What's Happening?
Thryv Therapeutics Inc. has announced the publication of a new study in JACC: Heart Failure, presenting human genetic, preclinical, and clinical evidence that supports the use of its lead SGK1 inhibitor, THRV-1268, for treating heart failure with reduced
ejection fraction (HFrEF). The study highlights SGK1 as a genetically validated cardiometabolic therapeutic target. Key findings indicate that THRV-1268 maintained cardiac function and outperformed empagliflozin monotherapy in an animal model of heart failure. Additionally, Phase 1 studies demonstrated a favorable safety profile and statistically significant QTcF shortening in individuals with obesity, consistent with cardiac target engagement. These findings provide a strong rationale for advancing THRV-1268 into Phase 2a clinical development through the ASPIRE-HF study, which is expected to begin enrollment in Q4 2026.
Why It's Important?
Despite advancements in guideline-directed medical therapy (GDMT), a significant residual risk persists in HFrEF patients, leading to high rates of worsening heart failure, hospitalization, and mortality. Approximately 40% of recently hospitalized patients on quadruple GDMT still experience adverse outcomes within 12 months. THRV-1268's potential to address both electrical and structural remodeling in the heart, along with its ability to improve multiple measures of adverse remodeling and reverse pathological gene-expression pathways, offers a novel therapeutic approach. The observed QTcF shortening is particularly important as QTc prolongation is associated with increased arrhythmia susceptibility and worse outcomes in heart failure patients. If successful, THRV-1268 could significantly improve the prognosis for HFrEF patients in the U.S., potentially reducing hospitalizations and mortality rates, and complementing existing standard-of-care therapies.
What's Next?
Thryv Therapeutics plans to initiate the ASPIRE-HF (Addressing SGK1-driven Prolonged QT and Impaired REmodeling in Heart Failure) study, a Phase 2a trial for THRV-1268 in adults with HFrEF and QTc prolongation. Enrollment for this study is expected to commence in Q4 2026, initially at sites in Australia, with potential expansion to other regions in 2027. The ASPIRE-HF study will evaluate the safety, pharmacokinetics, and effects of THRV-1268 on arrhythmic risk, cardiac remodeling, and established heart failure biomarkers. The company is also evaluating THRV-1268 in the WAVE II, a Phase 2/3 clinical study for patients with Long QT Syndrome Type 2. The outcomes of these trials will be crucial in determining the future development and potential market approval of THRV-1268.
Beyond the Headlines
The focus on SGK1 inhibition represents a promising new frontier in cardiovascular medicine. SGK1, a stress-responsive kinase, is implicated in various aspects of heart failure, including myocardial metabolic stress, inflammation, fibrosis, and electrical remodeling. Historically, the development of potent and selective SGK1 inhibitors has been challenging. Thryv Therapeutics' success in developing THRV-1268 suggests a breakthrough in this area, potentially opening doors for targeting other cardiometabolic and central nervous system diseases where SGK1 plays a role. This approach signifies a move towards more targeted therapies that address the underlying molecular mechanisms of disease, rather than just managing symptoms. The integration of human genetic data with preclinical and clinical evidence also highlights the increasing sophistication of drug discovery and development processes.
