KARDINAL: Monthly Tonlamarsen May Not Enhance BP Lowering in Resistant Hypertension

In a phase II trial dubbed KARDINAL, monthly injections of the angiotensinogen‑targeted antisense oligonucleotide tonlamarsen (developed by Kardigan) significantly suppressed plasma angiotensinogen (AGT) but did not further improve blood pressure (BP) lowering compared with a single dose in patients with resistant or uncontrolled hypertension already on multiple antihypertensive drugs. The findings, presented at the American College of Cardiology (ACC) 2026 Scientific Session and published in JACC, highlight both the promise and the limitations of targeting hepatic AGT production in the renin‑angiotensin‑aldosterone system (RAAS).

Key KARDINAL results

The KARDINAL trial enrolled adults with an office systolic BP > 135 mm Hg despite being on two to five antihypertensive medications, including ACE inhibitors and angiotensin receptor blockers (ARBs) in over 80% of participants. After a placebo lead‑in and active run‑in with a single subcutaneous 90‑mg injection of tonlamarsen, patients were randomized to either four additional monthly doses or matching placebo over 16 weeks (total 20‑week follow‑up).

The primary endpoints were change from baseline to week 20 in plasma AGT and clinic‑measured systolic BP. While monthly dosing drove a substantially greater decrease in AGT (−67.2% vs −23.0% with a single dose, P < 0.0001), the least‑squares mean reduction in office systolic BP was nearly identical between groups (approximately −6.7 mm Hg), with no statistically significant difference (P = 0.97).

Clinical implications and expert commentary

Lead investigator Luke J. Laffin, MD, emphasized that tonlamarsen suppresses hepatic angiotensinogen production, yet the trial suggests that residual AGT suppression and background RAAS inhibition may blunt any incremental BP benefit from repeated dosing. Daniel W. Jones, MD, a past president of the American Heart Association (AHA) and a key contributor to the 2025 US hypertension guidelines, cautioned that KARDINAL is a phase II trial and that it is too early to define tonlamarsen’s role in routine clinical management of hypertension.businesswire+3

Experts note that nucleic acid–based therapies like tonlamarsen and the small interfering RNA (siRNA) agent zilebesiran (studied in KARDIA‑2) represent a novel approach to RAAS modulation, potentially improving treatment adherence through periodic injection rather than daily oral agents. However, Morris Brown, MD, senior investigator of the BrigHTN trial with the aldosterone synthase inhibitor baxdrostat, stresses that AGT is not the rate‑limiting step for angiotensin II generation in most patients, so near‑complete AGT suppression may be needed to yield meaningful BP reductions beyond conventional RAAS‑directed therapy. 

Next steps and future directions

Despite the lack of incremental BP benefit from monthly dosing, tonlamarsen clearly modulates its intended molecular target, and post‑hoc analyses suggest more pronounced effects in patients with acute severe hypertension (ASH) or higher baseline BP. Sponsor Kardigan plans follow‑on studies, including the KARDINAL‑ASH phase 2b trial, to further explore tonlamarsen as a bridging therapy in high‑risk patients with severe hypertensive burden.finance.yahoo+2

In parallel, a broader pipeline of investigational agents—including lorundrostat and baxdrostat (aldosterone synthase inhibitors), as well as the endothelin receptor antagonist aprocitentan (now FDA‑approved for inadequately controlled hypertension)—continues to reshape the landscape of treatment‑resistant hypertension. The KARDINAL results underscore the need for larger, placebo‑controlled trials and a clearer understanding of factors driving treatment resistance before tonlamarsen can move from an intriguing RAAS‑targeted biologic to a practical tool in everyday hypertension care.