Obicetrapib tied to sizable LDL lowering on top of other therapies in high-risk patients
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Key takeaways:
- In patients with genetic high cholesterol on other therapies, obicetrapib lowered LDL by about 40% vs. placebo.
- Obicetrapib also improved other lipid parameters such as lipoprotein(a).
CHICAGO — In patients with heterozygous familial hypercholesterolemia with high LDL despite being on optimal medical therapy, obicetrapib greatly lowered LDL levels compared with placebo, according to the results of the BROOKLYN trial.
The phase 3 BROOKLYN trial, presented at the American Heart Association Scientific Sessions, included 354 patients diagnosed with heterozygous familial hypercholesterolemia (HeFH) with LDL greater than 70 mg/dL despite being on optimal medical therapy and normal triglyceride and lipoprotein(a) levels (mean age, 57 years; 54% women) who were randomly assigned 2:1 to obicetrapib 10 mg (NewAmsterdam Pharma) or placebo.
The cohort is typical of the FH population seen in clinics: “They are on good treatment, and yet I don’t have them where I want to get them in terms of an LDL cholesterol,” Stephen J. Nicholls, MBBS, PhD, director, of the Monash Victorian Heart Institute and professor of cardiology at Monash University in Melbourne, Australia, who presented the findings, told Healio.
More than 80% of patients were taking statins (with more than two-thirds taking high-intensity statins), about half were taking ezetimibe and approximately one-fifth were taking a PCSK9 inhibitor at baseline, Nicholls said during a presentation.
Despite being on those lipid-lowering therapies, patients had a mean baseline LDL of 119.9 mg/dL in the placebo group and 123.4 mg/dL in the obicetrapib group, he said.
The primary outcome of placebo-adjusted percent change in LDL for the obicetrapib group was –36.3% at 84 days and –41.5% at 365 days (P < .0001 vs. baseline for both), he said.
LDL lowering of at least 50% was achieved in 34% of the obicetrapib group but just 3% of the placebo group, Nicholls said.
The goal of LDL less than 100 mg/dL was achieved by 77% of the obicetrapib group and 40% of the placebo group, the goal of LDL less than 70 mg/dL was achieved by 51% of the obicetrapib group and 11% of the placebo group and the goal of LDL less than 55 mg/dL was achieved by 24% of the obicetrapib group and 1% of the placebo group, Nicholls said during the presentation.
‘A pretty good start’
“This is in the ballpark of what I expected based on the results of the ROSE and ROSE2 studies previously,” Nicholls told Healio. “If you told me we would get 41% lowering of LDL cholesterol at 12 months on top of the type of background therapy we had, and you told me we would get 77% of people to a primary prevention target of 100 [mg/dL], 51% of people to 70 [mg/dL], I’d take that. I think that’s a pretty good start. Obicetrapib by itself and in combination with ezetimibe ends up being a pretty effective tool to treat patients’ LDL cholesterol.”
In the obicetrapib group, the placebo-adjusted percent change in non-HDL was –34.5% at 84 days and –37.5% at 365 days, whereas the placebo-adjusted percent change in apolipoprotein B was –24.4% at 84 days and –25.8% at 365 days, he said.
HDL rose a placebo-adjusted 138.7% at 84 days and 121.4% at 365 days, whereas triglycerides fell a placebo-adjusted –11.7% at 84 days and –5.1% at 365 days in the obicetrapib group, he said.
Obicetrapib was also associated with reductions at 84 days and 365 days in LDL particles, high-sensitivity C-reactive protein and Lp(a), and 38% of the obicetrapib group achieved Lp(a) lowering of at least 50% compared with 3% of the placebo group, according to the presentation.
There were no differences between the groups in treatment-emergent adverse events, study drug-related adverse events or adverse events leading to study drug discontinuation, Nicholls said, noting there was also no difference between the groups in effect on BP.
“FH is a preventable form of cardiovascular disease, and we are increasingly recognizing that FH patients need to get to lower and lower LDL cholesterol levels,” Nicholls told Healio. “[Approval of obicetrapib] will mean many more people get there. The other finding that’s intriguing from BROOKLYN is the Lp(a) effect. If we are truly able to reduce Lp(a) 50%, in addition to lowering LDL 40%, that becomes an important additional benefit here.”
‘Time to take another look’
In a discussant presentation, Healio | Cardiology Today Editorial Board Member Karol E. Watson, MD, PhD, professor of medicine/cardiology at the David Geffen School of Medicine at UCLA, director of the UCLA Women’s Cardiovascular Health Center and the UCLA-Barbra Streisand Women’s Heart Health Program, co-director of the UCLA Program in Preventive Cardiology and director of the UCLA Fellowship Program in Cardiovascular Diseases, said CETP inhibitors have a long history of failure, but obicetrapib is different because the development program was designed to focus on its LDL-lowering effects rather than its HDL-raising effects. “It has favorable pharmacokinetic and pharmacodynamic properties compared to other CETP inhibitors, it has no adverse effect on blood pressure and we think it’s going to be a pretty safe, clean therapy,” she said. “I do think it’s time to take another look at this therapy.”
Top-line results of TANDEM
In other obicetrapib news, NewAmsterdam Pharma announced top-line results of the TANDEM trial of a fixed-dose combination of obicetrapib 10 mg and ezetimibe 10 mg vs. placebo in patients with atherosclerotic CVD or ASCVD risk factors and/or HeFH. The fixed-dose combination achieved a least-squares mean reduction in LDL of 48.6% (P < .0001) compared with placebo at day 84, the company stated in a press release.
The company intends to present TANDEM at an upcoming medical conference and publish it in a peer-reviewed journal, according to the release.
For more information:
Stephen J. Nicholls, MBBS, PhD, can be reached at stephen.nicholls@monash.edu.
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Nicholls SJ, et al. LBS.08. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2024; Chicago.
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