Akebia Therapeutics has moved pipeline candidate AKB-9090, an intravenous hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, into a Phase I first-in-human clinical trial in healthy adult volunteers. The FIH clinical trial, registered under NCT07429006 and set to begin dosing in March 2026, represents the company’s first foray into acute care indications with a drug class it has so far developed exclusively for chronic anemia.
AKB-9090 is being positioned for the prevention or treatment of cardiac surgery-associated acute kidney injury (CS-AKI), a complication that affects up to 30% of patients undergoing cardiac procedures and for which no pharmacological therapy has been approved. The study is being conducted in New Zealand through a collaboration with Emerald Clinical Trials and New Zealand Clinical Research (NZCR).
The decision to develop an IV-formulated HIF-PH inhibitor for an acute perioperative setting is a departure from the oral, chronic-use paradigm that has defined the class. Akebia’s own vadadustat (Vafseo), approved by the FDA in 2024 for anemia of chronic kidney disease in dialysis-dependent adults, is an oral pill taken daily. AKB-9090 shares the same pharmacological target — prolyl hydroxylase domain enzymes — but has been formulated for single or short-course intravenous delivery for use in the operating room and intensive care unit.
AKB-9090 SAD MAD study
The AKB-9090 clinical trial is a randomized, double-blind, placebo-controlled study structured in two stages. Stage 1 is a single ascending dose (SAD) phase enrolling approximately 40 participants across five dose cohorts. Stage 2 is a multiple ascending dose (MAD) phase enrolling approximately 30 participants across three dose cohorts, for a total planned enrollment of 70. The trial uses a sequential dose-escalation design and is overseen by a data monitoring committee. Eligible participants are healthy adults aged 18 to 60. Endpoints focus on safety and tolerability, including incidence of treatment-emergent adverse events, PK/PD measurements to inform tolerable doses.
Biologic rationale behind HIF stabilization beyond erythropoiesis
The HIF-PH inhibitor class was developed around a single core insight: prolyl hydroxylase enzymes act as cellular oxygen sensors, tagging HIF-α subunits for degradation when oxygen is abundant. Blocking these enzymes mimics hypoxia at the molecular level, stabilizing HIF-α and activating a broad transcriptional program that includes not only EPO production but also genes involved in iron metabolism, angiogenesis, glucose transport, and cytoprotection.
For chronic anemia, the therapeutic value of this pathway has been validated. Several HIF-PH inhibitor oral agents — daprodustat (GSK), vadadustat (Akebia/Otsuka), and roxadustat (FibroGen/AstraZeneca) — have received regulatory approval in at least one market. All are oral small molecules designed for repeated daily dosing in patients with chronic kidney disease.
Akebia’s AKB-9090 program rests on a different aspect of HIF biology. Preclinical evidence has shown that acute HIF stabilization can protect tissues from ischemia-reperfusion injury, the pathological cascade triggered when blood flow is restored to an organ after a period of ischemia. In cardiac surgery, the kidneys are particularly vulnerable to this insult. The hypothesis underlying AKB-9090’s development is that a short-course, perioperative IV infusion of a HIF-PH inhibitor could activate cytoprotective and anti-inflammatory gene programs in the kidney before or during the ischemic event, reducing the incidence or severity of acute kidney injury. AKB-9090 is a product of Akebia’s internal HIF-PH inhibitor platform, which also includes AKB-10108, a compound in preclinical development for retinopathy of prematurity. No licensing or acquisition deals associated with AKB-9090 have been publicly disclosed.
Cardiac surgery-associated acute kidney injury has no approved pharmacological treatment. Preventive strategies are limited to hemodynamic optimization, avoidance of nephrotoxins, and goal-directed fluid management. This absence of competition at the indication level is a potential advantage for Akebia, though the lack of approved therapies also reflects decades of clinical trial failures in AKI prevention more broadly.