Next-Generation PA Drugs
Aldosterone Synthase Inhibitors
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 the next couple of years, a new class of drugs that can lower aldosterone will be commercialized: aldosterone synthase inhibitors (ASIs).
Lorundrostat is a highly selective and potent aldosterone synthase inhibitor that significantly reduces plasma aldosterone levels by inhibiting the CYP11B2 pathway. A Phase 2 clinical trial was successfully completed in 2022, and a Phase 3 study is underway.
Dexfadrostat selectively inhibits the enzyme responsible for aldosterone production. A Phase 2 study was completed in 2022 that showed decreased ARR and systolic pressure.
JX09 (formally called PB6440) is a highly selective aldosterone synthase inhibitor. Preclinical data suggest very little impact on cortisol synthesis. A Phase 1 clinical trial is yet to be conducted.
Non-Steroidal Mineralocorticoid Blockers
Only two mineralocorticoid antagonists are currently available to treat primary aldosteronism: spironolactone and eplerenone. Both are steroidal drugs, and many patients do not tolerate their side effects. Non-steroidal mineralocorticoid blockers have become available since 2019. Despite offering better MR targeting with fewer side effects, none of these drugs have been studied in hyperaldosteronism, thereby perpetuating the substandard “off-label” prescribing of drugs to patients with primary aldosteronism.
A Phase 3 trial of Ocedurenone is underway in uncontrolled hypertension and advanced chronic kidney disease at 195 sites in North America, Europe, and Asia.
Safety and tolerability of Balcinrenone were established in 2017. The drug is undergoing a Phase 2 clinical trial for heart failure and kidney disease in Europe.
In July 2021, the US FDA approved Kerendia for the treatment of chronic kidney disease associated with type 2 diabetes.
Minnerbo is only available in Japan where it was approved in 2019 to treat hyperaldosteronism.
Other Aldosterone Inhibitors
Understanding of aldosterone pathophysiology considerably evolved in recent years (e.g., acknowledgement of MR expression outside of the distal nephron, acknowledgement of aldosterone synthesis occurring outside of the adrenal glands).
Investigating ways to address deficiencies in aldosterone production equally evolved. To name a few, neuropeptide substance P was found to reduce aldosterone by 30%, PCSK9 Inhibitor Evolocumab did so by 40%, and a novel atrial natriuretic peptide (ANP) analog was found to reduce aldosterone synthase. While in early stages, these investigations confirm the systemic nature of aldosterone, and the need to medically treat its excess with better targeted means than currently available.
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).