2024 Volume 31 Issue 10 Pages 1386-1397
Aims: Obicetrapib is a highly selective cholesteryl ester transfer protein (CETP) inhibitor shown to reduce low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB), when taken as monotherapy and in combination with ezetimibe on a background of statins, in clinical trials predominantly conducted in Northern European/Caucasian participants. We characterized the efficacy, safety, and tolerability of obicetrapib within an Asian-Pacific region population.
Methods: This double-blind, randomized, phase 2 trial examined obicetrapib 2.5, 5, and 10 mg/d, compared with placebo, for 8 weeks as an adjunct to stable statin therapy (atorvastatin 10 or 20 mg/d or rosuvastatin 5 or 10 mg/d) in Japanese men and women who had not achieved 2022 Japan Atherosclerosis Society Guidelines and had LDL-C ＞70 mg/dL or non-high-density lipoprotein cholesterol (non-HDL-C) ＞100 mg/dL and triglycerides (TG) ＜400 mg/dL. Endpoints included LDL-C, non-HDL-C, HDL-C, very low-density lipoprotein cholesterol, apolipoproteins, TG, steady state pharmacokinetics (PK) in obicetrapib arms, safety, and tolerability.
Results: In the 102 randomized subjects (mean age 64.8 y, 71.6% male), obicetrapib significantly lowered median LDL-C, apoB, and non-HDL-C, and raised HDL-C at all doses; responses in the obicetrapib 10 mg group were -45.8%, -29.7%, -37.0%, and +159%, respectively (all p＜0.0001 vs. placebo). The PK profile demonstrated near complete elimination of drug by 4 weeks. Obicetrapib was well tolerated and there were no adverse safety signals.
Conclusions: All doses of obicetrapib taken as an adjunct to stable statin therapy significantly lowered atherogenic lipoprotein lipid parameters, showed near complete elimination of drug by 4 weeks, and were safe and well tolerated in a Japanese population, similar to previous studies of obicetrapib conducted in predominantly Caucasian participants.
See editorial vol. 31: 1367-1369
ClinicalTrials.gov registration number: NCT05421078
Atherosclerosis resulting from plaque accumulation in the arterial wall progresses over decades and may lead to clinical events such as myocardial infarction and stroke1). Hypercholesterolemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD); reducing dyslipidemia is a cornerstone of ASCVD prevention1-3). Low-density-lipoprotein cholesterol (LDL-C) is generally considered the primary target for intervention in patients with hypercholesterolemia1, 2). While statins are the first-line pharmacologic therapy for LDL-C reduction, statin monotherapy and in combination regimens with other lipid-modifying drugs is underutilized and often inadequate for patients who experience statin intolerance or need additional LDL-C lowering to meet therapeutic objectives4-8). This illustrates the crucial need for additional lipid-lowering therapies for many patients at high risk for ASCVD with higher than optimal levels of LDL-C.
Obicetrapib is a novel, highly selective, cholesteryl ester transfer protein (CETP) inhibitor in development for the treatment of hypercholesterolemia and reduction of cardiovascular risk9-12). CETP inhibition impairs the transfer of cholesteryl esters from high-density lipoprotein (HDL) to apolipoprotein B (apoB)-containing particles, increases transintestinal cholesterol excretion, upregulates the expression of scavenger receptor class B type 1 and hepatic LDL receptors, and increases the catabolic rates of LDL and apoB13). Previous clinical trials demonstrated that obicetrapib taken with moderate-intensity statins, high-intensity statins, and ezetimibe is well tolerated and substantially reduces LDL-C (by ＞40% as monotherapy and ＞60% when co-administered with ezetimibe on top of high-intensity statin), but these trials were conducted predominantly in Caucasian populations with Northern European ancestries9-12). Thus, there is a lack of clinical experience with obicetrapib among individuals from the Asia-Pacific region. A phase 1, single-ascending dose study that included 32 healthy Japanese male subjects 18-55 years of age, compared to healthy male Caucasian subjects, showed no evidence of significant effects of ethnicity on the safety, pharmacokinetics (PK), or pharmacodynamics of obicetrapib9). The present study was designed to fill the gap in clinical experience and further characterize the safety, efficacy, and PK profile of obicetrapib in Japanese subjects with elevated LDL-C receiving statins.
