Obicetrapib Hits Target in Phase 3 BROOKLYN Trial for HeFH

Use of obicetrapib was associated with statistically significant reductions in LDL-C when added to maximally tolerated lipid modifying therapies in patients with heterozygous familial hypercholesterolemia (HeFH), according to topline results of the phase 3 BROOKLYN trial.

Announced by NewAmsterdam Pharma on July 29, 2024, topline data from the trial, which is the first of 4 phase 3 trials in the pivotal development program of obicetrapib, suggested use of the was associated with a statistically significant least squares (LS) mean reduction in LDL-C of 36.3% relative to placebo therapy at day 84 and this effect was sustained out to 1 year, with data pointing to a LS mean LDL-reduction of 41.5% at this time point. According to the announcement, statistically significant benefits were also observed for other lipid biomarkers, including HDL-C, non-HDL-C, lipoprotein(a) [Lp(a)], and apolipoprotein B (ApoB).

“The data announced today are another indication of obicetrapib’s potential to significantly reduce LDL-C in HeFH patients, a population already on multiple lipid-lowering therapies. I am incredibly encouraged by these results, which suggest that obicetrapib, if approved, has the potential to be a new oral option for a difficult-to-treat patient population and am excited to be a partner with the NewAmsterdam team on the remainder of the obicetrapib pivotal program,” said Stephen Nicholls, MBBS, PhD, director of the Monash Victorian Heart Institute and professor of Cardiology at Monash University.

A novel, oral, low-dose CETP inhibitor, obicetrapib is the source of excitement for many within cardiology and the lipidology communities as a result of findings from its phase 2 program, which included the ROSE2, TULIP, ROSE, and OCEAN trials.

A phase 3, randomized, double-blind, placebo-controlled, multicenter trial, BROOKLYN was designed to assess the efficacy and safety of obicetrapib 10 mg relative to placebo therapy as an adjunct to maximally tolerated lipid-lowering therapies among a population of patients with HeFH with inadequate LDL-C control. The trial randomized 354 patients in a 2:1 ratio to once-daily obicetrapib or placebo therapy. The trial’s primary endpoint of interest was the percent change from baseline in LDL-C with obicetrapib relative to placebo therapy after 84 days.

At day 84, use of obicetrapib was associated with a LS mean reduction of 36.3% (P < .0001) compared to placebo at day 84. Additional analysis indicated this effect sustained at day 365, where investigators observed a LS mean LDL-C reduction of 41.5% (P < .0001). Analysis of secondary efficacy endpoints highlighted use was associated with statistically significant improvements in HDL-C, non-HDL-C, Lp(a), and ApoB in a manner consistent with data reported from the prior clinical trials, which includes the

Safety data from the trial suggested obicetrapib was well-tolerated, with comparable results to placebo therapy and no increases in blood pressure observed in the trial. The overall treatment discontinuation rates were 7.6% and 14.4% in the obicetrapib and placebo arms, respectively. Further safety analyses indicated study drug-related treatment-emergent adverse emends occurred among 4.3% of the obicetrapib group and 6.8% of the placebo group.

As noted by NewAmsterdam Pharma in their July 29, 2024 announcement, BROOKLYN is just 1 of 4 phase 3 trials within their development program for obicetrapib, which also includes the BROADWAY, TANDEM, and PREVAIL studies.

• BROADWAY: Evaluating obicetrapib in adult patients with established ASCVD and/or HeFH with inadequate LDL-C control despite maximally tolerated lipid-lowering therapy. NewAmsterdam expects to report topline data in the fourth quarter of 2024.
• TANDEM: Evaluating obicetrapib as part of a FDC tablet with ezetimibe in patients with established ASCVD or multiple risk factors for ASCVD and/or HeFH with inadequate LDL-C control despite maximally tolerated lipid-lowering therapy. NewAmsterdam expects to report topline data in the first quarter of 2025.
• PREVAIL: Cardiovascular outcomes trial in patients with a history of ASCVD with inadequate LDL-C control despite maximally tolerated lipid-lowering therapy.

According to NewAmsterdam Pharma, the company expects full results from BROOKLYN to be presented at an upcoming medical conference and to publish the data in a major medical journal.

“HeFH affects 1 in 250 people worldwide and leads to increased risk of major adverse cardiovascular events, including stroke, myocardial infarction, or death, in the prime of life because of life-long burden of high LDL-C. Many individuals living with HeFH are unable to attain guideline-recommended LDL-C levels, despite currently available treatment options,” said Katherine Wilemon, Founder and CEO of the Family Heart Foundation. “Familial hypercholesterolemia often requires multiple therapies to achieve safer levels of LDL cholesterol. We are highly encouraged with these results and the potential to have another efficacious oral option.”

References:

1. NewAmsterdam Pharma. Newamsterdam Pharma announces positive topline data from Pivotal Phase 3 Brooklyn clinical trial evaluating Obicetrapib in patients with heterozygous familial hypercholesterolemia. NewAmsterdam Pharma Company N.V. July 29, 2024. Accessed July 29, 2024. https://ir.newamsterdampharma.com/news-releases/news-release-details/newamsterdam-pharma-announces-positive-topline-data-pivotal.
2. Ballantyne CM, Ditmarsch M, Kastelein JJ, et al. Obicetrapib plus ezetimibe as an adjunct to high-intensity statin therapy: A randomized phase 2 trial [published online ahead of print, 2023 May 31]. J Clin Lipidol. 2023;S1933-2874(23)00186-1. doi:10.1016/j.jacl.2023.05.098
3. Hovingh GK, Kastelein JJ, van Deventer SJ, et al. Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet. 2015;386(9992):452-460. doi:10.1016/S0140-6736(15)60158-1
4. Nicholls SJ, Ditmarsch M, Kastelein JJ, et al. Lipid lowering effects of the CETP inhibitor obicetrapib in combination with high-intensity statins: a randomized phase 2 trial. Nat Med. 2022;28(8):1672-1678. doi:10.1038/s41591-022-01936-7
5. National Library of Medicine. Randomized Study of Obicetrapib as an Adjunct to Statin Therapy (ROSE). Clinicaltrials.gov. Accessed July 29, 2024. https://clinicaltrials.gov/study/NCT04753606.