New data from the phase 2 ROSE2 trial is providing insight into the safety and tolerability, as well as LDL-lowering effects, of obicetrapib as an adjunct to high-intensity statin therapy as a monotherapy and in combination with ezetimibe.
Data from the phase 2 ROSE2 study presented at the National Lipid Association (NLA) Scientific Sessions 2023 is highlighting the potential of obicetrapib plus ezetimibe as an adjunct to statin therapy for improving management of dyslipidemia.
With the trial meeting its primary and secondary endpoints, results provide evidence use of the once-daily, oral, low-dose cholesteryl ester transfer protein (CETP) inhibitor from NewAmsterdam Pharma Company, in combination with ezetimibe, was associated with statistically significant and clinically meaningful reductions in LDL-C and apolipoprotein B (ApoB).1
“The 2022 ACC Expert Consensus Decision Pathway has recommended that very high-risk patients with LDL-C above 55mg/dl need additional therapy to maximize proven risk reduction. With these new recommendations, many more patients will fail to achieve guideline-mandated LDL-C goals, demonstrating the limitations of existing therapeutics and the critical need for new options,” said principal investigator Christie M. Ballantyne, MD, chief of Cardiovascular Research and professor at Baylor College of Medicine, who presented the data at NLA 2023.2 “The data presented today are highly encouraging, showing that the combination of obicetrapib and ezetimibe delivers robust impacts on multiple atherogenic lipid parameters. I believe the observed reductions in LDL-C, ApoB, Lp(a) and total and small LDL particles are potentially predictive of profound reductions in the risk of cardiovascular events and look forward to further characterizing the combination obicetrapib and ezetimibe regimen in a Phase 3 trial.”
A phase 2 double-blind, randomized, placebo-controlled trial, ROSE2 was designed with the intent of assessing the safety and efficacy of obicetrapib plus ezetimibe combination therapy as an adjunct to placebo therapy in patients with . Conducted at 18 clinical research sites in the US from March-September 2022, the trial assessed 231 patients for eligibility and randomized 119 patients. Of these 119, 97 were included in the primary analysis as 8 patients either discontinued the study, with 3 withdrawing, 2 discontinuing as the result of an adverse event, 2 lost to follow-up, and 1 classified as other.1
For inclusion in the trial patients were required to one 18-75 years of age with a fasting LDL-C greater than 70 mg/dL and triglycerides less than 400 mg/dL while on a stable dose of high-intensity statin therapy for at least 8 weeks preceding screening for the trial. For the purpose of analysis, high-intensity statin therapy 3was defined as atorvastatin 40-80 mg or rosuvastatin 20-40 mg. The trial included multiple exclusion criteria, such as current clinically manifest atherosclerotic cardiovascular disease including, but not limited to, a major adverse cardiovascular event within 3 months prior to randomization or New York Heart Association Functional Classification Class III or IV heart failure, concomitant use of PCSK9 inhibitors or bempedoic acid, BMI of 40 kg/m2 or greater, an HbA1c of 10% or greater, uncontrolled hypertension, renal dysfunction, and others.1
The 119-patient cohort was randomized in a 1:1:1 fashion to placebo therapy, 10 mg once-daily obicetrapib monotherapy, or combination therapy with 10 mg obicetrapib plus 10 mg ezetimibe. Per trial protocol, the treatment period lasted a total of 12 weeks study visits occurred at the clinic at week 4, week 12, and week 16 after randomization for safety and pharmacokinetic evaluations. Outcomes of interest for the investigators analyses included concentrations of lipids, apolipoproteins, lipoprotein particles, PCSK9, safety, and tolerability.1
Overall, 97 patients completed the trial and were included in the primary analysis. This cohort had a mean age of 62.6 years, 63.9% were male, 84.5% were White, and the cohort had a mean BMI of 30.9 kg/m2. Investigators pointed out calculated compliance with tablets, which was the delivery method for placebo and obicetrapib, in the on-treatment population was 97.3%, 100%, and 99.2%, respectively, in the placebo, obicetrapib monotherapy, and obicetrapib combination treatment groups. Additionally, investigators pointed out the calculated compliance with capsules, which was the delivery method for placebo and ezetimibe, was 97.4%, 100%, and 98.9%, respectively, in the placebo, obicetrapib monotherapy, and obicetrapib combination treatment groups.1
Upon analysis, results suggested the mean LDL-C decreased by 63.4%, 43.5%, and 6.35% from baseline to week 12 in the combination, monotherapy, and placebo groups, respectively (P < .0001). Further analysis demonstrated LDL-C thresholds of less than 100, less than 70, and less than 55 mg/dL were achieved by 100%, 93.5%, and 87.1%, respectively, of patients receiving combination obicetrapib plus ezetimibe compared to 66.7%, 16.7%, and 0.0%, respectively, among the placebo arm of the trial (P < .05). Investigators also called attention to significant reductions in concentrations of non-HDL-C, ApoB, and total and small LDL particles with obicetrapib combination as well as obicetrapib monotherapy arms.1
In analysis of safety endpoints, investigators noted treatment-emergent adverse events were reported by 35 participants of the 119-patient study cohort. Of these, 40% occurred in the placebo group, 20.5% occurred in the monotherapy group, and 27.5% occurred in the combination group. Investigators underlined most events were classified as mild or moderate in severity, with the most prevalent adverse events being nausea, urinary tract infection, and headache. Investigators highlighted there were no clinical meaningful changes in biochemical safety measures observed during the study.1
“We are particularly encouraged by the new lipid particle analysis, in which we observed reductions in Lp(a) and both total and small LDL particles in patients who received the combination of obicetrapib and ezetimibe,” said John Kastelein, MD, PhD, chief scientific officer of NewAmsterdam.2 “An observed reduction of almost 50% in Lp(a) levels and associated reduction of 95% in the highly atherogenic small LDL particles are potentially clinically relevant, as LDL particles are believed to be one of the most robust predictors of cardiovascular disease risk. Together, these data further reinforce the potential for obicetrapib to transform the treatment landscape.”