The present study was a placebo-controlled, double-blind, randomized, phase 2 trial of obicetrapib as an adjunct to stable statin therapy in Japanese subjects (NCT05421078). The trial was conducted from June 2022 to April 2023; nine clinical research sites in Japan enrolled participants (see list of Investigators in Supplementary Table 1). The protocol was approved by the duly constituted Institutional Review Board/Ethical Review Committee for each center, and all participants provided informed consent before their enrollment.
|
Tomomi Hakoda Nippon Kokan Fukuyama Hospital Fukuyama, Japan |
|
Satoshi Kuroyanagi Kishiwada Tokushu-Kai Hospital Osaka, Japan |
|
Yoshimitsu Yamasaki Kyosokai AMC NISHI-UMEDA Clinic Osaka, Japan |
|
Kenshi Fujii Sakurabashi Watanabe Hospital Osaka, Japan |
|
Atsushi Sueyoshi Uji Tokushu-Kai Hospital Osaka, Japan |
|
Akitaka Nakata Sanai Hospital Saitama, Japan |
|
Fumiki Oh Shinden Higashi Clinic Sendai, Japan |
|
Tatsushi Sugiura Soka-Sugiura Clinic Soka, Japan |
|
Toshiyuki Sugiura Sugiura Clinic Tokyo, Japan |
Participants included Japanese men and women (not pregnant, breastfeeding or planning to become pregnant) that were 18-80 years of age who had not achieved treatment goals in accordance with the 2022 Japan Atherosclerosis Society Guidelines for Prevention of ASCVD14), and had documented fasting LDL-C ＞70 mg/dL or non-HDL-C ＞100 mg/dL and triglycerides (TG) ＜400 mg/dL within the past three months, and were receiving atorvastatin 10 or 20 mg/d or rosuvastatin 5 or 10 mg/d at a stable dose for at least eight weeks prior to screening. Exclusion criteria included current clinically active, or an acute episode of, ASCVD, including, but not limited to, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure or unstable angina, or New York Heart Association Functional Classification Class III or IV heart failure; evidence of any other significant non-cardiac disease or condition; diagnosis of homozygous familial hypercholesterolemia or CETP deficiency; recent or concomitant use of proprotein convertase subtilisin kexin type 9 inhibitors, bempedoic acid, or statin other than atorvastatin or rosuvastatin; body mass index ≥ 35 kg/m2; glycated hemoglobin ≥ 10%; uncontrolled hypertension; active muscle disease or persistent creatine kinase ＞3 times the upper limit of normal (ULN); estimated glomerular filtration rate ＜45 mL/min/1.73 m2; liver enzymes ＞2 times ULN or total bilirubin ＞1.5 times ULN; significant anemia; and recent history of malignancy, alcohol or drug abuse.
Study VisitsParticipants were randomized using an automated interactive response technology system in a 1:1:1:1 ratio to the following treatment groups: one 2.5 mg obicetrapib tablet per day, one 5 mg obicetrapib tablet per day, one 10 mg obicetrapib tablet per day, or one matching placebo tablet per day, for an 8-week treatment period. Randomization was stratified according to screening LDL-C level of ≥ 100 or ＜100 mg/dL. Following randomization, participants were evaluated at the clinic at weeks 2, 4, and 8 (end of treatment) for efficacy, safety, and PK assessments, and at week 12 for final safety and PK assessments. During the 8-week treatment period, participants were instructed to take the study drugs orally once daily at approximately the same time each morning, and to bring all their study drug supply to the site at the clinic visits, where compliance was evaluated by counting unused tablets. The investigators, participants, clinical research organization, and sponsor of the trial were blinded to all lipid results from randomization until all participants had completed the final treatment visit and the database was locked.
AssessmentsFasting blood samples were collected at each clinic visit throughout the trial. Testing was completed by Medpace Reference Laboratories (Singapore) who performed the clinical laboratory analyses, and Medpace Bioanalytic Laboratories (Cincinnati, OH, USA) who performed the PK sample analysis as described previously12). Lipid parameters were measured at each visit and included LDL-C, apoB, non-HDL-C, HDL-C, very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein E (apoE), and TG. LDL-C was calculated using the Friedewald equation15, 16) unless TG ≥ 400 mg/dL or LDL-C ≤ 50 mg/dL, in which case LDL-C level was measured directly by preparative ultracentrifugation (i.e., beta-quantification). In addition, LDL-C was measured by preparative ultracentrifugation at baseline and at the end of treatment in all participants.
Statistical AnalysesThe primary endpoint was the percent change from baseline to week 8 in Friedewald-calculated LDL-C for each obicetrapib group compared with placebo. Secondary and other efficacy endpoints included apoB, non-HDL-C, HDL-C, VLDL-C, apoE, and TG. Safety and tolerability endpoints included clinical laboratory assessments, vital signs, physical examinations, and adverse events. A sample size of at least 100 evaluable participants (25 per treatment group) was expected to provide more than 90% power to detect a 30% difference in LDL-C reduction at week 8 (standard deviation of 25%) for each of the obicetrapib treatment groups compared to placebo at a two-sided significance level of 0.05. A total of 102 subjects were randomized.
