The investigational drug tonlamarsen, designed to lower blood pressure by reducing the production of angiotensinogen, a protein that turns into a blood pressure-regulating hormone, caused significant and sustained reductions in angiotensinogen, but its effect on blood pressure was less clear, according to a study presented at the American College of Cardiology’s Annual Scientific Sessions (ACC.26).
High blood pressure, also known as high blood pressure, can damage blood vessels and lead to cardiovascular disease, dementia, and other health problems, but about half of U.S. adults have uncontrolled high blood pressure. Tonlamarsen is one of several treatments being developed to help patients who continue to have high blood pressure despite taking multiple blood pressure-lowering drugs.
Tonlamarsen is given as a monthly injection and inhibits angiotensinogen, a precursor responsible for the production of angiotensin. The phase 2 study enrolled 206 patients at 39 sites in the United States with baseline systolic blood pressures of 135 mmHg to 170 mmHg, with a mean of 147 mmHg, despite taking two to five antihypertensive medications. The average age of participants was 61 years, approximately half were black or African American, and 41% were female.
After receiving the first placebo injection, all participants received a single dose of tonlamarsen at the start of the study (week 0). Half of the participants were randomly assigned to receive tonlamarsen and the other half to receive a placebo during four monthly injections from week 4 to week 20.
At 20 weeks, angiotensinogen levels decreased by an average of 67.2% from baseline in patients who continued taking tonlamarsen and by 23% in patients who switched to placebo (one of the study’s two primary endpoints). This was a significant difference between the groups with 44.1% supporting continued tonlamarsen.
Systolic blood pressure measurements taken in the clinic, the study’s other primary endpoint, decreased by an average of 6.7 mmHg in both study groups. This decrease occurred after the first dose of tonlamarsen was administered to all participants and was maintained in both study groups at week 20, with no significant differences between groups at this time. There were also no significant differences in secondary blood pressure outcomes, such as changes in home-measured blood pressure or the proportion of participants achieving target blood pressure levels.
Because the drug was administered monthly, we predicted that angiotensinogen would fully return to baseline levels by 20 weeks, but we found that the effects of tonlamarsen lasted much longer than expected. I was surprised that my blood pressure continued to drop after one dose. We also did not expect the finding that the rate of decrease in angiotensinogen did not necessarily correspond to the decrease in blood pressure after 20 weeks. This trial yielded unique data, although it currently raises more questions than it answers. ”
Luke Laffin, M.D., cardiologist at Cleveland Clinic and lead author of the study
Researchers believe the mixed results were caused by unexpected long-term effects of the drug, which was given to all study participants at the start of the trial. Four weeks after the first dose of tonlamarsen, half of the participants switched to placebo for the remaining 16 weeks, and half continued to take tonlamarsen. However, although the researchers identified several possible explanations, the specific factors behind the mixed results are unclear.
“One possibility, and what we think is most likely, is that tonlamarsen lowers blood pressure by about 6 to 7 mm Hg, and this blood pressure is maintained even as angiotensinogen levels increase,” Ruffin said. “Another possibility is that residual angiotensin suppression in the placebo participants resulted in a greater than expected reduction in blood pressure. It is also possible that the reduction in angiotensin with tonlamarsen does not lower blood pressure, but this is probably unlikely based on the fact that blood pressure decreased during the drug’s induction period.”
Participants randomized to continue tonlamarsen experienced a higher rate of injection site reactions, which was expected because these participants were receiving drug injections rather than a placebo.
In addition to the unexpected long-term suppression of angiotensinogen, Professor Ruffin said the study was relatively small and did not assess cardiovascular outcomes. The researchers are planning another study to evaluate the use of short courses of tonlamarsen in patients with acute severe hypertension.
The study was funded by Cardigan, the manufacturer of Tonramarsen.
The study was published online at the same time. jack At the time of the presentation.
Dr. Ruffin will present his study, “Cardinal: A Phase 2 Study of Tonlamarsen for the Treatment of Uncontrolled Hypertension,” on Saturday, March 28 at 3:45 PM CT/3:45 PM UTC in the main tent of the Great Hall.
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American College of Cardiology
