxadustat because the drug showed some concerning heart safety problems, and Akebia Therapeutics’ vadadustat was linked to increased heart-related risks compared with ESA in nondialysis-dependent patients in its own trial.

The question about HIF-PHIs was never about their efficacy. In terms of raising an anemia patient’s hemoglobin level, dapro was as effective as Amgen’s Aranesp in nondialysis patients in the phase 3 ASCEND-ND trial. On the same marker, it was as effective as either Aranesp or Amgen/Johnson & Johnson’s Epogen/Procrit in dialysis patients in the ASCEND-D trial.

One problem with conventional ESAs is their cardiovascular risks. In ASCEND-D, the risk of time to first MACE was similar between the two drugs with a hazard ratio of 0.93 in favor of dapro. Major cardio events happened in 25.2% of dapro takers throughout the trial period, versus 26.7% for ESA. MACE covers death of any reason, plus heart attack and stroke. Dapro matched up to ESA on each component event.

But the heart safety data all industry watchers are anticipating are in the nondialysis population, where neither roxa nor vada has succeeded. There, the risk of time to first MACE was similar between dapro and control, with a hazard ratio of 1.03, so the trial met its noninferiority bar. Investigators recorded a major cardio event in 19.5% of patients on dapro, compared with 19.2% for ESA.

However, on a so-called “on-treatment” MACE analysis, which counted events that had occurred between starting a drug and 28 days after the last dose, the results put dapro in an unfavorable light. There, the risk of first MACE was 40% higher for the GSK drug. The rates were 14.1% for dapro, versus 10.5% for Aranesp.

In a simultaneously published New England Journal of Medicine study, the researchers pointed out on-treatment analyses could confound the data. This analysis didn’t take into account different dosing intervals for the two drugs, which led to different observation periods, the team noted. After factoring in dosing, the results were “more consistent with the results of the primary analysis,” the researchers said.

RELATED: After FibroGen's FDA rejection in anemia, Akebia CEO aims to seize first-in-class opening with vadadustat

Beyond MACE, an important safety problem the FDA has flagged for roxa is an increased rate of blood clots. For both trials, GSK set a secondary endpoint aiming to show that dapro works better than ESA on the composite marker of MACE plus blood clots. However, neither trial was able to show superiority on that marker for the GSK drug.

In dialysis patients, the ASCEND-D trial showed a trend favoring dapro, but it just missed statistical significance on the MACE plus blood clots marker, Ajay Singh, M.D., of Harvard Medical School, principal investigator of the ASCEND program, said in an interview. The positive trend was driven by a lower number of vascular thrombosis events for dapro, he added.

The ASCEND-ND trial in nondiaysis patients didn’t follow that same favorable trend for dapro. The difference in thrombosis benefit may be the result of different trial population, Singh said, as vascular thrombosis may not occur as much in the nondialysis population.

Before concluding dapro is heart-problem-free at least when compared to ESAs, industry watchers have another data set to consider. In a third phase 3 trial dubbed ASCEND-ID in incident dialysis patients, a numerically higher rate of worsening high blood pressure cropped up in the dapro arm when compared with Aranesp, despite the dapro group being younger and having less history of heart failure. The rates were 24% for dapro and 19% for Aranesp.

The ASCEND-ID trial wasn’t powered to conclusively measure cardiovascular differences, Singh noted. The blood pressure difference deserves further investigation, but Singh said he’s not concerned about the signal.

“If you look at the broader population of stable dialysis patients in the [ASCEND-D] study and you look at hypertension as an adverse event of special interest, there was no trend that was unfavorable to dapro,” he said.

RELATED: GSK's Duvroq, Akebia's Vafseo win global first nods in Japan to challenge Astellas' anemia drug

In all, dapro essentially showed itself as a drug with a similar efficacy and safety profile as conventional ESAs. But the oral drug still deserves a place on the market with injectable agents, Singh said.

As it stands, the nondialysis population of anemia is relatively under-treated because some patients don’t have easy access to healthcare facilities and anemia treatment currently is a physician-supervised process, Singh noted. Plus, patients don’t like getting injections because they’re uncomfortable.

“If you can get an oral drug that they can take, you’re going to increase the proportion of people who should be treated to get treatment,” Singh said.

Editor's note: The story has been updated with additional ASCEND-ND data related to the on-treatment MACE analysis.