All statistical analyses were performed using SAS® version 9.4 (SAS Institute, Cary, NC, USA). The primary analysis population was the intent-to-treat (ITT) population, i.e., all randomized participants. Efficacy analyses were also conducted in a per protocol population (all participants in the ITT population with LDL-C measured at baseline and week 8, and with no major protocol deviations). The PK analysis was performed in all participants in the ITT population assigned to one of the three obicetrapib dose groups who had sufficient blood samples collected for valid estimation of PK parameters, and the safety analyses were completed in all participants who received at least one dose of any study drug.
The analysis of the percent change from baseline to end of treatment in Friedewald-calculated LDL-C (the primary endpoint) was performed with a mixed model for repeated measures (MMRM) approach using SAS® Proc Mixed. The analysis included fixed effects for treatment, visit, and treatment-by-visit interaction, and the baseline value as a continuous covariate. The Restricted Maximum Likelihood estimation approach was used with an unstructured covariance matrix. Least squares (LS) means, standard errors (SE), and two-sided 95% confidence intervals for each treatment group and for the pairwise comparisons of each dose of obicetrapib to the placebo group were determined, and the LS means for the pairwise comparison and its SE were used for the hypothesis testing. To maintain the overall alpha level on the primary endpoint, the hypothesis testing was performed sequentially at the two-sided alpha=0.05 significance level. The first comparison was the 10 mg obicetrapib group vs. placebo; if significant, the comparison of the 5 mg group vs. placebo was performed next followed by the 2.5 mg group vs. placebo. Hypothesis testing proceeded in this hierarchical step-down fashion until a comparison was not significant at which point the remaining sequential tests were deemed not significant.
The MMRM model included all available assessments of percent change in LDL-C from baseline to weeks 2, 4, and 8. The model assumed the data were missing at random. Missing data were not imputed for the primary efficacy endpoint analysis; for other analyses, the model implicitly estimated missing data by assuming they followed the same distribution as observed data conditioned on baseline value and changes over time. Similar MMRM models as described for the primary endpoint were used to analyze the secondary and other efficacy endpoints, but without adjustment for multiplicity. Nominal p-values are provided when applicable. Normality was checked using the Shapiro-Wilk test.
Three sensitivity analyses were performed for the primary efficacy endpoint in the ITT population: MMRM with imputation, analysis of covariance (ANCOVA) with fixed effects of treatment group and baseline LDL-C value as a continuous covariate, and LDL-C by preparative ultracentrifugation. Safety and PK analyses were summarized descriptively; no statistical inference was applied to these endpoints.
All of the 102 randomized subjects completed the treatment and safety/PK follow-up periods and were included in the primary analyses (Supplementary Fig.1). The per protocol analysis excluded one participant in the obicetrapib 5 mg group with uncontrolled blood pressure at screening. Participants had a mean age of 64.8 years, mean body mass index of 25.6 kg/m2, 71.6% were male, and, by design, 100.0% were Asian (Japanese) (Table 1). Approximately 48% of the participants were taking atorvastatin 10 or 20 mg and 52% were taking rosuvastatin 5 or 10 mg. Calculated compliance with taking placebo, 2.5, 5, and 10 mg obicetrapib tablets was 97.0%, 97.5%, 98.4%, and 98.2%, respectively.
ITT defined as all randomized participants; safety defined as all participants who received at least one dose of any study drug; PK defined as all participants in the ITT population who had sufficient blood samples collected for valid estimation of PK parameters; PP defined as all participants in ITT population who had baseline and week 8 LDL-C values and no major protocol deviation that potentially impacted the primary efficacy endpoint. Abbreviations: ITT, intent to treat; PK, pharmacokinetic; PP, per protocol.
| Characteristica |
Placebo (N = 26) |
Obicetrapib 2.5 mg (N = 25) |
Obicetrapib 5 mg (N = 25) |
Obicetrapib 10 mg (N = 26) |
|---|---|---|---|---|
| Age, y | 63.3±9.44 | 65.8±8.09 | 67.8±9.46 | 62.5±9.90 |
| Sex, n (%) | ||||
| Male | 20 (76.9) | 15 (60.0) | 19 (76.0) | 19 (73.1) |
| Femaleb | 6 (23.1) | 10 (40.0) | 6 (24.0) | 7 (26.9) |
| Ethnicity, n (%) | ||||
| Hispanic or Latino | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) |
| Not Hispanic or Latino | 26 (100.0) | 25 (100.0) | 25 (100.0) | 26 (100.0) |
| Race, n (%) | ||||
| Asian | 26 (100.0) | 25 (100.0) | 25 (100.0) | 26 (100.0) |
| Body mass index, kg/m2 | 25.5±3.94 | 25.2±3.83 | 25.8±3.33 | 26.1±3.59 |
| LDL-C category, n (%) | ||||
| ＜100 mg/dL | 9 (34.6) | 9 (36.0) | 9 (36.0) | 10 (38.5) |
| ≥ 100 mg/dL | 17 (65.4) | 16 (64.0) | 16 (64.0) | 16 (61.5) |
| Current statin therapy, n (%) | ||||
| Atorvastatin 10 mg | 8 (30.8) | 10 (40.0) | 11 (44.0) | 8 (30.8) |
| Atorvastatin 20 mg | 7 (26.9) | 2 (8.00) | 1 (4.00) | 2 (7.70) |
| Rosuvastatin 5 mg | 9 (34.6) | 12 (48.0) | 12 (48.0) | 16 (61.5) |
| Rosuvastatin 10 mg | 2 (7.70) | 1 (4.00) | 1 (4.00) | 0 (0.00) |
Abbreviation: LDL-C, low-density lipoprotein cholesterol
a Values are mean±standard deviation unless otherwise indicated.
