Aldosterone synthase

Lorundrostat selectively inhibits human CYP11B2 (IC50 = 9 nM), reduces plasma aldosterone and systolic blood pressure, and can be used for research on obesity- or renin-induced hypertension.

Between July 2021 and June 2022, 200 participants were randomized, with final follow-up in September 2022. Following 8 weeks of treatment in participants with suppressed PRA, changes in office systolic blood pressure of -14.1, -13.2, -6.9, and -4.1 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once daily of lorundrostat and placebo, respectively. Observed reductions in systolic blood pressure in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were -10.1 and -13.8 mm Hg, respectively. The least-squares mean difference between placebo and treatment in systolic blood pressure was -9.6 mm Hg (90% CI, -15.8 to -3.4 mm Hg; P = .01) for the 50-mg once-daily dose and -7.8 mm Hg (90% CI, -14.1 to -1.5 mm Hg; P = .04) for 100 mg daily. Among participants without suppressed PRA, 100 mg once daily of lorundrostat decreased systolic blood pressure by 11.4 mm Hg (SD, 2.5 mm Hg), which was similar to blood pressure reduction among participants with suppressed PRA receiving the same dose. Six participants had increases in serum potassium above 6.0 mmol/L that corrected with dose reduction or drug discontinuation. No instances of cortisol insufficiency occurred. Conclusions and relevance: Among individuals with uncontrolled hypertension, use of lorundrostat was effective at lowering blood pressure compared with placebo, which will require further confirmatory studies [2].

Study Procedures [2]
Participants underwent 2 to 4 weeks of prescreening, a 2-week placebo run-in period to ensure eligibility, and then randomization and treatment for 8 weeks. A final visit was conducted 2 to 4 weeks following completion of the double-blind treatment (eFigure 1 in Supplement 2). Cohort 1 participants were randomly assigned in a 1:1:1:1:1:1 ratio to placebo or 1 of 5 lorundrostat doses (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily). An independent data and safety monitoring board performed an interim analysis in January 2022, and randomization to the 2 lowest doses of lorundrostat (12.5 mg once daily and 12.5 mg twice daily) was discontinued due to lack of consistent meaningful reduction of BP. A second cohort randomized participants to placebo or 100 mg once daily of lorundrostat in a 1:6 ratio. An additional interim analysis was performed following the last participant visit from cohort 1 and full enrollment of cohort 2 to guide dose selection in future studies. Following randomization, all participants’ study visits were conducted at weeks 1 through 8. Efficacy assessment with AOBP (average of the last 2 of 5 unattended measurements using an automated oscillometric sphygmomanometer device after approximately 5 minutes of rest in a seated position) was measured weekly throughout the study. Twenty-four-hour ambulatory BP monitoring was measured at baseline and once again prior to the 8-week visit.

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Sample Size Calculation and Power [2]
The study was designed to provide information regarding a safe and effective dose of lorundrostat for subsequent efficacy trials. The sample size was based on the point and interval estimation of the difference in means between each dose group and placebo in change from baseline at week 8 in systolic AOBP. A sample size of 30 participants per group was estimated to provide the half-width of the 2-sided 90% CI of 3.8 mm Hg with a common standard deviation assumed to be 9 mm Hg. This was considered to have adequate precision to guide the evaluation of systolic BP changes across different dose levels for selection of doses and regimens to be investigated in future studies. All analyses of cohort 2 of the study were exploratory in nature, and no formal sample size considerations were undertaken for this cohort.

Safety endpoints [2] No deaths occurred during the trial. Three serious adverse events occurred; only one of which was considered treatment-related. A subject in Group 2 who was randomly assigned to receive 100 mg lorundrostat once daily experienced worsening hyponatremia and had to discontinue the drug. A total of 110 subjects (55%) experienced adverse events during the trial (Table 3). Most adverse events were assessed as mild by the investigators. No adrenocortical insufficiency occurred during the trial. The corticotropin stimulation test results of subjects in Groups 1 and 2 who were randomly assigned to receive 100 mg lorundrostat once daily were normal, and all subjects receiving corticotropin therapy had cortisol stimulation values greater than 18 µg/dL (eFigure 4 in Supplementary Material 2). Pre-specified adverse events of particular concern included hypotension in 3 subjects (2%). The mean increase in serum potassium was similar across the dose groups, with an increase of 0.25 mmol/L in both the 50 mg and 100 mg once daily groups. During the trial, serum potassium levels were higher than 6.0 mmol/L in 6 subjects (3.6%) (Table 3). No interventions other than discontinuation of the drug or reduction of the lorendsat dose were required for any of the cases of hyperkalemia.

