Back From the Brink: Obicetrapib Performs Well in BROADWAY, TANDEM
The novel CETP inhibitor, once tested for the now-defunct pathway of HDL raising, reduces LDL as well as Lp(a).
Once-daily obicetrapib (NewAmsterdam Pharma)—an investigational, highly-selective cholesteryl ester transfer protein (CETP) inhibitor—safely lowers LDL-cholesterol levels on its own and in combination with ezetimibe in patients with heterozygous familial hypercholesterolemia (FH) or atherosclerotic cardiovascular disease (ASCVD) already on maximum tolerated doses of lipid-lowering therapy, according to new data from two trials.
The findings from BROADWAY and TANDEM, presented yesterday at the 2025 European Atherosclerosis Society Congress and simultaneously published in the New England Journal of Medicine and the Lancet, respectively, represent great possibility: obicetrapib belongs to a class of drugs that has disappointed many who believed the hypothesis that raising HDL would curb disease.
“We’ve been looking at inhibiting CETP for more than 20 years as a potential approach to the prevention of cardiovascular disease,” Stephen Nicholls, MBBS (Monash University, Clayton, Australia), who presented the BROADWAY data, told TCTMD. In the beginning, he explained, researchers were focused on upping HDL cholesterol with these agents, but came to realize LDL lowering was instead a more effective way to reduce MACE.
The new data are “really intriguing” and “extend what we’re learning about this agent and the class in general,” he added. Obicetrapib seems to be well tolerated by patients, Nicholls highlighted, “and that’s important because we’ve had CETP inhibitors in the past that haven’t been.”
Prior agents like anacetrapib (Merck), evacetrapib (Lilly), torcetrapib (Pfizer), and dalcetrapib (Roche) have all been abandoned, some because they caused harm to patients. The first of the CETP inhibitors, torcetrapib, famously collapsed in the ILLUMINATE trial when investigators showed that treatment raised blood pressure and increased risk of cardiovascular events and all-cause mortality.
Obicetrapib is unique as it was the most effective CETP inhibitor at decreasing LDL. NewAmsterdam, a company created by lipid experts John Kastelein, MD, and Michael Davidson, MD, acquired the rights to it from Amgen and have since tested it as an add-on therapy for LDL cholesterol lowering.
With several lipid-lowering avenues now available for clinicians to explore with their patients, it’s still important to continue building up the toolkit, said Ashish Sarraju, MD (Cleveland Clinic, OH), lead investigator of the TANDEM study
“Our aim should be to provide patients and doctors with as many different options in terms of route of administration, efficacy, safety, and tolerability as possible [so they can] play with the permutations of medications,” he told TCTMD. “That’s where studying new therapies like this makes sense,” especially for situations in which lowering LDL quickly is more urgent.
Lipid specialist Leandro Slipczuk, MD, PhD (Montefiore Medical Center, Bronx, NY), who wasn’t involved in either study, told TCTMD that the complex puzzle of managing LDL cholesterol has not yet been solved. “Having new tools like obicetrapib, I think, is amazing,” he said. Outcomes data, however, will be needed to move forward with it.
LDL and Lp(a) Down in BROADWAY
In BROADWAY, Nicholls and colleagues randomized 2,530 patients (mean age 65 years; 34% women) with heterozygous FH (17%) or a history of atherosclerotic cardiovascular disease (ASCVD; 89%) to receive 10 mg of obicetrapib once daily (n = 1,686) or placebo (n = 844) for 1 year. Patients were enrolled between December 2021 and August 2023 at centers in China, Europe, Jaman, and the US.
To be included in the study, patients were required to have either LDL ≥ 100 mg/dL or non-HDL ≥ 130 mg/dL. Additionally, patients with an LDL level of 55-100 mg/dL or a non-HDL level of 85-130 mg/dL were included if they had at least one additional cardiovascular risk factor. Most patients (91%) were on statins at baseline, including 70% on high-intensity statin therapy. A further 27% were on ezetimibe and 4% were on PCSK9 inhibitors. Notably, 11.5% of patients discontinued the trial regimen early for reasons related to adverse events (4.4%), patient decision (3.6%), and loss to follow-up (2.1%).
By day 84, the least-squares mean percent change in LDL from baseline (primary endpoint) was -29.9% with obicetrapib and +2.7% in the placebo group (P < 0.001). This difference in LDL was maintained through 1 year.
Obicetrapib also lowered lipoprotein(a)—which was a mean of 39 nmol/L at baseline—more than did placebo, with a between-group difference of -33.5% at day 84.