b The obicetrapib 2.5 mg group included one woman of childbearing potential, and the obicetrapib 10 mg group included two women of childbearing potential.
Concentrations of lipoprotein lipids and apolipoproteins at baseline and during the treatment period, and percent changes from baseline to the end of treatment are presented in Table 2 and Fig.1. Median Friedewald-calculated LDL-C was significantly reduced by 24.8%, 31.9%, and 45.8% for obicetrapib doses of 2.5, 5, and 10 mg, respectively, compared to a reduction of 0.89% with placebo (p＜0.0001 for each dose vs. placebo). Results for the three sensitivity analyses, i.e., LDL-C response to obicetrapib vs. placebo measured by preparative ultracentrifugation, using MMRM with multiple imputation under missing not at random, and using ANCOVA, were similar to those for the primary analysis. Non-HDL-C and apoB concentrations were also significantly reduced from baseline with obicetrapib vs. placebo by up to 30.3% and 26.3%, respectively, at the highest obicetrapib dose (p＜0.0001 for each dose vs. placebo). Additionally, obicetrapib significantly increased HDL-C and apoE by up to 159% and 26.3%, respectively, with obicetrapib 10 mg (p＜0.01 for each dose vs. placebo). There were no significant differences in the responses to obicetrapib vs. placebo for VLDL-C or TG.
| Lipid and Time Point |
Placebo (N = 26) |
Obicetrapib 2.5 mg (N = 25) |
Obicetrapib 5 mg (N = 25) |
Obicetrapib 10 mg (N = 26) |
|---|---|---|---|---|
| LDL-C (Friedewald-calculated) a | ||||
| Baseline, mg/dL | ||||
| Mean (SD) | 110 (37.1) | 102 (26.6) | 106 (27.5) | 109 (32.5) |
| Median (min, max) | 110 (57.0, 208) | 97.0 (58.0, 160) | 102 (70.0, 171) | 103 (66.0, 180) |
| Week 8 change, % | ||||
| Mean (SD) | -0.78 (14.6) | -25.9 (21.3) | -33.8 (13.2) | -36.8 (25.7) |
| Median (min, max) | -0.89 (-38.6, 27.8) | -24.8 (-66.0, 17.7) | -31.9 (-56.8, -2.90) | -45.8 (-73.0, 45.5) |
| LS Mean (SE)4 | -0.48 (3.77) | -26.3 (3.84) | -33.8 (3.84) | -36.6 (3.77) |
| P-value vs. placebo | ＜0.0001 | ＜0.0001 | ＜0.0001 | |
| LDL-C (Preparative ultracentrifugation) b | ||||
| Baseline, mg/dL | ||||
| Mean (SD) | 110 (34.0) | 102 (27.5) | 106 (26.1) | 109 (30.1) |
| Median (min, max) | 106 (66.0, 195) | 97.0 (67.0, 161) | 103 (70.0, 165) | 106 (68.0, 180) |
| Week 8 change, % | ||||
| Mean (SD) | 0.43 (15.5) | -26.1 (23.5) | -30.5 (15.0) | -36.3 (24.5) |
| Median (min, max) | 0.67 (-35.3, 32.5) | -26.0 (-67.6, 41.9) | -30.4 (-57.8, -2.70) | -43.7 (-72.0, 30.9) |
| LS Mean (SE)4 | 0.69 (3.93) | -26.5 (4.01) | -30.5 (4.00) | -36.1 (3.93) |
| P-value vs. placebo | ＜0.0001 | ＜0.0001 | ＜0.0001 | |
| ApoB a | ||||
| Baseline, mg/dL | ||||
| Mean (SD) | 91.7 (22.1) | 90.3 (19.2) | 94.2 (20.3) | 93.5 (19.9) |
| Median (min, max) | 86.5 (52.0, 147) | 84.0 (64.0, 135) | 91.0 (63.0, 146) | 90.0 (63.0, 141) |
| Week 8 change, % | ||||
| Mean (SD) | -1.23 (10.6) | -19.8 (15.4) | -24.5 (13.9) | -26.7 (15.0) |
| Median (min, max) | -0.36 (-26.1, 21.7) | -22.5 (-45.6, 12.7) | -21.4 (-53.4, 1.00) | -29.7 (-56.4, 9.50) |
| LS Mean (SE) | -1.42 (2.41) | -20.4 (2.46) | -23.9 (2.46) | -26.3 (2.41) |
