Purpose:
Branched-chain amino acids (BCAA), including leucine, isoleucine, and valine, are essential amino acids, and their metabolism has been shown to be dysregulated in heart failure, leading to elevated levels. These essential amino acids share a common metabolic pathway whereby they are first reversibly transamidated to branched-chain ketoacids (BCKA: ketoleucine, ketoisoleucine, ketovaline) and then irreversibly converted to their CoA species by the branched-chain ketoacid dehydrogenase (BCKDH) enzyme complex. This complex is negatively regulated by phosphorylation by BCKDH kinases (BDK or BCKDK), leading to increased concentrations of both the branched-chain amino acids and their respective branched-chain ketoacids, which may have a toxic effect on cardiac function. Therefore, a BDK inhibitor should enhance BCAA catabolism and is hypothesized to be a treatment for heart failure with preserved ejection fraction.
This study aims to evaluate the efficacy and safety of oral PF-07328948, a BDK inhibitor, in adults with heart failure with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF).
PF-07328948, as an inhibitor of branched-chain α-keto acid Dehydrogenase kinase (BDK), should lead to an increase in branched-chain amino acid (BCAA) and branched-chain keto acid (BCKA) catabolism, which are impaired in heart failure. Hence, this study targets underlying impairment in BCAA/BCKA catabolism through inhibition/degradation of BDK with expected improvement in clinically meaningful outcomes in HFmrEF and HFpEF. Patients will be randomized to daily doses of 100 mg, 200 mg, 400 mg, or placebo.
Description:
Heart Failure (HF) represents a global pandemic, impacting over 60 million individuals worldwide. The prevalence of heart failure with preserved ejection fraction (HFpEF) with left ventricular ejection fraction (LVEF) ≥50%, also known as the “stiff heart syndrome,” is increasing across all populations with high rates of hospitalization and mortality, reaching up to 80% and 50% respectively, within a 5-year timeframe. The five-year mortality rate is worse than most types of cancer. The prevalence of heart failure with mildly reduced ejection fraction (HFmrEF) with LVEF 41%-49% among all HF patients is estimated to range from 10-25%. Both HFmrEF and HFpEF are major healthcare issues not only because of the high mortality rate but also because they lead to significant disability and recurrent hospitalizations. The main goal of treatments is to implement measures that can improve patient prognosis and reduce the societal burden of the disease.
Current treatments that have been found to be useful in HFpEF and HFmrEF include the use of drugs such as SGLT2 inhibitors dapagliflozin and empagliflozin alone and the non-steroidal mineralocorticoid inhibitor finerenone. However, there are limits to the ability of these treatments to prevent death and progression of the heart failure condition. Therefore, we are seeking out new treatments to improve outcomes such as cardiovascular mortality and the need for heart exacerbations leading to hospitalizations.
Key Eligibility Requirements:
(Please note: Additional eligibility requirements may be assessed at the time of study screening evaluation.)
- Clinical diagnosis of NYHA Class II-IV chronic heart failure
- LVEF >40% based on most recent assessment
- If LVEF ≥50%, one or more of the following structural heart abnormalities must be present:
o Average E/e’ ≥11
o Left atrial (LA) volume index >34 mL/m²
o LV mass index ≥115 g/m² for males and ≥95 g/m² for females - Have at least one of the following:
o An elevated natriuretic peptide defined as an NT-proBNP:
o ≥300 ng/L for patients with BMI <30.0 kg/m² in NSR
o ≥150 ng/L for patients with BMI ≥30.0 kg/m² in NSR
o ≥600 ng/L for patients with BMI <30.0 kg/m² in persistent or permanent atrial fibrillation
o ≥300 ng/L for patients with BMI ≥30.0 kg/m² in persistent or permanent atrial fibrillation
o Hospitalization with a primary diagnosis of decompensated HF requiring IV loop diuretic treatment within 12 months
o Urgent outpatient visit for worsening HF requiring IV loop diuretic treatment within 6 months - Able to perform the 6-minute walk test
- (HbA1c) ≥5.7% and <10.0%
- BMI: ≥27.0 and <50.0 kg/m² or a BMI <27.0 kg/m² in the setting of one or more of the following:
o A diagnosis of type 2 diabetes mellitus
o Concomitant use of GLP-1 RA therapy
o Waist circumference >94 cm (37 inches) for males or >80 cm (31 inches) for women - Receiving therapy with an SGLT2i for at least 30 days prior to randomization
Patients May Be Excluded From Trial Participation If They Have:
- Life-threatening or uncontrolled arrhythmias, including sustained ventricular tachycardia and atrial fibrillation or atrial flutter with resting ventricular rate >110 bpm
- Type 1 diabetes mellitus
- Prior intolerance/known hypersensitivity to an SGLT2i or contraindication to an SGLT2i
- Presence of hemodynamically significant valvular heart disease (e.g., moderate or severe valvular disease)
- Prior history of deep vein thrombosis or pulmonary embolism, unless currently established on therapeutic anticoagulation
- Active malignancy requiring treatment (except for basal cell or squamous cell carcinomas of the skin)
- eGFR <30 mL/min/1.73 m²
- Hemoglobin ≤9 g/dL
- UACR ≥2200 mg/g
The information we are providing includes important background on a variety of important cardiovascular conditions and ongoing clinical trials. We encourage you to use this information in discussions with your health care professional. Since enrollment in clinical trials are limited in time, we can’t guarantee their availability at any given time. However, we have continued access to new clinical trial opportunities and will share them as soon as they are available.