Bempedoic Acid Therapy for Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD), the most commonly inherited kidney disease, is characterized by the development of cysts in the kidney that impair function. Of those affected, half will progress to end-stage kidney disease by age 60, requiring dialysis or kidney transplant. To date, no effective and safe therapies exist for this deadly disease. Tolvaptan (Tol), the only FDA-approved drug for treatment of ADPKD, has some benefit in slowing kidney disease progression, but Tol causes frequent urination and thirst and also injures the liver in a small number of patients. The investigators' goal, therefore, is to develop new strategies to treat ADPKD that are safe and tolerable. The development of cysts in ADPKD patients results from two main cellular processes. The first is cell growth with an increase in the number of kidney cells that make up the outer surface of the cyst. The second is an increase in fluid secretion into the cysts that develop. The investigators have shown that an enzyme, AMP-activated protein kinase (AMPK), when activated can inhibit both of those processes. Moreover, genetic mutations that cause ADPKD may alter the energy metabolism of the cell, which in turn inhibits AMPK activity. Bempedoic acid (BA), a medication that is FDA-approved for the treatment of individuals with high cholesterol and has a good safety record, activates AMPK. In addition to activating AMPK, BA inhibits a second enzyme called ATP-citrate lyase (ACLY), which is involved in cholesterol synthesis. ACLY has received growing attention as a novel target for cancer treatment. ACLY inhibition blocks increases of cell numbers by inhibiting the lipid synthesis that is required for creation of new cell membranes. This study will test whether targeting these pathways through treatment with BA will help reverse dysfunctional metabolism in individuals with ADPKD and slow disease progression. The investigators will test this using a phase 2 clinical trial in which 120 individuals with rapidly progressive ADPKD and an estimated glomerular filtration rate of 35 or greater will be treated with either BA or placebo (inactive look-alike pill) for two years. Participants on or off a stable dose of Tol will be included in the study. Participants will be recruited from the U. of Vermont, U. of Maryland, and Tufts University, which have active PKD clinics and are recognized by the PKD Foundation as Centers of Excellence. Through follow-up visits and lab work, the investigators will assess the safety and tolerability of BA in the participants as the primary outcomes. The secondary goals are to assess preliminary efficacy and effects of BA on quality of life in study participants. The growth of cysts results in increased volume or size of the kidneys and liver. Total and cyst volumes of the kidney and liver and visceral abdominal fat content via magnetic resonance imaging (MRI) will be measured to gauge the effectiveness of this drug. The investigators also predict that proteins and small molecules involved in regulating cell energy metabolism, inflammation, and injury, as well as proteins directly involved in AMPK and ACLY function, will be altered in ADPKD patients. Levels of these proteins and small molecules may then subsequently change with BA therapy. Exploratory, mechanistic goals of this study are to identify prognostic and predictive urinary biomarkers in study participants. Successful completion of this study would have a significant impact on individuals with ADPKD by laying the groundwork for a new treatment strategy as well as by providing a new way to help guide treatment decisions. In summary, the goals of this phase 2 randomized, double-blind, placebo-controlled clinical trial are to test the safety, tolerability and preliminary efficacy of the drug bempedoic acid, FDA-approved to lower cholesterol, when used in ADPKD patients.

