Analysis Suggests Benefits of Lorundrostat Most Apparent with Elevated BMI, Baseline Blood Pressure

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An analysis of data from the phase 2 Target-HTN trial has resulted in the identification of an endotype predictive of enhanced response to lorundrostat treatment among adults with uncontrolled or treatment-resistant hypertension.

Presented at the American Society of Nephrology Kidney Week 2023, results of the study suggest increasing BMI was linked to increased response to lorundrostat, with those in the greatest tertile of baseline blood pressure levels and elevated BMI experiencing a median reduction in systolic blood pressure of 32 mmHg.¹

“We were able to show in this post-hoc analysis additional evidence corroborating the association between BMI and blood pressure reduction with lorundrostat. Individuals trying to manage obesity and hypertension in tandem are at an increased risk for poor outcomes, and a treatment that can provide an enhanced response to this population holds great promise,” said David Rodman, MD, chief medical officer for Mineralys.²

Lorundrostat grabbed headlines in early September 2023 when results of the phase 2 Target-HTN trial were published in JAMA and presented at the 2023 American Heart Association (AHA) Hypertension Scientific Sessions. A prospective, multicenter phase 2 trial, Target-HTN was conducted at 43 sites across the US and enrolled a population of patients aged 18 years or older, with a systolic automated office blood pressure (AOBP) of 130 mmHg or greater while taking 2 or more antihypertensive medications for at least 4 weeks at maximum tolerated doses.³

The trial was designed with 2 cohorts, with those included in the initial cohort randomized to placebo or 1 of 5 dosages of lorundrostat and those included in cohort 2 randomized in a 1:6 ratio to placebo or lorundrostat 100 mg once daily.³

Among cohort 1, which included patients with suppressed plasma renin activity, changes in systolic AOBP from baseline to week 8 were −14.1, −13.2, −6.9, and −4.1 mmHg among the 100 mg, 50 mg, and 12.5 mg once daily of lorundrostat and placebo, respectively. Analysis of the twice-daily doses indicated reduction of −10.1 and −13.8 mmHg was observed for the 25 mg and 12.5 mg groups, respectively. Investigators highlighted the least-squares mean difference between placebo and treatment in systolic blood pressure was −9.6 mmHg (90% Confidence Interval [CI], −15.8 to −3.4 mmHg; P = .01) for the 50 mg once-daily dose and −7.8 mmHg (90% CI, −14.1 to −1.5 mmHg; P = .04) for 100 mg daily.³

Among cohort 2, the mean systolic blood pressure decreased by 11.4 mmHg (SD, 2.5 mmHg) with use of lorundrostat, which was similar to blood pressure reduction among participants with suppressed plasma renin activity receiving the same dose. When assessing safety outcomes, results suggested 6 participants experienced increases in serum potassium greater than 6.0 mmol/L, which was corrected with dose reduction or drug discontinuation. Additionally, there were no instances of cortisol insufficiency observed in the trial.³

At Kidney Week 2023, a team of investigators presented data from an analysis assessing the value of different predictive factors using linear regression. Factors of interest for the study included plasma renin activity, baseline BMI, and baseline blood pressure.¹

Upon analysis, investigators determined renin plasma activity was not considered a useful predictor of response. However, a correlation was observed between BMI and systolic blood pressure reduction (r= -0.27, P=.017). Further analysis of the planned development doses of 50 and 100 mg daily suggested these groups achieved a reduction in placebo-adjusted median systolic blood pressure of -16.7 (-25.5 to -7.9; P=.002) mmHg and -12.3 (-21.6 to -3.1; P=.030) mmHg, respectively, in subjects with BMI of 30kg/m2 or greater. Additional analysis suggested there was no significant effect of lorundrostat on systolic blood pressure in subjects with a BMI of 25 to 30kg/m2 (2.2 and -4.5 mmHg, respectively).¹

Investigators pointed out a statistically significant association between BMI and reduction in systolic blood pressure in subjects with a BMI ranging from 22.5 to 40kg/m2. According to investigators, elevated baseline blood pressure was similarly predictive of a favorable median systolic blood pressure reduction in the 50mg and 100 mg once daily cohorts, with the lowest tertile of baseline systolic blood pressure experiencing reductions of-3.5 and -2.5 mmHg, respectively, and the highest tertile experiencing reductions of -34.3 and -17.5mmHg, respectively. Investigators suggested this was possibly due to the relative importance of aldosterone-mediated hypertension in obese individuals. Additionally, a positive association was also observed between obesity and serum leptin at baseline (r=0.47; P <.001).¹

“We continue to believe that we’re entering a precision-medicine era when it comes to hypertension treatments – an era in which physicians can identify and confidently prescribe an anti-hypertensive treatment for each patient according to their underlying biological factors, such as obese individuals with aldosterone-dependent hypertension,” Rodman added.²

References:

1. Cizman B, Laffin LJ, Rajicic N, Rodman DM. Identification of a Hypertensive Endotype with a Median Treatment Effect of -32mmHg in Response to the Novel Aldosterone Synthase Inhibitor Lorundrostat. Paper Presented at: American Society of Nephrology Kidney Week 2023. November 1-5, 2023.
2. Mineralys Therapeutics presents new post-hoc analysis from Target-HTN Phase 2 trial of Lorundrostat in late-breaking poster session at ASN Kidney Week 2023 meeting. Mineralys Therapeutics, Inc. November 2, 2023. Accessed November 2, 2023. https://ir.mineralystx.com/news-events/press-releases/detail/31/mineralys-therapeutics-presents-new-post-hoc-analysis-from.
3. Laffin LJ, Rodman D, Luther JM, et al. Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension: The Target-HTN Randomized Clinical Trial. JAMA. 2023;330(12):1140–1150. doi:10.1001/jama.2023.16029