Lorundrostat shows promise as novel agent for uncontrolled HTN cases

Mineralocorticoid receptor antagonists (MRAs) have been conventionally used in cases of resistant hypertension but the antiandrogenic- and progestogenic-related adverse effects are common barriers to wider MRA use. In the recently published Target-HTN Randomized Clinical Trial, a novel aldosterone synthase inhibitor Lorundrostat has shown promise for the management of resistant hypertension and is expected to broaden the future horizon of aldosterone antagonism in the management of hypertension.

To compare the safety and efficacy of lorundrostat, 200 participants taking >/= 2 antihypertensive drugs were enrolled. Out of them, first cohort of 163 patients had suppressed plasma renin (plasma renin activity [PRA] ≤1.0 ng/mL/h) and elevated plasma aldosterone (≥1.0 ng/dL). The second cohort had 37 participants with PRA greater than 1.0 ng/mL/h.

Participants were randomized to placebo or 1 of 5 dosages of lorundrostat in the initial cohort (12.5 mg-100 mg once daily or 12.5 mg or 25 mg twice daily). In the second cohort, participants were randomized in a 1:6 ratio to placebo or lorundrostat, 100 mg once daily.

The primary outcome showed that 8 weeks after adding lorundrostat or placebo to background therapy, lorundrostat, 50 mg once daily or 100 mg once daily, lowered seated automated office systolic blood pressure significantly more than placebo.

Also, the reduction in 24-hour ambulatory systolic blood pressure appeared to show a dose response from 12.5 mg once daily to 100 mg once daily.

Safety aspects:

Consistent with its high selectivity for aldosterone synthase, there was no signal of an effect of this novel drug on cortisol synthesis. As a consequence of inhibiting aldosterone synthesis, as expected, serum potassium levels increased with lorundrostat treatment, with 6 patients developing potassium levels above 6 mmol/L, each requiring dose reduction or drug withdrawal.

Further analyzing the results in an accompanying editorial, Bryan Williams, M.D., notes “the placebo-corrected systolic blood pressure response to lorundrostat in patients receiving background thiazide diuretic therapy (55%-60%) appeared to be more than twice that seen in those not receiving diuretic therapy. This supports the concept that uncontrolled hypertension is often a sodium-retaining state, requiring dual diuretic therapy to optimize the blood pressure response in such patients”.

He further adds, “almost half of the patients (48%) in this study would be classified as obese (body mass index >30), and the systolic blood pressure response in these patients appeared to be more than twice that in those who had a body mass index of 30 or lower. This is consistent with evidence suggesting that obesity is associated with relative aldosterone excess and sodium retention.”

To conclude, among individuals with uncontrolled hypertension, use of lorundrostat was effective at lowering blood pressure compared with placebo, which will require further confirmatory studies.

Source: JAMA Cardiology: doi:10.1001/jama.2023.17087, doi:10.1001/jama.2023.16029