Lorundrostat in Participants With Uncontrolled Hypertension and Treatment-Resistant Hypertension
Manish Saxena, Luke Laffin, Claudio Borghi, Beatriz Fernandez Fernandez, Jalal K. Ghali, Branko Kopjar, Krishna Polu, Simon D. Roger, B. T. Slingsby, Frank Strutz, Liffert Vogt, Matthew R. Weir, David Rodman, , John Mark Joyce, Nandita Jones, Sujeeta Dhakhwa, Susan Angel, Fadi Chalhoub, Leticia Goodwin, Tatyana Miroshnikova, Patricia Ann W. Brown, Robert Molpus, Felipe Suplicy, Beckie Klipper, Keung Lee, Andrew Chow, Karla Alfonsin, Becky Hogan, Lon Lynn, Paul Lunseth, Alexandra Lynch, Andres Patron, George Kaleel Rafeedie, Marilyn Patron, Igor Lukianov, George Rafeedie, John David Lentz, Luis A. Diaz-Secades, Esmil Perez, Damarys Sacasa, Leticia Jimenez, Yadiel Sanchez, Atul Chugh, Jai Radhakrishnan, Vijay U. Rao, Kaitlin E. Ziedonis, Ayanna Guzman-Nguyen, Lora McGill, Lisa S. Usdan, Valerie K. Arnold, Carolyn J. Scatamacchia, Keerthi G. Heckle, Codi Anthony, Melissa Flowers, Henry Punzi, Kathy Cassidy, Waymon Drummond, John Flack, Farrell Mendelsohn, James Powell, Hunter Coore, Nakeydia Bryant, Farah Madhani-Lovely, Sujatha Pitani, Angela Dunlap, Amanda Merlino, Alexis Steele-Griffen, Charles Crump, Scott Harnsberger, Alexander White, Richard Marshall, Bhanu Visvalingam, Viviana Hargis, Richard Mohammed, Nora Borello, Joseph Soufer, Malgorzata Chustecka, Jillian Reid, Amanda Pacheco, Nashwa Gabra, Magda Hanna, Josefina Manalo, Roccio Harbison, Reshma Markan, Lianette Ramos, Carl Diener, Vicki Kalen, Enrique Murrieta Cifuentes, Shawn G. Platt, Carly Widup, Nayeli Lopez, Dilwar Ajani, Caroline Mbogua, Minhas Ladiwala, Daniela Oviedo, Leonel Reyes, MD Reyes, Carl E. Dukes, Pragati Choudhary, Michael Dunn, Ronald Anderson, Ariana Bauer, Brian Hollis, Alexandra Suslow, Melissa Frampton, Antonio Mendes, Tara Strandwitz, Sonia Thompson, Michael McCartney, Marc Shay, MaryBeth Sampson, Joanne Monaghan, Madeline Puracchio, Adam Tanzer, Michael J. McCartney, Deborah Green-LaRoche, Christa Riekert, Ramana Puppala, Marshall Nash, Ambreen Hamid, Arvind Krishna, Hedi Daugherty, Erica Ness, Manuchehr Darani, Ashley Duzik, Hikyhe Ogannesian, Claire Presswood, Elias Siraj, Barbara Rizzardi, Vanesa Abad, Ashlee Wright, Deirdre McMullen, Hilary Spears, Graciela Lopez, Kenneth Maynard, Arundathi Prasad, Annie Raphael, William Ross Davis, Jaynier Moya Hechevarria, Jayler Valde Hechevarria, Ronoel Penalver, Mariela Manzanares Angulo, Yuniarka Garcia, Marwan Kaskas, Sreedhara B. Alla, Yeona DaCosta Auld, Mary Lawrence, Sabrina Boyte, Martyna Lopez, Yogesh Paliwal, Amit Paliwal, Mia Curtis, Sarah Gordon, Yebin Kwon, Bassel Ashouri, Nidal Morrar, Geoffrey Lipscomb, Christine Fuller, Stanley Koch, Mary Imig, Sarah Wildenradt, Heather Akins, Adam Kaplan, Angelique Ferraris, Maurie Tarlac, David DeAtkine, Michael Adams, Margarita Nunez, David Estes, Dionne Clarke, Mohammed Allaw, Chelsea Miles, Melody Werne, Joseph Newburg, Laura Pearlman, Steven Rutter, Jacquilyn McCormick, Aamir Jamal, Dayan Gandhi, Rajan Sibu, Brandon Bonilla, Steven Cox, Shanda Gower, Angela Genovese, Sharee Wright, Samantha Ting, Nelson P. Kopyt, Jennifer Bashour, Debbie Bridges, Cristina Puig, Angela Okolie, Elisa Swieboda, Stephanie Smith, Akber Safder, Beatriz Colon, Anand Irimpen, Mark Warren, Regina Dodis, Matthew Hager, Tonni Gortman, Mohan