[1]. International Nonproprietary Names for Pharmaceutical Substances (INN). WHO Drug Information, Vol. 36, No. 2, 2022.

[2]. Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension: The Target-HTN Randomized Clinical Trial. JAMA. 2023 Sep 26;330(12):1140-1150.

Importance: Excessive aldosterone production is a common pathogenic factor in classic aldosteronism and obesity-related hypertension. Therapies that inhibit aldosterone synthesis may lower blood pressure. Objective: To compare the safety and efficacy of the aldosterone synthase inhibitor lorendestat versus placebo, and to analyze its dose-dependent safety and efficacy to guide dose selection for future trials. Design, Location, and Participants: A randomized, placebo-controlled, dose-range trial enrolled adults with hypertension who were taking two or more antihypertensive medications and whose blood pressure was poorly controlled. Initially, 163 participants with plasma renin activity (PRA) ≤1.0 ng/mL/h and elevated plasma aldosterone levels (≥1.0 ng/dL) were enrolled, followed by 37 participants with PRA >1.0 ng/mL/h. Intervention: In the initial cohort, participants were randomized to either placebo or one of five different doses of lorendestat (12.5 mg, 50 mg, or 100 mg once daily, or 12.5 mg or 25 mg twice daily). In the second cohort, participants were randomly assigned in a 1:6 ratio to either the placebo group or the lorendestat group (100 mg once daily). Primary outcome: The primary endpoint was the change in autologous systolic blood pressure from baseline to week 8 of the study. [2]

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Both 50 mg and 100 mg of lorendestat once daily significantly reduced autologous systolic blood pressure, superior to placebo. The reduction in blood pressure was particularly pronounced in participants with hypertension and obesity. Lorendestat was well tolerated, with a slight increase in serum potassium and a slight decrease in eGFR expected, suggesting a good safety profile, especially at the 50 mg once daily dose. The results support further investigation of lorendestat as a treatment for refractory hypertension. [1]

C24H33N7O2

451.564524412155

451.269

C, 63.84; H, 7.37; N, 21.71; O, 7.09

1820940-17-7

126567187

Light yellow to yellow solid powder

1.5

2

7

6

33

639

0

N1(CC(N[C@@H]2CC[C@@H](NC(C)=O)CC2)=O)CCN(C2=NC(C3=CC=C(C)C=C3)=CN=N2)CC1

YHGVDZULVMINCJ-UHFFFAOYSA-N

InChI=1S/C24H33N7O2/c1-17-3-5-19(6-4-17)22-15-25-29-24(28-22)31-13-11-30(12-14-31)16-23(33)27-21-9-7-20(8-10-21)26-18(2)32/h3-6,15,20-21H,7-14,16H2,1-2H3,(H,26,32)(H,27,33)

N-(4-acetamidocyclohexyl)-2-[4-[5-(4-methylphenyl)-1,2,4-triazin-3-yl]piperazin-1-yl]acetamide

Lorundrostat; 1820940-17-7; Lorundrostat [INN]; KA8W5LDS6Z; UNII-KA8W5LDS6Z; 1-Piperazineacetamide, N-(trans-4-(acetylamino)cyclohexyl)-4-(5-(4-methylphenyl)-1,2,4-triazin-3-yl)-; N-(trans-4-(Acetylamino)cyclohexyl)-4-(5-(4-methylphenyl)-1,2,4-triazin-3-yl)-1-piperazineacetamide; N-(trans-4-Acetamidocyclohexyl)-2-(4-(5-(4- methylphenyl)-1,2,4-triazin-3-yl)piperazin-1- yl)acetamide;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~33.33 mg/mL (~73.81 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.54 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.54 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)