Marked LDL Lowering With Obicetrapib in HeFH: BROOKLYN

The investigational CETP inhibitor obicetrapib—a drug initially developed to raise HDL-cholesterol levels—has passed another milestone in its quest towards approval, this time in patients with heterozygous familial hypercholesterolemia (FH).

NewAmsterdam Pharma, the company pursuing clinical-stage testing with the drug, announced today that the BROOKLYN study met its primary endpoint, which was a significant reduction in LDL-cholesterol levels from baseline to day 84 when compared with placebo.

Adding obicetrapib 10 mg in patients treated with statins and other drugs reduced LDL cholesterol by 36.3% at day 84 and this benefit was sustained out to 1 year. More than half of patients got their LDL-cholesterol levels down to less than 70 mg/dL, reported NewAmsterdam chief scientific officer John Kastelein, MD, PhD, in a conference call with financial analysts.

The drug was also well tolerated, he said, with no significant difference in treatment-emergent adverse events between the placebo- and obicetrapib-treated patients. In fact, the discontinuation rate was twice as high in the placebo group as in the active-treatment arm. Close to 96% of the obicetrapib-treated patients completed the study and there were no safety issues seen, including no increases in blood pressure—a side effect that doomed at least one prior CETP inhibitor—and no increases in liver enzymes, high-sensitivity CRP, or changes in renal function.

CETP inhibitors were originally developed to increase HDL-cholesterol levels and to prevent major cardiovascular events, but either were shown to be harmful, as with Pfizer’s torcetrapib in ILLUMINATE, or ineffective, such as with evacetrapib in ACCELERATE and dalcetrapib in dal-OUTCOMES. Obicetrapib was first developed by Amgen and shown to be the most potent of the CETP inhibitors for reducing LDL cholesterol levels. NewAmsterdam, a company created by Kastelein and chief executive officer Michael Davidson, MD, acquired rights to the drug and has been pursuing testing ever since.

“Heterozygous familial hypercholesterolemia is by far the most prevalent autosomal dominant genetic disease in the world,” said Kastelein. “One in every 250 children has this disease, meaning there are tens of millions of these patients across the globe. When I first started studying heterozygous FH, premature death at the age of 30 was not uncommon. We have learned since then that if we treat LDL-cholesterol levels of FH patients to normal, these patients can actually have a normal lifespan.”

To get genetically elevated LDL-cholesterol levels down to the normal range requires multiple lipid-lowering therapies, said Kastelein. NewAmsterdam is positioning obicetrapib as an add-on to maximally tolerated lipid-lowering therapy.

Data to be Published at Later Date

The BROOKLYN trial randomized heterozygous FH patients 2:1 to obicetrapib or placebo. All patients had baseline LDL-cholesterol levels exceeding 70 mg/dL despite maximally tolerated lipid-lowering therapy. Close to 90% were taking a statin, including 79% on high-intensity statin therapy, while 54% were taking ezetimibe and 14% were on a PCSK9 inhibitor. Baseline LDL levels were 123 mg/dL, a testament to how challenging it is to treat heterozygous FH patients, said Kastelein.

The reduction in LDL cholesterol occurred quickly. By 30 days, those treated with obicetrapib had a near 40% reduction in LDL cholesterol. At 1 year, the placebo-adjusted difference in LDL cholesterol was 41.5%. At day 84, nearly one-quarter of patients achieved an LDL level of less than 50 mg/dL.

In the last couple years, investigators have shown obicetrapib to be safe and effective when used as a monotherapy in ROSE and when combined with ezetimibe in ROSE2, both of which were small phase 2 studies. A larger phase 3 study, known as BROADWAY, is currently underway and those results are expected later this year. TANDEM, a trial testing obicetrapib when used in combination with ezetimibe, is also ongoing.

The big test for obicetrapib will come with PREVAIL, the 9,500-patient cardiovascular outcomes study in patients with atherosclerotic cardiovascular disease (or LDL ≥ 55 mg/dL with CVD risk factors or ≥ 55 mg/dL without). Enrollment was completed in April 2024, but trial results are not expected until at least 2026.