| P-value vs. placebo | ＜0.0001 | ＜0.0001 | ＜0.0001 | |
| Non-HDL-C a | ||||
| Baseline, mg/dL | ||||
| Mean (SD) | 135 (35.0) | 132 (33.5) | 137 (33.6) | 134 (32.9) |
| Median (min, max) | 132 (89.0, 224) | 124 (86.0, 221) | 132 (80.0, 215) | 132 (81.0, 207) |
| Week 8 change, % | ||||
| Mean (SD) | -1.80 (12.3) | -25.4 (19.3) | -30.4 (13.8) | -30.3 (23.3) |
| Median (min, max) | -0.37 (-33.3, 24.2) | -23.7 (-62.4, 15.6) | -29.8 (-52.8, 1.3) | -37.0 (-66.3, 35.8) |
| LS Mean (SE) | -1.72 (3.40) | -25.7 (3.46) | -30.1 (3.46) | -30.3 (3.40) |
| P-value vs. placebo | ＜0.0001 | ＜0.0001 | ＜0.0001 | |
| HDL-C a | ||||
| Baseline, mg/dL | ||||
| Mean (SD) | 53.2 (14.6) | 55.6 (17.5) | 53.0 (11.3) | 54.9 (14.2) |
| Median (min, max) | 55.5 (24.0, 77.0) | 52.0 (35.0, 100) | 57.0 (29.0, 71.0) | 53.0 (36.0, 82.0) |
| Week 8 change, % | ||||
| Mean (SD) | 5.57 (13.3) | 135 (56.5) | 153 (46.9) | 159 (43.2) |
| Median (min, max) | 5.22 (-20.7, 33.3) | 114 (57.3, 307) | 144 (74.1, 255) | 159 (76.6, 282) |
| LS Mean (SE) | 3.90 (7.14) | 137 (7.28) | 151 (7.28) | 160 (7.14) |
| P-value vs. placebo | ＜0.0001 | ＜0.0001 | ＜0.0001 | |
| VLDL-C a | ||||
| Baseline, mg/dL | ||||
| Mean (SD) | 25.2 (8.98) | 27.5 (14.6) | 30.8 (14.3) | 25.2 (10.5) |
| Median (min, max) | 24.0 (11.0, 43.0) | 23.0 (10.0, 67.0) | 29.0 (10.0, 69.0) | 22.0 (14.0, 61.0) |
| Week 8 change, % | ||||
| Mean (SD) | 0.27 (41.3) | -2.20 (47.0) | -11.3 (29.2) | 9.80 (55.8) |
| Median (min, max) | -8.64 (-51.4, 138) | -8.71 (-62.7, 152) | -14.3 (-52.8, 74.1) | -4.55 (-44.4, 221) |
| LS Mean (SE) | -1.02 (8.40) | -1.71 (8.66) | -7.99 (8.60) | 8.02 (8.50) |
| P-value vs. placebo | 0.9543 | 0.5636 | 0.4509 | |
| ApoE a | ||||
| Baseline, mg/dL | ||||
| Mean (SD) | 4.13 (0.68) | 4.39 (1.33) | 4.45 (0.99) | 3.98 (0.85) |
| Median (min, max) | 4.15 (2.90, 5.20) | 4.20 (2.70, 8.70) | 4.40 (2.20, 6.60) | 3.90 (2.20, 5.80) |
| Week 8 change, % | ||||
| Mean (SD) | 1.17 (13.3) | 31.2 (42.6) | 33.2 (41.6) | 36.3 (39.7) |
| Median (min, max) | 0.00 (-21.6, 41.9) | 31.3 (-30.8, 137) | 23.5 (-51.5, 136) | 26.3 (-10.3, 165) |
| LS Mean (SE) | 0.30 (6.90) | 32.6 (7.05) | 35.1 (7.06) | 34.1 (6.93) |
| P-value vs. placebo | 0.0015 | 0.0007 | 0.0008 | |
| TG a | ||||
| Baseline, mg/dL | ||||
| Mean (SD) | 126 (45.5) | 148 (106) | 154 (71.9) | 126 (52.5) |
| Median (min, max) | 120 (53.0, 217) | 115 (48.0, 542) | 145 (48.0, 344) | 111 (68.0, 307) |
| Week 8 change, % | ||||
| Mean (SD) | 0.85 (42.3) | -2.32 (46.5) | -10.7 (29.1) | 14.7 (59.7) |
| Median (min, max) | -6.88 (-52.9, 144) | -8.63 (-62.5, 152) | -11.4 (-53.2, 71.5) | -2.91 (-44.4, 214) |
| LS Mean (SE) | -0.41 (8.93) | -1.29 (9.10) | -9.03 (9.11) | 13.4 (8.93) |
| P-value vs. placebo | 0.9452 | 0.5019 | 0.2767 | |
Abbreviations: Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LS, least squares; SD, standard deviation; SE, standard error; TG, triglycerides; VLDL-C, very low-density lipoprotein cholesterol
a LS means, SE, and p-values are from a mixed model for repeated measures with treatment, visit, and treatment-by-visit as factors and baseline value as a covariate. Missing at random was assumed for all missing data.
