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.

Atrasentan, an ETA receptor antagonist discovered by Abbott (AbbVie) in the 1990s, was initially developed for prostate cancer. Due to insufficient clinical data for approval, AbbVie shifted its focus to chronic kidney diseases, conducting a large trial (SONAR) with over 5,000 patients. AbbVie later exited kidney disease drug development and out-licensed atrasentan to Chinook. Novartis then surprised everyone with a $3.2B buyout of Chinook. This case exemplifies the complexities of drug discovery for kidney diseases and the long journey from initial research to clinical success.

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).

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 [...]

On Monday, Mar. 27th (12:15 PM ET), our Drug Hunter team will be sponsoring a luncheon at ACS Spring 2023 in Indianapolis with a presentation on scientific gems from 2022’s drug approvals ( request an invitation here ). Each newly approved drug has an interesting scientific story, and you can see our overview of all 36 of the novel small [...]

A newly disclosed sGC activator in Ph. II for CKD/DKD. This month, researchers at BI reported promising preclinical results for a newly disclosed sGC activator, BI-685509, which is in several Ph. II trials including for treatment of chronic kidney disease (CKD) and diabetic kidney disease (DKD) ( NCT04736628 , NCT04750577 ). In rodents, the [...]

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.

In 2021, the FDA approved two new drugs for endocrinology-related indications, including severe hypoglycemia in diabetes, and chronic kidney disease (CKD) associated with type 2 diabetes. This article and slide deck explores each in more detail, including but not limited to their: target rationale discovery disease context original patents [...]

“Compound 19” (iron-binder) is an oral inhibitor of the hypoxia-inducible factor (HIF) propyl hydroxylase domain (HIF-PHD), increasing HIF levels to activate EPO transcription and promote hematopoiesis for treatment of anemia. Interestingly, this compound is modeled to make a bi-dentate interaction with an iron co-factor of HIF-PHD via a [...]

“Compound 9” is the first potent M3-selective positive allosteric modulator, with potential utility as a biological tool compound. It does have secondary activity against M5 at high doses though. It’s quite a large zwitterion, which is somewhat unusual for GPCRs.