Kardinal
Phase 2 Study of Tonlamarsen, an Antisense Oligonucleotide Targeting Angiotensinogen, in Uncontrolled Hypertension
Presented by Luke Laffin — Cleveland Clinic
Subspecialty: Hypertension
Published in JACC
Key Result
Tonlamarsen achieved 67% reduction in plasma angiotensinogen (p<0.0001) but did NOT reduce office systolic BP more than single dose at Week 20 (both ~6.7 mmHg, p=0.97). Intriguingly, BP effects persisted after dosing stopped. Phase 2b trial in acute severe hypertension planned.
What did this trial find?
The KARDINAL phase 2 trial tested tonlamarsen, an antisense oligonucleotide targeting angiotensinogen (AGT), in 206 adults with uncontrolled hypertension on ≥2 antihypertensives. While multi-dose tonlamarsen achieved a 67% reduction in plasma AGT vs. 23% with a single dose (p<0.0001), both groups showed identical ~6.7 mmHg reductions in office systolic BP at Week 20 (p=0.97), creating a scientific paradox. The unexpectedly prolonged BP effect from a single dose has generated meaningful debate about mechanism, trial design, and clinical positioning, with the company pivoting toward acute severe hypertension for Phase 2b.
Why does this trial matter?
There is genuine interpretation debate here. The trial produced a scientific paradox—massive biomarker effect but no incremental BP benefit from continued dosing—which the lead author acknowledges 'raises more questions than it gives answers.' Outside commentary is cautious but limited to one named expert (Daniel Jones). The company's spin diverges from independent assessments. This is a real controversy around trial design, mechanism interpretation, and clinical positioning, though the volume of independent expert commentary is modest.
Study Design
Phase 2, randomized, double-blind, placebo-controlled trial across 39 U.S. sites
Clinical Implications
While tonlamarsen effectively suppresses angiotensinogen, the disconnect between AGT reduction and blood pressure lowering raises questions about the AGT-targeting mechanism for chronic hypertension. The persistent BP effects after dosing cessation are an intriguing signal that warrants further investigation in acute severe hypertension.
Abstract
The KARDINAL phase 2 trial evaluated tonlamarsen, an antisense oligonucleotide targeting angiotensinogen (AGT), in 206 adults with uncontrolled hypertension despite treatment with two or more antihypertensive medications, across 39 U.S. sites. Patients with office systolic BP >135 mm Hg underwent a 4-week placebo run-in, then all received a single 90 mg injection and were randomized to either four more monthly doses (multi-dose group) or placebo for 16 weeks. The co-primary endpoints were percent change in plasma AGT at Week 20 and change in office systolic BP at Week 20. Patients receiving five monthly 90 mg doses achieved a 67% mean reduction in plasma AGT levels vs 23% in the single-dose group (p<0.0001). However, both groups showed similar reductions of approximately 6.7 mmHg in office systolic blood pressure at Week 20 (p=0.97). The AGT endpoint was met but the BP endpoint was not. Notably, blood pressure effects appeared to persist and even increase after dosing stopped.