b LS means, SE, and p-values are from an analysis of covariance model with treatment group as a factor and baseline LDL-C from preparative ultracentrifugation as a covariate.
Abbreviation: LDL-C, low-density lipoprotein cholesterol.
Treatment-emergent adverse events (TEAEs) were reported by 47 (46.1%) of the 102 participants: 15 (57.7%) in placebo, 9 (36.0%) in obicetrapib 2.5 mg, 8 (32.0%) in obicetrapib 5 mg, and 15 (57.7%) in obicetrapib 10 mg. TEAEs reported by more than one participant overall are shown in Table 3. All TEAEs were mild or moderate in severity and unrelated to the study drug. There were none that led to study drug discontinuation or withdrawal from the study, and no deaths were reported during the study. The most common TEAEs reported overall were nasopharyngitis, back pain, COVID-19, diabetes mellitus, and hypoglycemia. One participant in the obicetrapib 5 mg group experienced a serious adverse event of angina pectoris, which was rated as mild and not related to the study drug. There were no clinically meaningful changes in biochemical safety measures or vital signs in any obicetrapib group compared with placebo.
|
System organ class Preferred terma |
Placebo (N = 26) |
Obicetrapib 2.5 mg (N = 25) |
Obicetrapib 5 mg (N = 25) |
Obicetrapib 10 mg (N = 26) |
|---|---|---|---|---|
| n (%) | ||||
| Any TEAEb | 15 (57.7) | 9 (36.0) | 8 (32.0) | 15 (57.7) |
| Infections and infestations | 5 (19.2) | 0 (0.0) | 2 (8.0) | 4 (15.4) |
| Nasopharyngitis | 3 (11.5) | 0 (0.0) | 1 (4.0) | 2 (7.7) |
| COVID-19 | 1 (3.8) | 0 (0.0) | 1 (4.0) | 1 (3.8) |
| Metabolism and nutrition disorders | 4 (15.4) | 3 (12.0) | 1 (4.0) | 3 (11.5) |
| Diabetes mellitus | 0 (0.0) | 2 (8.0) | 0 (0.0) | 1 (3.8) |
| Hypoglycemia | 0 (0.0) | 2 (8.0) | 0 (0.0) | 1 (3.8) |
| Decreased appetite | 1 (3.8) | 0 (0.0) | 0 (0.0) | 1 (3.8) |
| Diabetes mellitus inadequate control | 1 (3.8) | 0 (0.0) | 0 (0.0) | 1 (3.8) |
| Hyperglycemia | 2 (7.7) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Musculoskeletal and connective tissue disorders | 4 (15.4) | 2 (8.0) | 1 (4.0) | 3 (11.5) |
| Back pain | 3 (11.5) | 0 (0.0) | 0 (0.0) | 2 (7.7) |
| Arthralgia | 1 (3.8) | 0 (0.0) | 0 (0.0) | 1 (3.8) |
| Investigationsc | 2 (7.7) | 0 (0.0) | 2 (8.0) | 3 (11.5) |
| Blood pressure increased | 0 (0.0) | 0 (0.0) | 1 (4.0) | 1 (3.8) |
| Gastrointestinal disorders | 1 (3.8) | 2 (8.0) | 2 (8.0) | 0 (0.0) |
| Diarrhea | 1 (3.8) | 0 (0.0) | 1 (4.0) | 0 (0.0) |
| Respiratory, thoracic, and mediastinal disorders | 0 (0.0) | 0 (0.0) | 0 (0.0) | 3 (11.5) |
| Rhinitis allergic | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (7.7) |
| Vascular disorders | 1 (3.8) | 1 (4.0) | 0 (0.0) | 0 (0.0) |
| Hypertension | 1 (3.8) | 1 (4.0) | 0 (0.0) | 0 (0.0) |
Abbreviation: TEAE, treatment emergent adverse event
a Terms were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 25.0.
b TEAEs were defined as AEs that started after the first dose of study drug.
c Investigations is the MedDRA system organ class defined as laboratory tests and other medical investigations that gave an unusual reading.