Background and Rationale: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common monogenic kidney disease affecting \~1:700 individuals with half of patients progressing to end-stage kidney disease by age 60. ADPKD is characterized by excessive epithelial cell proliferation and cAMP-dependent luminal fluid secretion that manifests as progressive cyst development. There is growing recognition that metabolic derangements occur in ADPKD cells contributing to cyst formation and expansion, including increased glycolysis, impaired mitochondrial fatty acid oxidation, and reduced activity of the metabolic sensor AMP-activated protein kinase (AMPK). Tolvaptan (Tol), the only FDA-approved drug for ADPKD, modestly slows disease progression in patients but has dose-dependent side effects limiting its tolerability, including polyuria and thirst, and rare hepatotoxicity, which requires close liver function test monitoring. New therapeutic strategies are greatly needed for ADPKD patients, especially ones that target complementary signaling pathways that may afford additivity in slowing disease progression when used together with Tol and may permit lower Tol dosing in patients. Recent preclinical work suggests that bempedoic acid (BA) may serve as an exciting new therapy for ADPKD in this regard. BA is an ATP-citrate lyase (ACLY) inhibitor FDA-approved to treat hypercholesterolemia. BA is a pro-drug that gets activated only in kidney and liver, the main organs affected in ADPKD, and catalyzes a key step in fatty acid and sterol synthesis important for cell growth and proliferation. BA also directly activates AMPK and promotes mitochondrial oxidative metabolism. Together, these effects target key dysregulated pathways in ADPKD and support the potential of this drug for the treatment of ADPKD. In preclinical studies BA treatment inhibited cyst growth and improved mitochondrial health in model ADPKD kidney cells and mice. Importantly, BA treatment appears to be safe and well tolerated in patients with mild-moderate CKD with no dose adjustment, although its use has never been studied specifically in ADPKD patients. Hypothesis/Objectives: The investigators hypothesize that BA will be safe and tolerable in ADPKD patients and that repurposing BA for use in these patients will be beneficial in improving ADPKD disease features, both with and without concurrent Tol use. In Specific Aim 1 they will perform a randomized, placebo-controlled, double-blind, phase 2, multicenter clinical trial that will evaluate the safety, tolerability, quality of life, and preliminary efficacy of BA for 120 participants with ADPKD who are at high risk for rapid progression, either with or without concomitant Tol therapy, over a two-year period. Longitudinal changes in estimated GFR (eGFR), height-adjusted total kidney and liver volumes (htTKV and htTLV), kidney and liver cyst volumes (KCV and LCV), visceral abdominal fat, and urinary biomarkers will be assessed. In Specific Aim 2 the investigators will perform exploratory analyses and identification of prognostic and predictive urinary biomarkers related to disease severity and the expected metabolic effects of BA both before and after initiation of the study drug to evaluate potentially relevant biomarkers that correlate with ADPKD disease severity and response to BA. Study Design: The investigators will perform a pilot-level, double-blind, phase 2, parallel-group, placebo-controlled multicenter clinical trial to evaluate BA in ADPKD patients over a two-year period. Each arm will consist of approximately 60 ADPKD patients who are at risk for rapid disease progression and may be either on or off tolvaptan, recruited from three geographically and ethnically diverse patient populations at Tufts U., U. Maryland, and U. Vermont. It is anticipated that each clinical site will recruit 40 participants who will be randomized in a 1:1 ratio to receive either placebo or BA (180 mg oral daily). For the primary endpoints, the study will evaluate safety, as defined by all and targeted adverse events (e.g., hyperuricemia/gout and liver transaminitis). Tolerability will be assessed by the % participants still taking study drug at 24 months and % adherence by pill counting, as well as the % participants who answer 'yes' to the question of whether they could tolerate taking the study drug for the rest of their lives. For the quality of life secondary endpoint, health-related quality of life metrics, including pain, discomfort, fatigue, emotional distress, and impaired mobility will be assessed via validated ADPKD questionnaires. For the secondary endpoint of preliminary efficacy, the investigators will estimate the effect of BA on htTKV, KCV, htTLV, LCV, and visceral abdominal fat by MRI at 0, 12, and 24 months during treatment, as well as estimated glomerular filtration rate (eGFR) by CKD-Epi and cystatin C equations with each visit. Clinical lab measurements will be performed at baseline prior to initiation of the study drug, at 2 weeks, 6 weeks, and 3 months, and then every 3 months thereafter for a total of 2 years. Patient surveys will be performed and urine will be collected from participants at each in-person study visit (occurring at baseline, 3, 6, 12, 18, and 24 months) to measure targeted urinary metabolic and other disease biomarkers that may correlate with ADPKD disease severity and response to BA. Inclusion criteria will include ADPKD patients aged 18-60 years, at risk for rapid disease progression with Mayo Imaging Classifications (MIC) 1C-1E or MIC 1B with defined eGFR decline \>3 ml/min/yr, eGFR ≥35 ml/min, and English-speaking. Participants will be stratified by Tol use (stable Tol dose for \>3 months prior to baseline visit). Exclusion criteria will include proteinuria \>500 mg/day, current BA use, diabetes, known unstable cerebral aneurysm, active coronary artery disease, systemic kidney-impacting diseases, pregnancy or lactation, and implanted ferromagnetic objects. Clinical Impact: Successful completion of this study could have a significant clinical impact, as it will provide the necessary foundation for a larger, phase 3 study to test BA efficacy in ADPKD patients. Given the established safety record and preclinical data showing the effects of BA in the disease process, it is expected that BA could alter clinical practice. Moreover, identification of biomarkers for disease severity and therapeutic response would significantly improve the management of ADPKD patients.