• An investigational monoclonal antibody reduced high-sensitivity C-reactive protein and other inflammatory markers with quarterly dosing.
• Phase 2 data support further study in high CV risk populations.

MUNICH — Treatment with the investigational interleukin-6 inhibitor pacibekitug was associated with large, sustained decreases in high-sensitivity C-reactive protein among adults with chronic kidney disease, according to phase 2 data.

IL-6 is believed to drive inflammatory risk in CVD and elevated hsCRP reflects both IL-6 pathway activation and systemic inflammation, Healio | Cardiology Today Editorial Board Member Deepak L. Bhatt, MD, MPH, MBA, director of the Mount Sinai Fuster Heart Hospital, said during a Hot Line presentation at the European Society of Cardiology Congress.

“We studied various doses and dosing intervals, but the bottom line is a 50 mg subcutaneous dose of pacibekitug, given quarterly, appeared highly efficacious,” Bhatt told Healio. “There was about an 85% reduction in hsCRP over the course of about 6 months. We chose to study patients with [chronic kidney disease] because they have known elevations in CRP. We thought this would be a relatively straightforward population to identify and then look for CRP reductions.”

The TRANQUILITY trial included 141 adults with stage 3 or 4 chronic kidney disease (CKD) and hsCRP levels between 2 mg/L and 15 mg/L (median, 4.5 mg/L). The mean age of participants was 69 years, 64% were women and 63% were white. Researchers randomly assigned participants to one of four study arms for 6 months, followed by a 6-month follow-up period: placebo, pacibekitug at quarterly doses of 25 mg or 50 mg, or a monthly dose of 15 mg.

“A difference between this IL-6 inhibitor vs. other IL-6 inhibitors out there in clinical use for noncardiovascular conditions ... is it has this option of quarterly dosing,” Bhatt said during a press conference.

Key endpoints for the trial included time-average hsCRP reduction from baseline through 90 days and 180 days, hsCRP target attainment of less than 2 mg/L and less than 1 mg/L and safety and tolerability.

Compared with placebo, participants assigned to the three pacibekitug dosing arms saw sustained, dose-dependent reductions in hsCRP through day 180 (25 mg quarterly pacibekitug, 76%; 50 mg quarterly pacibekitug, 85%; 15 mg monthly pacibekitug, 89%; placebo, +7%; P < .0001 for all pacibekitug doses vs. placebo), Bhatt said. Participants also experienced reductions in other inflammatory markers with pacibekitug compared with placebo, including reductions in serum amyloid A ranging from 38% to 57%, reductions in fibrinogen ranging from 25% to 37% and reductions in lipoprotein(a) ranging from 19% to 31%, Bhatt said.

“This is currently an investigational medicine, but in the context of this phase 2 trial, [pacibekitug] showed reductions in signs of inflammation over 6 months,” Bhatt said during the press conference. “That might be important for people at high risk for heart disease.”

Bhatt said there were no safety or tolerability concerns observed with pacibekitug (discontinuation rate, 1.9%), adding that the data support moving to a phase 3 study for adults at high CV risk to assess whether the drug can prevent CV events.

As Healio previously reported, topline data from the phase 3 ZEUS trial showed ziltivekimab, another investigational IL-6 inhibitor, reduced inflammatory markers in patients with atherosclerosis and CKD but did not lower risk for major adverse CV events.

“Of course, everyone is asking what the implications of that [trial] are [compared with] the IL-6 inhibitor we studied,” Bhatt told Healio. “We were never considering going into CKD for a phase 3 trial, and I certainly would not do that now given what we know of ZEUS, with the caveat, it says from a press release, that it appears to have been negative. The next step for phase 3 would be [a trial with] patients with coronary atherosclerosis, in particular, patients who have a history of plaque rupture, such as a prior MI. That is where we know the biology of inflammation matters most.”

Deepak L. Bhatt, MD, MPH, MBA, is director of the Mount Sinai Fuster Heart Hospital, the Dr. Valentin Fuster Professor of Cardiovascular Medicine at Icahn School of Medicine at Mount Sinai and a Healio | Cardiology Today Editorial Board Member. Bhatt can be reached at deepak.bhatt@mountsinai.org or on X @DLBhattMD.