Mean plasma levels of obicetrapib at 2, 4, and 8 weeks of treatment, and 4 weeks after the end of the treatment period (week 12) are shown in Fig.2. At the end of treatment, mean plasma levels of obicetrapib in the 2.5 mg, 5 mg, and 10 mg treatment groups were 194 ng/mL, 362 ng/mL, and 506 ng/mL, respectively. Four weeks after the end of the treatment period, obicetrapib levels had decreased by 93.4%, 93.5%, and 95.2%, to mean levels of 13.2 ng/mL, 24.6 ng/mL, and 27.6 ng/mL, respectively.
Abbreviation: EOT, end of treatment.
In this trial of Japanese men and women who had not achieved their treatment goals according to the 2022 Japan Atherosclerosis Society Guidelines for Prevention of ASCVD14) and had LDL-C ＞70 mg/dL or non-HDL-C ＞100 mg/dL while receiving stable stain therapy, LDL-C, apoB, and non-HDL-C were significantly decreased and HDL-C and apoE were significantly increased with all doses of obicetrapib administered (2.5, 5, and 10 mg) compared with placebo. The 45.8% median reduction in LDL-C in the highest dose obicetrapib group is consistent with previous responses to obicetrapib 10 mg in combination with moderate or high-intensity statins in trials conducted in predominantly non-Hispanic white (Caucasian) populations, suggesting no effect of race or ethnicity on lipid outcomes10-12). An understanding of an investigational agent in a variety of racial/ethnic groups is a key component of a global drug development program. Furthermore, the regulatory agencies of some countries, such as Japan, require that drugs marketed in that country have been tested in their population17). Evaluations of other historical CETP inhibitors, including evacetrapib and anacetrapib, in Japanese patients with dyslipidemia have also found similar effects of reducing LDL-C and increasing HDL-C as in non-Japanese populations18, 19).
The prevalence of ASCVD is lower in Japan compared to Western countries20). While this is typically attributed to lifestyle differences, it may also be attributable to differences in certain clinical parameters, including lipoprotein lipids, and to genetic differences20-22). The first genetic deficiencies of CETP were discovered in Japan; in fact, genetic CETP deficiency is rare in ethnic groups other than East Asians21, 22). Mendelian randomization analyses in populations with European ancestry have consistently shown that on-target inhibition of CETP will decrease risk of coronary heart disease; this has also recently been confirmed to occur in East Asians23, 24). A large, drug target Mendelian randomization study in 1,320,016 European and 146,492 East Asian individuals indicated that lower CETP was associated with lower LDL-C in both groups, although the effects were more pronounced in European individuals25). Furthermore, lower CETP activity was associated with lower risk for coronary heart disease in individuals with both ancestries: East Asian odds ratio, 0.89; 95% confidence interval, 0.84-0.94 vs. European odds ratio, 0.95; 95% confidence interval 0.92-0.99; p-value for interaction =0.05 25). These findings are consistent with the reported reductions in LDL-C and ASCVD observed in the cardiovascular outcome trial of anacetrapib, which included a substantial number of patients from China25, 26). The ongoing Cardiovascular Outcomes Study to Evaluate the Effect of Obicetrapib in Patients with Cardiovascular Disease (PREVAIL; NCT05202509) will directly examine the effects of obicetrapib on reducing ASCVD risk. PREVAIL is globally enrolling 9000 patients from 377 locations, including 20 sites in China and 19 in Japan; it has an expected date of completion in late 2026.
The statins administered in this trial, atorvastatin 10-20 mg and rosuvastatin 5-10 mg are considered moderate-intensity statins. Maximum doses of all statins, except pitavastatin, approved for use in Japan are lower than those in other countries, including the U.S., due to increased risk for statin-associated muscle symptoms in persons of Asian ancestry27). A previous examination of obicetrapib in the Netherlands and Denmark which administered 10 mg obicetrapib as monotherapy and in combination with moderate intensity statins, 10 mg rosuvastatin or 20 mg atorvastatin, for 12 weeks reported LDL-C reductions of 45.3%, 63.3%, and 68.2%, respectively10). Since then, two phase 2 trials of 10 mg obicetrapib monotherapy administered on top of high-intensity statins, in trials that included ＜5% of participants with Asian ancestry, demonstrated LDL-C reductions of 43.5% and 45.7%11, 12).
