Baxdrostat selectively targets aldosterone synthase, which is encoded by the CYP11B2 gene. Importantly, it has low affinity for 11ß-hydroxylase, the enzyme responsible for cortisol synthesis, which is encoded by the CYP11B1 gene. In multiple preclinical in vivo studies, baxdrostat significantly lowered aldosterone levels without affecting cortisol levels, across a wide range of doses. Similar observations were made in multiple Phase 1 clinical trials in healthy volunteers.
Multiple Phase 1 clinical trials of baxdrostat have been conducted in healthy volunteers to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of baxdrostat. Baxdrostat was well tolerated in healthy volunteers across all Phase 1 clinical trials conducted to date, with no serious adverse events, or SAEs, or treatment-emergent adverse events, or TEAEs, leading to treatment withdrawal associated with baxdrostat. In addition, a Phase 1 clinical trial was conducted in subjects with varying degrees of renal function. In this trial, one SAE not related to baxdrostat was observed.
Based on the preclinical and clinical data available to date, we are developing baxdrostat in multiple diseases where aldosterone plays a significant role in disease pathophysiology, including hypertension and primary aldosteronism. We are also exploring its utility in ameliorating complications of chronic kidney disease.
Our Phase 2 trial (BrigHtn) in patients with treatment resistant hypertension was completed in 2022. BrigHtn topline results, published in August 2022, demonstrated that treatment with baxdrostat at 1 mg and 2 mg led to a statistically significant lowering of SBP in patients with rHTN. Patients treated with baxdrostat at 2 mg demonstrated a 20.3 mmHg reduction in SBP and a placebo-corrected reduction of 11.0 mmHg (p value = 0.0001). The 1 mg dose demonstrated a 17.5 mmHg reduction in SBP resulting in a significant placebo-adjusted SBP decline of 8.1 mmHg (p value = 0.003).
ABOUT HYPERTENSION
Hypertension, or high blood pressure, is a condition that affects as much as 20% of the global population. It is also one of the world’s leading causes of mortality. Left untreated, hypertension can reduce cardiovascular outcomes and cause several complications, including heart disease, stroke, chronic kidney disease and premature death. Heart disease and stroke, in particular, are among the leading causes of death in the U.S. Unfortunately, hypertension is also considered a “silent killer” because it is often asymptomatic.
According to the United States Centers for Disease Control and Prevention, or the U.S. CDC, approximately 500,000 people still die every year in the United States with uncontrolled blood pressure listed as a primary or secondary cause of death. Despite decades of understanding the importance of controlling hypertension and the widespread availability of multiple approved therapies, only 43.7% of the 116 million U.S. adults with hypertension achieve blood pressure levels of less than 140/90 mm Hg.
Hypertensive patients whose blood pressure is not controlled (BP > 130/80 mmHg) despite treatment with up to two antihypertensive agents are referred to as having uncontrolled hypertension (uHTN). Patients who fail to maintain blood pressure levels of 130/80 mm Hg or less, despite being compliant with at least three antihypertensive agents, of which one is a diuretic, are considered to have treatment resistant hypertension (rHTN).
One potential cause of rHTN and uHTN is a build-up of aldosterone, which helps regulate blood pressure. Many hypertension medications are designed to lower the amount of aldosterone in the body. However, aldosterone levels can sometimes increase even if you are taking medications to reduce it. This makes it difficult to control blood pressure.
About Primary Aldosteronism
Primary aldosteronism (PA), also known as Conn’s syndrome or primary hyperaldosteronism, is a hormonal disorder caused by changes to the adrenal glands that produce aldosterone. PA ultimately leads to the overproduction of aldosterone.
Aldosterone is a steroid hormone synthesized in the adrenal gland. When activated, aldosterone causes the body to hold onto more salt and water, causing blood pressure to go up.
In patients with PA, the overproduction of aldosterone leads to an increase in salt and water retention that causes elevated blood pressure levels, or hypertension. An estimated 20% to 30% of patients in the U.S. with rHTN have primary aldosteronism.
About Chronic Kidney Disease (CKD)
Chronic kidney disease (CKD) is a progressive condition that causes the kidneys to function less effectively over time. According to the CDC, CKD afflicts approximately 15% of the U.S. adult population, or approximately 37 million people. Hypertension, diabetes and glomerulonephritis, or inflammation of the tiny filters in the kidneys, are considered the leading conditions that cause, worsen, or increase the risk of kidney damage Hypertension and diabetes, in particular, can damage the blood vessels in the kidney, making it harder for the kidney to filter blood successfully. Aldosterone plays a significant role in the development of CKD.
Aldosterone is a steroid hormone synthesized in the adrenal gland that regulates water and salt balance in the human body. It causes retention of water and salt by the kidney, described as a genomic effect that contributes to the development of hypertension. This increase in blood pressure and aldosterone’s other effects (such as enhanced oxidative stress, inflammation and fibrosis) can cause kidney damage. Specifically, these negative effects put excess pressure on the kidneys, especially as the disease progresses over several years.
Ongoing Clinical Trials
We are currently evaluating baxdrostat (CIN-107) in four Phase 2 clinical trials for hypertension, hypertension in CKD and primary aldosteronism.
- HALO: A Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Multiple Dose Strengths of CIN-107 as Compared to Placebo After 8 Weeks of Treatment in Patients With Uncontrolled Hypertension
- OLE: An Open-Label Extension Study of Patients Previously Enrolled in Study CIN-107-124 (HALO) to Evaluate the Long-Term Safety and Effectiveness of CIN-107
- FigHtn-CKD: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Parallel-Group, Dose-Ranging Study to Evaluate CIN-107 for the Treatment of Patients With Uncontrolled Hypertension and Chronic Kidney Disease
- Spark-PA: A Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, and Effectiveness of CIN-107 for the Management of Blood Pressure in Patients With Primary Aldosteronism
To learn more about our clinical study of baxdrostat, visit www.ClinicalTrials.gov.