The total rates of adverse events were 59.7% in the study arm and 60.8% for placebo (including 4.5% in each arm related to the trial regimen), with no apparent differences noted between the groups in terms of event severity, relationship to the study drug, or rationale for stopping treatment. Liver-enzyme and muscle enzyme abnormalities were reported in 0.6% and 0.3% of the obicetrapib group, respectively. The overall risk of cardiovascular events, an underpowered endpoint, was numerically lower in the study arm than in the placebo arm (4.2% vs 5.2%; HR 0.79; 95% CI 0.54-1.15).
The idea that you have an agent that lowers both LDL and Lp(a) by at least 30% as a combination is pretty appealing. Stephen Nicholls
Nicholls said while the LDL lowering seen in BROADWAY was “predictable,” especially following the success seen in last year’s BROOKLYN trial of obicetrapib in heterozygous FH, the “emerging story” is that of the drug’s effect on Lp(a).
“Nobody talks about it much, but the idea that you have an agent that lowers both LDL and Lp(a) by at least 30% as a combination is pretty appealing,” he said, adding that outcomes data from the ongoing PREVAIL study, which are expected in early 2026, will show whether this additive effect will lower cardiovascular risk.
“We’ve learned a lot from previous clinical trials to design this clinical development program,” Nicholls said. “We think we’ve given this agent the best scenario to be able to demonstrate what it can do. Now we just have to kind of sit back and wait.”
TANDEM Data
The TANDEM trial built upon the positive findings of the ROSE and ROSE2 studies, which showed that using obicetrapib as an add-on to high-intensity statin therapy and ezetimibe can successfully lower LDL.
Researchers randomized 407 patients (mean age 68 years; 43% women) with heterozygous FH or ASCVD (or at high risk for ASCVD) to one of four 84-day treatment regimens between March and July 2024:
- Fixed dose combination of obicetrapib 10 mg plus ezetimibe 10 mg
- Obicetrapib 10 mg monotherapy
- Ezetimibe 10 mg monotherapy
- Placebo
All patients had baseline LDL levels ≥ 70 mg/dL even with maximally tolerated lipid-lowering therapy excluding ezetimibe or were statin intolerant.
At the end of the study, combination therapy had lowered LDL by 48.6% compared with placebo, by 27.9% compared with ezetimibe monotherapy, and by 16.8% compared with obicetrapib monotherapy. Compared with placebo, obicetrapib monotherapy reduced LDL by 31.9%.
Each of the three treatment groups reported adverse event rates in just over half of patients, while this rate was just over one-third in the placebo-treated patients. Rates of serious adverse events were low and comparable across all four groups (3-7%).
Patients Win With Options
Sarraju said it is “encouraging” to see the success of the fixed-dose combination in TANDEM, especially with no safety signals. “Overall, this aligns with an increasing focus on early combination therapy as a way to achieve LDL target goals in contrast with our traditional approach in the field, which has been starting a monotherapy, maybe at a lower or moderate dose and increasing the dose over time or adding a second agent over time,” he said.
Combination therapy has found success and acceptance in the treatment of hypertension, Sarraju explained, and “there’s increasing recognition that this idea of combination therapy for lipid treatment may make sense to try to cut down on the number of pills the patient has to take but also get them to their goal faster.”
With so much choice, it will ultimately come down to the patient’s preferred route of administration—oral or injectable medications—as well as access, cost, and potential side effects.
This aligns with an increasing focus on early combination therapy as a way to achieve LDL target goals. Leandro Slipczuk
Nicholls said obicetrapib will likely appeal to patients with elevated levels of both LDL and Lp(a) who may not qualify for the injectable medications.
“You have to have a really, really high Lp(a) level to get into the ongoing trials of those agents,” he said. Some patients have “levels that are less elevated but are still elevated and are still associated with higher risk where perhaps those injectables aren’t going to be frontline therapy. You could imagine an oral tablet that does lots of things, lowers Lp(a) little bit, and may be less expensive and may potentially be more accessible . . . has the potential to be pretty attractive for use in those patients.”
Slipczuk added that while injectables might be great for some patients, especially given that they don’t have to be administered as often, they’re not accessible in many parts of the world. Physicians will need to be better about not only screening patients for LDL, but also identifying which treatment fits into their patient’s lives, he said. “Having another pathway that we can use for lipid lowering is obviously very attractive for preventive cardiologists, in particular if it’s having a dual effect on LDL and lipoprotein(a).”
Patients ultimately benefit and are more likely to adhere to treatment when they see more options, Nicholls argued. “Then we can actually sit down and have a proper conversation with a patient and say, ‘Okay, you’ve got a high risk. I think your LDL’s too high. We need to get that down further. Now, here are a whole bunch of ways that we can do that.’”
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