Kesani, Carol M. Budgin, Holly Mechling, Adam Karns, Sarom Hong, Edith Sisneros, Vishweshwar Ranga, Maya Pudi, Ahmed Awad, William Smith, Kristin Morgan, Jody Mahan, Robert Noveck, Lauren Degregoria, Tabitha Gray, Ronald Stumbris, Taran Parmar, Paul Beckett, Gary Soucie, Berta Bates, Jerry Punch, Richard Gibson, Jennifer Winbigler, Elizabeth Parker, Hunter Cooper, Savannah Kidd, Linda Carol Johnson, Oscar Linn, Stephee Haun, Cyndi Puckett, Larry Reed, Mavis Matsumoto, Julie Braun, Krishanthi Jayathilaka, Jennifer Hines, Ramy Joseph Toma, Samantha Williams, Meghan Golson, William Kirby, Jazmine Henry, Adrienne Baltscheit, Harold Bays, Taylor Codey, Barbara Ritchey, David Liljenquist, Anil Chhabra, Michael Gates, Sarah Dobrosky, John Hanley, Rani Ramsey Rabah, Audrey Jones, Paul Hartley, Kenneth S. Hershon, Dennis Lewis, Clarisa Baltazar, Billy Hour, Veronica Macias, Citlali Garcia, Pascal Dabel, Jehad Haggiagi, Jocelyn Marin, Jose Cardona, Evelio H. Sosa, Rainer Pacheco, Brian MacGillivray, Randall H. Schuster, Abha Gyani, Gary L. Boyd, Heather Miller, Norma Saenz, Pink L. Folmar, Hayes T. Williams, Latorya Franks, Faheem Shaikh, Deidra Meredith, Tzu-Jen Tzao, Gee Perez, Jeffrey Wayne, Esther Gayoba, Tammy Ward, Jalal Ghali, Olusola Gbinigie, Rambod Rouhbakhshh, John Johnson, Tameka Fortune, Robert Brahan, Leah Prentiss, David Butuk, Janelle Poole, Scott Frisby, Taylor Conrad, Carlos Sariol-Curbelo, Neira I. Segarra-Ortiz, Nestor Gonzalez, Jennifer Ringrose, Stephen S. Chow, Ronald Ahkras, Richard Assef, Elise Irani, Anthony A. Olofintuyi, Mary Macleod, German Guzman Gutierrez, David Counter, Sandra Williams, Manish Saxena, David Collier, Armida Balawon, Francis Galera, Arooj Ayub, Maryam Butt, Munirah Islam, Rahat Uddin, Joseph Cheriyan, Spoorthy Kulkarni, James Goodman, Pablo Kostelec, Sahan Mendis, Cong Ying Hey, Sarah Rayne, Richard Gaunt, Christine Voss, Teresa Connolly, Indranil Dasgupta, Pauline Swift, Rebecca Suckling, Mona Wahba, Laijee Benny, Paula-Jane Marrett, Michael Waldron, Jan Knobloch, Ronan Sheehan, Maisie Rowe, Syazrah Salam, Nicholas Jacobsen, Rutesh Patel, Linsay McCallum, Bryony Martin, Maggie Rostron, Ramandeep Gill, Hayley King, Jonathan Garstang, Simon Macartney, Sally Feltham, Timothy Doulton, Lawrence Barnes, Susan Keast, Robert Allen, Nicola Donlin, Ruth Graham, Andreas Hajineocli, Dominique Stephan, Antoine Cremer, Christophe Mariat, Benoit Franko, Maizé Ducret, Etienne Cellot, Déborah Chaintreuil, Antoine Metzger, Ivona Milic, Isabelle Rey, Mathilde Pibarot, Sandra Jost-Turillot, Blandine Lafitte, Olivier Moranne, Kerstin Sturm, Peter Klaus Hahn, Sascha Öhm, Suganthi Luci Magimaiseelan, Saskia Kerschischnik, Peter Heymer, Jan Winkler, Andrea Günzel, Lars Raddatz, Nadine Voß, Markus van der Giet, Alla Reimer, Khalida Sidigy, Jan Wagner, Annette Weerda, Belinda Ehrhardt, Ulrike Rudolph, Rolf Wachter, Franziska Loricke, Thomas Jung, Nikolaus Jung, Anja Kruszek, Andreas Pfuetzner, Karl Fengler, Anna Oliveras i Serrano, Fernando Jaen Aguila, Jose Ramon Gonzalez Juanatey, Pilar Mazón Ramos, Diego Iglesias Álvarez, José Seijas Amigo, Fernando Martínez García, Maria Jose Forner, Alba Morales Cano, Nicolas Roberto Robles Pérez-Monteoliva, Alvaro Alvarez Lopez, Juan Villa Rincon, Rafael Santamaria Olmo, Maria Victoria Pendón Ruiz de Mier, Ana Isabel Robles, Cristian