Daprodustat is the first HIF-prolyl hydroxylase domain (PHD) inhibitor that has been approved for the treatment of anemia in chronic kidney disease (CKD) and marks the first novel anemia treatment approved in the US in >30 years. PHDs have been attractive targets for treating anemia, especially in CKD patients, because the enzymes regulate levels of hypoxia-inducible factors (HIFs) including HIF-2, which induces the production of erythropoietin that in turn stimulates red blood cell production. The small molecule drug has similar safety and activity as epoetin alfa, an injected biologic.

An old BMS program revitalized as a first-in-class drug in a new indication. Despite Travere Therapeutics having a checkered industry history due to ties to Martin Shrkeli, there appears to be potentially differentiating efficacy for sparsentan’s ( Filspari ) accelerated approval thanks to its novel dual-antagonistic mechanism. It’s also [...]

Inaxaplin (VX-147), developed by Vertex, is an inhibitor of APOL1 channel activity currently in a Ph. II/III pivotal study for the treatment of chronic kidney disease caused by specific variants of the APOL1 gene. It was recently granted Breakthrough Therapy designation by the FDA and PRIME designation by the EMA. The discovery story, which is an excellent case study for the use of MetID. Inaxaplin has been called “the most important genomic-driven drug discovery for chronic kidney disease this century”, acting on a target with a fascinating human genetic validation story.

The arachidonic acid (AA) metabolite, 20-hydroxy-5,8,11,14-eicosatetranoic acid (20-HETE), has been extensively studied as a modulator of kidney function and a mediator of kidney diseases over decades. The receptor for 20-HETE, the G-coupled protein receptor GPR75, was only recently identified (2017), and GPR75/20-HETE pathway modulators are of industry interest in many disease areas including obesity (e.g. 2020 Regeneron patent filing) and kidney diseases (e.g. 2018 Taisho patent filing).

Vadadustat (Vafseo) from Akebia Therapeutics is an oral hypoxia-inducible factor prolyl-4-hydroxylase domain (HIF-PHD) inhibitor developed for anemia in patients with chronic kidney disease (CKD). It received FDA approval on March 27th, 2024 for patients on dialysis for at least three months, after regulatory challenges including an earlier complete response letter due to safety concerns. This makes vadadustat the second FDA-approved HIF-PHD inhibitor for the treatment of anemia in CKD for dialysis-dependent patients after GSK’s daprodustat’s approval in Feb. 2023.