038: Lorundrostat Concentration-QTc Results from the First-in-Human Study in Healthy Participants Demonstrate Lack of Relevant Effect & Replaces the Thorough QT Study

Statement of Purpose, Innovation or Hypothesis: Lorundrostat is a selective inhibitor of aldosterone synthase (CYP11B2) that causes suppression of aldosterone production. Safety pharmacology studies included a test of human ether-a-go-go-related gene (hERG) channel inhibition. As part of its First-in-Human (FiH) trial, a cardiodynamic evaluation was performed after single and multiple ascending doses (SAD and MAD) of lorundrostat with the objective to evaluate the effect of lorundrostat on electrocardiogram (ECG) parameters, including the QTc interval.

Description of Methods & Materials: The hERG assay was conducted in HEK-293 cells. The cardiodynamic evaluation was performed in the SAD and MAD parts of the FiH study in healthy male participants. Doses in the SAD ranged from 5 to 800 mg and from 40, 120 and 340 mg daily for 7 days in the MAD. Serial ECGs were extracted from continuous ECG recordings (Holters) at pre-specified time points that were matched with PK blood collection through 24 hours post-dose on Day 1 in the SAD and on Day 1 and Day 7 in the MAD. The primary analysis was concentration–QTc analysis with change-from-baseline QTcF (∆QTcF) as the dependent variable, lorundrostat concentration as the explanatory variate, treatment and time as fixed effects. The secondary analysis was a by-timepoint analysis using a mixed model for repeated measures with ∆QTcF as the dependent variable and time, treatment, and time-by-treatment interaction as fixed effects. In addition, a categorical analysis was performed for the SAD and MAD, separately.

Data & Results: Lorundrostat weakly inhibited hERG with a half-maximal inhibitory concentration (IC50) of 95.4 µmol/L. In the SAD, the estimated slope of lorundrostat plasma concentration in the concentration-QTc relationship was shallow, slightly positive, and statistically significant (0.00061 ms per ng/mL [90% CI: 0.00004, 0.00118]) with a non-statistically significant treatment effect-specific intercept of 0.77 ms. The effect on placebo-corrected ΔQTcF can be predicted to 3.43 ms (90% CI: 0.56, 6.30) and 5.14 ms (90% CI: 0.96, 9.33) at the geometric mean C_max in the 400 mg (4388 ng/mL) and 800 mg (7205 ng/mL) dose groups, respectively. In the MAD, the estimated slope of lorundrostat plasma concentration in the concentration-QTc relationship was also very shallow, slightly positive and statistically significant (0.00088 ms per ng/mL [90% CI: 0.00017, 0.00159]) with a large and statistically significant treatment effect-specific intercept of -5.29 ms. In the by-timepoint analysis, lorundrostat at the studied doses did not have a clinically relevant effect on the QTc interval or other ECG parameters. Based on the concentration-QTc analysis, an effect of lorundrostat on placebo-corrected ΔQTcF >10 ms can be excluded for a lorundrostat plasma concentration of up to approximately 7800 ng/mL, which is 4.8-fold higher than the predicted C_max at maximum clinical efficacious dosage of 100 mg once-daily, and also higher than the high clinical exposure scenario (~1.2-fold increase in C_max) when lorundrostat is given with strong CYP3A4 inhibitors.

Interpretation, Conclusion or Significance: These results demonstrate that the plasma exposure from the maximum planned lorundrostat dosage of 100 mg once-daily, and exposure up to 4.8-fold higher, will not prolong the QTc interval. Based on these data, the FDA has granted a waiver for the thorough QT study.

Disclosures: Tortorici MA is an employee of Mineralys Therapeutics, Inc. Darpo B is Chief Scientific Officer, Cardiac Safety at Clario and owns stock and holds stock options for Clario. Xue H is an employee of Clario. Smith S is a consultant for Mineralys Therapeutics, Inc. Rodman DA is an employee of Mineralys Therapeutics, Inc.

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Additional Information/Authors: None