Rodelo, Isabel Lopez, Maria Victoria Pendon, Andrés Carmona, Alberto Ortiz Arduan, Nieves Martell Claros, Egidio Imbalzano, Aurora Lo Porto, Marianna Chiappalone, Massimo Volpe, Luana Orlanda, Marianna Gigliotti De Fazio, Cristina Panico, Giuliano Tocci, Giulia Nardoianni, Giovanni Marco Dutti, Emanuele Barbato, Marco Russo, Gianluca Campo, Marta Belmonte, Maria Lorenza Muiesan, Paolo Cimaglia, Matteo Serenelli, Elisa Mosele, Giuseppe Boriani, Riccardo Sarzani, Agostino Virdis, Davide Matteo Maremmani, Ferdinando De Negri, Elisabetta Fini, Giovanni Gori, Elisa Iacopini, Guido Iaccarino, Francesca Viazzi, Lucia Macciò, Michela Piaggio, Giuseppe Chirco, Rita Del Pinto, Alessandro Maloberti, Amedeo Mugellini, Claudio Borghi, Arrigo F.G. Cicero, Davide Agnoletti, Federica Piani, Gianluca Rubini, Chiara Grassi, Federica Fogacci, Maurizio Volterrani, Jaap Deinum, Liffert Vogt, Wafa Karar, Marlon van de Putte, Wilko Spiering, Simone C.C. Hartong, Ralitsa Pancheva, Iskren Garvanski, Goritsa Borisova, Nikolay Iliev, Krasimira Tsoneva, Daniel Trendafilov, Mariya Tsvetkova, Ivan Denev, Miroslav Stoyanov, Daniel Lyubenov, Borislav Borisov, Marieta Hristova, Vladmir Zhelev, Ivaylo Ivanov, Vladimir Ivanov, Kremena Kancheva, Kiril Petrov, Gabriela Tseneva, Barbara Rewerska, Maciej Podziewski, Artur Artemuk, Ewa Satora, Iwona Chrostek, Grzegorz Skoczylas, Stanisław Pilowski, Dominika Oszejko, Grzegorz Kania, Maciej Kania, Ewa Okonska-Jagoda, Milena Guz-Kawka, Agata Kuziemska, Justyna Pedowska-Wloszek, Joanna Dziuda, Aleksandra Rosiak-Kawka, Anna Foder, Maciej Żechowicz, Paulina Nowek, Marta Drankowska-Bendorf, Michał Smoliński, Wioletta Żechowicz, Marek Konieczny, Jolanta Kitowska-Koterla, Katarzyna Bartnicka-Maslowska, Maciej Kotwica, Andrzej Bissinger, Magdalena Olszewska -Jander, Beata Wojciechowska, Joanna Szczepankowska, Andrzej Wiecek, Agata Kujawa-Szewieczek, Natalia Slabiak-Blaz, Theodora Mariana Nicoleta Benedek, Codrut Ioan Ciurea, Raluca Maria Laculiceanu, Raluca Elena Ouatu, Stefan Dan Cezar Mot, Minodora Andor, Valentina Gabriela Ciobotaru, Elena Divna Muresan, Cristiana Bustea, Mihaela Viviana Ivan, Adrian Apostol, Carina Bogdan, Oana Sandu, Petru Marius Turcan, Tiberiu Liviu Dragomir, Andreea Rachieru, Olguta Octavia Vasile, Gabriela Palade, Elisabeta Badila, Cristina Florescu, Petre Ciobanu, Simona Daniela Neamtu, Alina Mariana Paraschiv, Ranjit (Roy) Rasalam, Munro Neville, Victoria Husk, Rebecca Waterfield, Shelley Westgarth-Nugent, Markus Schlaich, Sayeh Heidari Nejad, Damon Bell, Omar Azzam, Apreesh Sharma, Anu Joyson, Simon Roger, Viduranga Wijeratne, Ferdinandus De Looze, Eniko Ujvary, Ian Wong, Leonie Kelly, Kristi McLendon, Peter Hay, Andrew Hung, James Bennett, Elijah McKee, Nathan Dwyer, Christopher Levi, Thomas Polasek, Michael Harrison, Robert Scott, Stephanie Wallace, Amy Morrison, Alan Parnham, Jagadeesh Kurtkoti, Yusuf Eqbal, Bianca Garcia, Elif Ilhan Ekinci, Nupoor Tomar, Frank Gao, Cecila Pham, Alexander Yao, Jasmin Seah, Tania RedmanImportance
Uncontrolled hypertension remains a global health concern and dysregulated aldosterone production is a central mechanism. Lorundrostat, a novel aldosterone synthase inhibitor that reduces aldosterone production, demonstrated efficacy in participants with uncontrolled hypertension, including those with treatment-resistant hypertension.
