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

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

Adrenal Gland

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)

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.

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Questionnaire
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What is hypertension and why is it important?
Hypertension is defined by the American College of Cardiology and the American Heart Association as resting blood pressure above 130/80 mm Hg. When medication is required, there are several classes used to lower blood pressure including calcium channel blockers, thiazide diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs). Depending on the severity of hypertension, one or more of these agents would be administered to reduce blood pressure. Control of blood pressure is important because chronic hypertension significantly increases the risk of heart disease, stroke and kidney disease, amongst other diseases.
What are guidelines for treatment of high blood pressure?

Guidelines were updated by the American College of Cardiology (ACC) and the American Heart Association (AHA) in 2017 (see table below). New data indicated that guidelines needed to be more stringent, and the two medical associations acted accordingly.

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (2003 Guideline)

The American College of Cardiology/American Heart Association Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults (2017 Guideline)

Normal

systolic: less than 120 mm Hg
diastolic: less than 80 mm Hg

Normal

systolic: less than 120 mm Hg
diastolic: less than 80 mm Hg

At Risk (prehypertension)

systolic: 120–139 mm Hg
diastolic: 80–89 mm Hg

Elevated

systolic: 120–129 mm Hg
diastolic: less than 80 mm Hg

High Blood Pressure (hypertension)

systolic: 140 mm Hg or higher
diastolic: 90 mm Hg or higher

High blood pressure (hypertension)

systolic: 130 mm Hg or higher
diastolic: 80 mm Hg or higher
How well is hypertension treated today?
Despite a number of medications available to lower blood pressure, a significant percentage of patients do not lower their SBP below 140 mm Hg. In fact, according to National Health and Nutrition Examination Survey Data published in the Journal of the American Medical Association in 2021 (doi:10.1001/jama.2020.14545), except for an improvement from 31.8% reaching goal in 1999-2000 to approximately half in the 2007 through 2014, the percentage of patients reaching SBP below 140 mm Hg dropped to 43.7% in 2017-2018. If this large sample of almost 52,000 patients is any indication, then too many patients are not well controlled on their current blood pressure medications. It is likely that even fewer patients are reaching the goal of less than 130 mm Hg SBP, based on the 2017 ACC/AHA guidelines.
What did the Systolic Blood Pressure Intervention Trial (SPRINT) clinical trial show?
The SPRINT trial evaluated the impact of the current SBP goal (<140 mm Hg) with more intensive SBP control (<120 mm Hg) on cardiovascular morbidity and mortality (NEJM, DOI: 10.1056/NEJMoa1511939; NCT01206062). The study found that in patients at high risk of cardiovascular events, targeting SBP to <120 mmHg resulted in lower rates of fatal and non-fatal major cardiovascular events (compared to those targeting <140 mm Hg.  (5.2% vs. 6.8%, hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.64–0.89; p < 0.0001). All-cause mortality was reduced to 3.3% in the intensive management arm vs. 4.5% in the routine management arm ((p = 0.0003). The challenge to treating hypertensive patients today is how to get these patients below 120mm Hg when a majority of hypertensive patients on treatment do not get below 140 mm Hg.
What is treatment resistant hypertension (rHTN)?
Treatment resistant hypertension (rHTN) is defined by failure to maintain blood pressure levels of 130/80 mm Hg or less despite treatment with at least  three antihypertensive medications, preferably at optimal doses and including a diuretic.
What is aldosterone?
Aldosterone is the primary mineralocorticoid steroid hormone produced by and secreted from the adrenal glands. It functions to regulate sodium reabsorption and potassium excretion from the kidney, which results in water retention or loss and thus regulates blood pressure. Dysregulation of aldosterone can result in a variety of pathological processes including hypertension, cardiovascular disease and kidney disease.
What is primary aldosteronism (PA)?
PA is a hormonal disorder in which the adrenal glands produce too much aldosterone that often leads to hypertension that can be difficult to treat. In an article published in the Annals of Internal Medicine (https://doi.org/10.7326/M20-0065) in 2020, PA was found to occur in 16% to 22% of hypertensive patients with increasing aldosterone levels associated with more severe hypertension or TRH. Most available treatments, with the exception of mineralocorticoid receptor antagonists (MRAs) do not directly or significantly affect aldosterone levels. However, MRAs are associated with multiple adverse effects, including a variety of anti-androgenic effects.
What is the relationship with obesity and aldosterone levels?
Obesity is strongly associated with hypertension. Not surprisingly, Elevated aldosterone levels has also been associated with obesity, particularly abdominal obesity, and the level of aldosterone is positively correlated with BMI (doi: 10.1161/HYPERTENSIONAHA.116.07806).
Can aldosterone activity be blocked?
Currently, the only approved class of medications that block the actions of aldosterone are mineralocorticoid receptor antagonists (MRAs) such as eplerenone and spironolactone. However, they do not prevent aldosterone production nor necessarily decrease circulating aldosterone Although effective in inhibiting aldosterone binding to its receptor and lowering blood pressure, significant side effects occur, especially hyperkalemia, as well as impotence and gynecomastia in men. Because of its side effect profile, this class of drugs is used as a last resort or fourth-line agent fir rHTN. CIN-107 is potentially the first-in-class agent to reduce the synthesis of aldosterone, not just block the actions at the receptor like MRAs.
Where can I find additional References?
References can be found here under the Pipeline Page.