Next-Generation PA Drugs
For the first time since the discovery of primary aldosteronism over 60 years ago, advances in medical treatment are about to become reality for millions of patients worldwide. In coming years, a new class of drugs (aldosterone synthase inhibitors) will achieve a goal that, until now, has remained out of reach: lowering aldosterone levels. Additionally, three non-steroidal mineralocorticoid blockers hold the potential of improved ways to manage the effects of elevated aldosterone compared with the only two steroidal antagonists currently available (i.e., Spironolactone and Eplerenone).
Aldosterone Synthase Inhibitors
MLS-101 is a highly selective and potent aldosterone synthase inhibitor that significantly reduces plasma aldosterone levels by inhibiting the CYP11B2 pathway without effecting other hormones like cortisol.
In a Phase 1 study in healthy volunteers, MLS-101 demonstrated a safe and tolerable profile while selectively reducing aldosterone.
A multi-site Phase 2 proof-of-concept study of MLS-101 is currently underway in the US.
CIN-107 is a highly selective aldosterone synthase inhibitor, which impedes the enzyme responsible for the synthesis of aldosterone.
Phase 1 single ascending dose clinical study established that the drug is well tolerated, and demonstrated specificity for aldosterone inhibition with significant dose-dependent aldosterone lowering effect.
CIN-107 is undergoing Phase 2 clinical study across the US to determine dose selection.
PB6440 is a highly potent and selective inhibitor of aldosterone synthase that has demonstrated dose-dependent aldosterone reduction without significant increase in 11-deoxycorticosterone or deoxycortisol in both rodent and primate models.
No evidence of toxicity has been observed, and pharmacokinetic profiles are deemed suitable for once-daily dosing in humans. The first in-human clinical trial of BP6440 will be initiated in 2022.
Acknowledging that Spironolactone and Eplerenone cause further aldosterone activity via non-MR mechanisms, Angion is leveraging its extensive experience with cytochrome P450 modulators to develop compounds with improved specificity for CYP11B2 relative to CYP11B1.
In non-human primate models, one such compound markedly reduced aldosterone production with minimal impact on cortisol production following ACTH challenge.
Non-Steroidal Mineralocorticoid Blockers
KBP-5074 has a longer half-life and increased MR affinity than current MRAs. Phase 2 studies confirmed its efficacy and tolerability. Phase 3 trial has started and is expected to be extended to 156 sites in North America, Europe and Asia.
Esaxerenone (MINNEBRO™) received marketing approval in January 2019 in Japan where the drug is used to treat patients with primary aldosteronism. In the absence of worldwide licensing agreements, the drug is not made available outside of Japan.
In July 2021, the US FDA approved Finerenone (KERENDIA™) for the treatment of patients with chronic kidney disease associated with type 2 diabetes. Despite better MR targeting than current MRAs, Finerenone was not studied in primary aldosteronism.
Sign Our Open Letter
Spironolactone and Eplerenone were not adopted for treatment of primary aldosteronism based on evidence from rigorous clinical trials. Instead, the use of the drugs relies on secondary data gathered from widespread off-label prescribing. This substandard practice lacks the quality and safety granted to any new medication, and is once again bound to prevail with non-steroidal mineralocorticoid blockers.
We invite you, your friends, and family members to sign the Foundation’s Open Letter to request the inclusion of patients with primary aldosteronism in clinical trials of all drugs targeting excess aldosterone, as opposed to limiting their study and approval to conditions present in more advanced stages of the disease (e.g., diabetes, kidney disease).