Objective
To evaluate the efficacy and safety of lorundrostat for lowering blood pressure (BP) when added to a prescribed regimen of 2 to 5 antihypertensive medications in adults with uncontrolled hypertension and treatment-resistant hypertension.
Design, Setting, and Participants
In this phase 3, randomized clinical trial, adults with uncontrolled hypertension, including those with treatment-resistant hypertension, were enrolled between November 2023 and September 2024 at 159 clinic sites across 13 countries. The last date of follow-up was January 24, 2025.
Intervention
Randomization ratio of 1:2:1 to 50 mg/d of lorundrostat for 6 weeks followed by 100 mg/d of lorundrostat for 6 weeks (n = 270) if they met prespecified criteria, 50 mg/d of lorundrostat for 12 weeks (n = 541), or daily placebo for 12 weeks (n = 272). The prespecified criteria included systolic BP of 130 mm Hg or greater, potassium level of 4.8 mmol/L or less, sodium level of 135 mmol/L or greater, an estimated glomerular filtration rate (eGFR) of greater than 45 mL/min/1.73 m2, and less than a 25% reduction in eGFR.
Main Outcome and Measures
The primary outcome was change in automated office systolic BP at week 6 for participants randomized to 50 mg of lorundrostat vs placebo. Adverse events of special interest included dose reduction, interruption, or discontinuation due to events such as hyperkalemia, hyponatremia, and reduction in kidney function.
Results
Of the 1083 participants, the mean age was 61.6 years (SD, 10.3 years), 508 (46.9%) were female, 311 (28.7%) were Black or African American, 733 (67.7%) were White, and 685 (63.3%) had a body mass index of 30 or greater (obesity). At randomization, 432 participants (39.9%) were taking 2 prescribed antihypertensive medications and 651 (60.1%) were taking 3 or more. For the pooled 50 mg of lorundrostat group (n = 808), the least-squares mean change in automated office systolic BP at week 6 was −16.9 mm Hg (95% CI, −19.0 to −14.9 mm Hg) vs −7.9 mm Hg (95% CI, −11.5 to −4.2 mm Hg) for the placebo group (least-squares mean difference, −9.1 mm Hg [95% CI, −13.3 to −4.9 mm Hg]; P < .001). Hyponatremia, hyperkalemia, and reduction in kidney function were reported more often with lorundrostat vs placebo. In the 50 mg of lorundrostat group with possible escalation to 100 mg, treatment discontinuation occurred in 1 participant (0.37%) due to hyperkalemia, in 1 (0.37%) due to hyponatremia, and in 0 due to reduction in kidney function. In the 50 mg of lorundrostat group, treatment discontinuation occurred in 2 participants (0.37%) due to hyperkalemia, in 2 (0.37%) due to hyponatremia, and in 3 (0.56%) due to reduction in kidney function. Treatment-emergent adverse events occurred in 49.9% of participants (538/1078) and were mostly mild or moderate in severity.
Conclusions and Relevance
The efficacy and safety of lorundrostat, an aldosterone synthase inhibitor, was demonstrated for lowering BP in adults with uncontrolled hypertension, including those with treatment-resistant hypertension.
Trial Registration
ClinicalTrials.gov Identifier: