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Abstract: TH-PO1121

Identification of a Hypertensive Endotype with a Median Treatment Effect of -32mmHg in Response to the Novel Aldosterone Synthase Inhibitor Lorundrostat

Session Information

  • Late-Breaking Posters
    November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

  • 1602 Hypertension and CVD: Clinical

Authors

  • Cizman, Borut, Mineralys Therapeutics, Radnor, Pennsylvania, United States
  • Laffin, Luke Joseph, Cleveland Clinic Center for Clinical Research, Cleveland, Ohio, United States
  • Rajicic, Natasa, Cytel Inc, Waltham, Massachusetts, United States
  • Rodman, David M., Mineralys Therapeutics, Radnor, Pennsylvania, United States
Background

Uncontrolled and treatment-resistant hypertension are common challenges faced by clinicians. We previously reported the novel aldosterone synthase inhibitor, lorundrostat, 25mg BID, 50mg QD or 100mg QD, demonstrated median serum aldosterone reduction of 65-70% and observed mean systolic BP(SBP) reduction of -10.1, -13.2 and -14.1mmHg, respectively (n=25-28), vs placebo (-4.1 mmHg, n=29). The top quartile of the pooled group (n=81) had a median [IQR] SBP reduction of -32mmHg (n=21, [-37.5 to -27]); the bottom quartile had no change (Fig 1).

Methods

To identify predictive factors differentiating these groups, BP response to lorundrostat 100mg QD was compared in subjects with low plasma renin activity (PRA) ≤1.0ng/ml/hr vs PRA >1.0ng/ml/hr.

Results

Low PRA was not a useful predictor of response (low [n=25] -12.1 [2.68] mmHg, normal to high [n=30] -11.4 [2.48] mmHg). A correlation was observed between BMI and SBP reduction (r= -0.27, p=0.017). In the planned development doses of 50mg and 100mg QD, reduction in placebo-adjusted median (CI) SBP of -16.7 (-25.5, -7.9) mmHg and -12.3 (-21.6, -3.1) mmHg in subjects with BMI ≥30kg/m2 (n=15,12), respectively, was observed (p=0.002 and 0.030). No significant effect of lorundrostat on SBP in subjects with BMI 25-30kg/m2 (n=11,9) was seen (2.2 and -4.5 mmHg, respectively). Elevated baseline BP was similarly predictive of a favorable median SBP reduction in the 50mg and 100mg QD cohorts (lowest tertile of baseline SBP -3.5, -2.5 mmHg, highest tertile -34.3, -17.5mmHg, respectively), possibly due to the relative importance of aldosterone-mediated hypertension in obese individuals. A positive association was also observed between obesity and serum leptin at baseline (r=0.47, p<0.001).

Conclusion

While this association does not establish cause and effect, serum leptin is a direct stimulus for adrenal aldosterone production, and its investigation as a predictor of lorundrostat response warrants further investigation.

Funding

  • Commercial Support – Mineralys Therapeutics