Ligand Pharmaceuticals Incorporated presented positive results from a Phase 1 clinical trial of its Captisol-enabled (CE) Iohexol program at ASN Kidney Week 2019 in Washington, D.C. The CE-Iohexol program was established in January 2018 to develop a Captisol-enabled, next-generation contrast agent for diagnostic imaging with a reduced risk of renal toxicity. The trial achieved the primary endpoint demonstrating pharmacokinetic bioequivalence between CE-Iohexol injection and a reference Iohexol injection (OMNIPAQUE™) after intravenous (IV) administration in healthy adults. CE-Iohexol injection was safe and well tolerated, and adverse events were in line with the known safety profile of OMNIPAQUE.
Contrast agents are used to enhance diagnostic imaging. Despite their benefits and widespread use, contrast agents may place patients at an increased risk for acute kidney injury (AKI), especially those with certain risk factors undergoing cardiac interventional procedures utilizing intravascular iodinated contrast.1 CE-Iohexol is designed to reduce the risk of AKI during imaging procedures where iodinated contrast agents are administered. In preclinical studies using an animal model of AKI, CE-Iohexol administered at a dose similar to the clinical usage of iohexol in humans significantly reduced renal injury compared to iohexol alone and increased survival from 50% to 88%.2
The goal of the Phase 1 trial was to establish pharmacokinetic bioequivalence to support subsequent clinical trials that could support the submission of a 505(b)(2) new drug application (NDA) to the U.S. Food and Drug Administration (FDA). The trial design consisted of a single-center, randomized, double-blind, two-period crossover study to determine relative bioavailability of CE-Iohexol and a reference Iohexol injection (OMNIPAQUE) after IV administration in a population of 24 healthy adults (NCT03869983).
Highlights of the data presented include:
- In two treatment periods, subjects received each treatment as a single IV dose of 80 milliliters (mL) infused over approximately 20 seconds by a power injector: CE-Iohexol, 755 mg/mL iohexol (350 mg I/mL)/50 mg CAPTISOL®/mL; OMNIPAQUE, 755 mg/mL iohexol (350 mg I/mL).
- Bioequivalence between CE-Iohexol and OMNIPAQUE was demonstrated for the key pharmacokinetic (PK) parameters of area under the concentration-time curve (AUC) and maximum concentration (Cmax).
- Geometric mean ratio of AUCs for CE-Iohexol and OMNIPAQUE was 1.0 with 94% confidence interval of 0.98-1.02. Geometric mean ratio of Cmax for CE-Iohexol and OMNIPAQUE was 1.0 with 94% confidence interval of 0.95-1.06.
- The means of AUC, Cmax, as well as half-life and elimination constant, were similar between treatments; the mean elimination constant was 0.3/hour for both treatments.
- Based on these results, it can be concluded that CE-Iohexol is bioequivalent to the reference OMNIPAQUE following IV injection in healthy adults.
- No subject had a serious adverse event or discontinued from the study due to an adverse event. All adverse events were mild to moderate in severity and the incidence of subjects with adverse events was similar in both treatment groups.
- The most common adverse event was a sensation of warmth, which is an adverse event known to occur during IV administration of iodinated contrast agents such as OMNIPAQUE.3
- There were no clinically significant abnormal physical examination findings, and there were no clinically meaningful changes in vital signs, laboratory parameters., hematology, urinalysis or ECG results.
- Overall, administration of the Captisol-containing CE-Iohexol following IV injection was safe and well tolerated in normal healthy subjects.
About Captisol-enabled Iohexol
More than 30 million imaging procedures are performed each year in the United States. Iodinated contrast agents represent more than 60% of all X-ray imaging agents sold with an annual U.S. market of approximately $1.5 billion.4 Iohexol (marketed as OMNIPAQUE™ by GE Healthcare), the most widely-used injectable diagnostic contrast agent for imaging procedures, has global sales exceeding $500 million and no generic competition in the United States.
Contrast-induced acute kidney injury (CI-AKI) is the acute impairment of renal function following intravascular administration of an iodinated contrast agent, and occurs most frequently following coronary angiography, percutaneous coronary intervention and contrast-enhanced computed tomography, especially among patients at risk of renal injury such as those with advanced age, diabetes or heart failure. CI-AKI is an issue with broad medical visibility as more than 50% of cardiovascular imaging procedures are performed in patients age 65 or older.5
Currently no products are approved to prevent or treat CI-AKI in this setting, and therefore Ligand believes a significant opportunity exists for a safer formulation of contrast agents. The goal is for CE-Iohexol to establish a new safety standard that enables a future partner to gain meaningful market share.