Obicetrapib-Ezetimibe Combo Cuts LDL-C in TANDEM Trial

NewAmsterdam Pharma announced promising results from its Phase III TANDEM clinical trial, evaluating a fixed-dose combination of obicetrapib and ezetimibe. This therapy targets patients with high cardiovascular risk due to atherosclerotic cardiovascular disease (ASCVD), ASCVD risk factors or heterozygous familial hypercholesterolemia (HeFH).

In the news release, John Kastelein, chief scientific officer of NewAmsterdam Pharma, said millions of people struggle to meet low-density lipoprotein cholesterol (LDL-C) goals despite existing therapies, leaving them at heightened cardiovascular risk.

Obicetrapib, a cholesterol ester transfer protein (CETP) inhibitor, reduces cholesterol transfer between lipoproteins, while ezetimibe limits cholesterol absorption in the intestines. Together, they form a once-daily oral therapy designed for patients who cannot achieve their targets with current treatments.

The TANDEM trial enrolled 407 participants with baseline LDL-C levels averaging 97 mg/dL despite maximally tolerated statin use in 74 percent of patients. Over 84 days, the combination therapy achieved a 48.6 percent average LDL-C reduction compared to placebo, with over 70 percent of patients reaching LDL-C levels below 55 mg/dL. The therapy also outperformed its individual components, showing statistically significant improvements over both obicetrapib and ezetimibe monotherapies. Its safety profile was favorable, with tolerability comparable to placebo.

Michael Davidson, chief executive officer of NewAmsterdam Pharma, expressed optimism about the combination therapy’s potential to simplify LDL-C management and address unmet needs, especially in underserved high-risk populations.

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Statins currently remain the first-line treatment for lowering LDL-C, effectively blocking cholesterol production in the liver. Yet, many patients fail to achieve guideline-recommended LDL-C levels even with high-intensity statin therapy.

Recently, Novartis’s V-INITIATE trial demonstrated that early addition of Leqvio (inclisiran), a twice-yearly injectable therapy, to maximally tolerated statin therapy led to a 60 percent reduction in LDL-C levels compared to just seven percent with usual care. Four in five patients receiving Leqvio achieved guideline-recommended LDL-C targets, highlighting the potential of structured non-statin therapies to complement statins in ASCVD management.

NewAmsterdam’s exploration of the fixed-dose combination of obicetrapib and ezetimibe in the TANDEM trial offers a promising solution for patients who struggle to meet their LDL-C goals. But this trial is just one of four in NewAmsterdam’s global Phase III program. Other trials, including BROOKLYN, BROADWAY and PREVAIL, aim to evaluate obicetrapib’s potential both as a standalone therapy and in combination with ezetimibe across diverse patient populations.

The BROOKLYN trial is evaluating obicetrapib as a monotherapy in HeFH patients. The trial recently showed a sustained LDL-C reduction of 41.5 percent after one year compared to placebo, including significant improvements in cardiovascular biomarkers, including lipoprotein(a) and apolipoprotein B.

The ongoing BROADWAY trial evaluates obicetrapib as a standalone therapy alongside maximally tolerated lipid-lowering treatments, while the PREVAIL cardiovascular outcomes trial explores its potential to reduce major adverse cardiovascular events like heart attack and stroke. With over 9,500 patients enrolled in PREVAIL, this study is expected to provide critical insights into obicetrapib’s role in long-term cardiovascular risk reduction.

Building on TANDEM’s success, NewAmsterdam plans to pursue regulatory approval for the fixed-dose combination and share further results at upcoming medical conferences. If approved, this therapy could significantly advance cardiovascular care.