Kardigan’s tonlamarsen reduced a key biomarker for hypertension in a phase 2 trial, but missed the study’s other goal of significantly reducing blood pressure.
The biotech evaluated monthly 90 mg doses of the antisense oligonucleotide, which is licensed from Ionis Pharmaceuticals, in the mid-stage Kardinal study of 198 patients with uncontrolled hypertension. Tonlamarsen is designed to target angiotensinogen (AGT) in order to regulate the renin-angiotensin‑aldosterone system, a hormone system that controls blood pressure.
The trial demonstrated a statistically significant reduction in levels of AGT, hitting one of the trial’s primary endpoints. Specifically, AGT had fallen 67% by Week 20 for patients who received five monthly doses of tonlamarsen compared to a 23% reduction among those who received a single dose followed by placebo.
However, the company was unable to demonstrate a statistically significant difference between the in-office systolic blood pressure (oSBP) of the two cohorts at the same time-point, missing the study’s co-primary endpoint. Kardigan blamed this miss on an “unexpected, prolonged reduction in blood pressure in the single-dose arm.”
Kardigan explained that both treatment groups had seen a “clinically meaningful” reduction in oSBP compared to baseline. The single-dose cohort saw oSBP fall from 9.8 mmHg to 3.5 mmHg, while the five-dose group saw a fall from 9.8 mmHg to 3.6 mmHg.
Patients with the highest hypertensive burden—defined as baseline oSBP of over 150 mmHg—experienced the greatest reduction, Kardigan noted. The company used this data to justify its plans to launch a phase 2b study in patients with acute severe hypertension post-hospitalization later this year.
Related
Meanwhile, participants in the five-dose cohort experienced a decline in surges of at-home systolic blood pressure (hSBP) above 150 mmHg over the course of the study relative to baseline.
“The Kardinal clinical trial supported tonlamarsen’s hypothesized mechanism of action by demonstrating sufficient modulation of angiotensinogen, resulting in clinically meaningful blood pressure lowering, and potential for a favorable safety profile, particularly in patients with higher hypertensive burden,” the biotech’s co-founder and Chief Medical Officer Jay Edelberg, M.D., Ph.D., said in the March 28 release.
“Together, these findings strengthen our therapeutic hypothesis for tonlamarsen in patients with acute severe hypertension and will inform the Kardinal-ASH phase 2b clinical trial in this high-risk population with an urgent unmet medical need,” Edelberg added.
As well as those plans to launch a phase 2b study of tonlamarsen, Kardigan also has two other cardio drugs in late-stage development. They include danicamtiv, a phase 2b/3-stage cardiac myosin activator licensed from Bristol Myers Squibb and originally discovered by MyoKardia.
Kardigan launched last year with $300 million after being founded by a team of former MyoKardia execs, including co-founder, CEO and chair Tassos Gianakakos, who previously led MyoKardia for seven years.
Since then, Kardigan scored a $254 million series B, which it has used to fund development of tonlamarsen and danicamtiv as well as ataciguat, a guanylate cyclase activator from Sanofi and the Mayo Clinic that Kardigan is pursuing for calcific aortic valve stenosis.
Gianakakos told Fierce earlier this year that Kardigan plans to market and commercialize its potential products itself. The Bay Area biotech also has a phase 2 program that is currently under wraps.
