Prolyl hydroxylase inhibitors for Anemia Treatment in CKD Patients: What’s the Unmet Need?

From the Chair

Prolyl hydroxylase inhibitors (PHIs) stimulate the erythropoietin gene to produce endogenous erythropoietin and represent a potentially exciting alternative class of agents over conventional parenterally administered erythropoiesis-stimulating agents (ESA) in treating anemia of chronic kidney disease (CKD). Unlike ESAs, PHIs are oral rather than injectable. And, unlike conventional ESAs, appear to modulate iron homeostasis in the body. Thus, PHIs represent an oral agent that corrects anemia of kidney disease. The primary mechanism for this is activating the erythropoietin gene, but a potential collateral benefit could be also favorably influencing iron metabolism.

Three PHIs are under clinical development. The first in class, roxadustat, recently failed to receive approval by the US FDA, but is approved in Europe. The other two agents, vadadustat and daprodustat, will likely be reviewed by the US FDA in the spring and fall of 2022, respectively [disclosure: I am the academic lead for the Ascend Clinical Trial program for daprodustat].

We recently published two papers in the New England Journal of Medicine^1.2 that randomly assigned either dialysis or non-dialysis patients to daprodustat or conventional ESA. The two coprimary outcomes were hemoglobin efficacy and a cardiovascular composite (MACE or all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke). In each of the trials, daprodustat was non-inferior or no worse than conventional ESA for MACE, and for correction of hemoglobin; daprodustat was also well tolerated.

Even with approval, however, the biggest question that most nephrologists will ask about PHIs is, “Why use them?”

The obvious advantage of PHIs over conventional ESAs is that an oral medication is generally more convenient for patients compared to an injectable agent, even if it is self-administered as a subcutaneous injection. Still, perhaps more important than this is that the widespread availability of an oral agent (once approved) is likely to increase accessibility to anemia treatment especially among CKD patients not undergoing dialysis. This is because patients often  need to jump through hoops to receive anemia treatment. In dialysis patients a conventional ESA is administered three times each week and dialysis unit staff administer the drug in a very controlled and regulated manner. In patients not on dialysis (but also those patients on dialysis who are on peritoneal dialysis and/or home dialysis), an oral drug such as PHI is easy for patients to take and there are no logistical hoops once the drug is dispensed.

As the awareness about PHIs as a new class of anemia drugs increases after their approval, many nephrologists are going to ask: “What are the benefits for patients with respect to hard end points, like mortality or cardiovascular complications?” Of course, this is an important point and the phase 3 PHI trials, including for daprodustat, have not demonstrated superiority over conventional ESA for hard end points. But they weren’t designed to, although if there were a major favorable signal, it would have been observed. That said, it is conceivable that using moderate doses of ESA has similar safety to using an orally administered PHI agent, and that no signal being observed is because at lower doses to incompletely correct anemia, conventional ESAs are quite safe. A question that hasn’t been answered is whether PHIs might end up being safer when the goal of treatment is to achieve a normal hemoglobin.

PHIs induce endogenous production of erythropoietin, and erythropoietin levels are at a fraction of peak levels compared with those observed after administration of intravenous or subcutaneous epoetin alfa. A randomized trial using a PHI in both arms, one arm probably at a lower and the other at  higher dose of PHI that aims for a normal Hb in one arm versus the FDA standard of 10-11 g/dL in the other has not been done.

So, my take is that there are still some ways to go to truly understanding the potential of PHIs in treating the anemia of CKD. There is no question that PHIs represent a major development and have much promise. They do meet an unmet need. The next step is for the FDA to approve one or more PHI agents. After that, or in parallel, additional studies are needed, including those that explore the effect of PHIs on iron metabolism. It’s likely that phase 4 studies will need to be considered to tease out the potential for beneficial effects and/or evaluate safety in subgroups of patients. And the experiment of evaluating whether a PHI can be used to normalize the Hb in CKD patients will need to be considered.

References

1. Singh AK, Carroll K, Perkovic V, et al. ASCEND-D Study Group. Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis. N Engl J Med. 2021 Dec 16;385(25):2325-2335. doi: 10.1056/NEJMoa2113379. Epub 2021 Nov 5. PMID: 34739194.
2. Singh AK, Carroll K, McMurray JJV, et al. Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis. N Engl J Med. 2021 Dec 16;385(25):2313-2324. doi: 10.1056/NEJMoa2113380. Epub 2021 Nov 5. PMID: 34739196.