The significant increase in plasma apoE with obicetrapib (+26.3% at the 10 mg dose) also has potential clinical relevance to ASCVD risk reduction, as well as to Alzheimer’s Disease28). ApoE acts as a lipid transporter; it is the main ligand for clearance of VLDL and chylomicron remnants. In the periphery, apoE is produced predominantly by hepatocytes and macrophages, but it is also expressed by cells in the central nervous system. ApoE deficiency, i.e., gene deletion in mice or polymorphisms in humans, has been shown to accelerate pathogenesis of atherosclerosis and brain pathology29). Further investigation into the potential mechanisms for obicetrapib’s effect on apoE in subjects taking statins is needed.
As expected, the results of the safety analyses showing obicetrapib to be safe and well tolerated in this current study of obicetrapib were consistent with previous reports from trials in predominantly non-Japanese participants as well as in the subgroup of healthy male Japanese patients enrolled in a single ascending dose investigation of obicetrapib, which found no effect of ethnicity on safety, PK, or pharmacodynamic effects9-12). Overall, obicetrapib taken for 8 weeks was well tolerated and there were no apparent differences between the obicetrapib and placebo groups for any category of TEAEs. There was one serious adverse event, which was assessed as not drug-related by the investigator. Furthermore, the observed mean plasma concentration of obicetrapib for this Japanese population is in line with what was demonstrated in previous studies conducted in Caucasian individuals10-12). Thus, taken together, the PK findings, lipid-modifying effects, and favorable safety profile confirm the appropriateness of utilizing a 10 mg dose of obicetrapib in patients from China and Japan participating in ongoing phase 3 trials.
Although this trial was limited by its relatively small sample size and short treatment period, it was adequate to demonstrate significant effects on lipids. Another potential limitation of this study was that it did not measure the effects of obicetrapib on the concentrations of lipoprotein particles or lipoprotein(a) among Japanese subjects. In the Study to Evaluate the Effect of Obicetrapib in Combination with Ezetimibe as an Adjunct to High Intensity Statin Therapy, 10 mg obicetrapib in combination with 10 mg ezetimibe significantly reduced total and small LDL particles by 72% and 95%, respectively, and altered the HDL profile in a manner suggesting it increased cholesterol flux through the HDL fraction12). The results from the Randomized Study of Obicetrapib as an Adjunct to Statin Therapy also indicated that 10 mg obicetrapib on top of high-intensity statin reduced lipoprotein(a) by 56.5%11). In addition to the ongoing cardiovascular outcome trial of obicetrapib mentioned previously, PREVAIL, three other phase 3 trials of obicetrapib are underway, as well as several phase 1 and 2 trials designed to further investigate the effects of obicetrapib on lipoprotein metabolism, and its safety and PK profile in various populations.
This study demonstrated the lipid-modifying efficacy, safety, and PK profile of obicetrapib in Japanese men and women with dyslipidemia and supports the continued global investigation of obicetrapib for reducing dyslipidemia and preventing ASCVD.
The authors wish to acknowledge the writing assistance of Liana Guarneiri, RD, PhD, a Clinical Scientist with Midwest Biomedical Research, Addison, Illinois, USA.
This trial was funded by NewAmsterdam Pharma.
M.H-S. is an outside director and received stock. received honoraria from Amgen and MEDPACE. M.H.D., M.D., A.H., E.W., D.K., A.N. (Nield), and J.J.P.K. are employees of NewAmsterdam Pharma B.V. and they also report that they receive stock or stock options. M.H.D. is Chief Executive Officer of NewAmsterdam Pharma. M.D. is Vice President of Research & Development of NewAmsterdam Pharma. A.H. is Executive Director, R&D of NewAmsterdam Pharma. E.W. is Executive Director of Clinical Operations of NewAmsterdam Pharma. D.K. is Chief Operating Officer of NewAmsterdam Pharma. A.N. (Nield) is Executive Vice President and Head of Global Regulatory Affairs of NewAmsterdam Pharma. J.J.P.K. is Chief Scientific Officer of NewAmsterdam Pharma and Emeritus Professor of Medicine at the University of Amsterdam, The Netherlands. M.R.D. is an employee of Midwest Biomedical Research, which has received consulting fees and/or grant funding from NewAmsterdam Pharma, Acasti Pharma, Beren Therapeutics, Eli Lilly and Company, Indiana University and Foundation, Matinas BioPharma, NorthSea Therapeutics, and 89Bio. A.N. (Nakata), A.S., and S.K. have no conflicts of interest to report.
M.H-S.: Conceptualization, Investigation, Supervision, Writing – Review & Editing. M.H.D.: Conceptualization, Writing – Review & Editing. M.D.: Conceptualization, Methodology, Funding Acquisition, Investigation, Project Administration, Supervision, Visualization, Writing - review & editing. A.H.: Conceptualization, Methodology, Project administration, Funding Acquisition, Writing – review & editing. E.W.: Conceptualization, Investigation, Project administration, Supervision, Writing – Review & Editing. D.K.: Conceptualization, Methodology, Project administration, Funding Acquisition, Writing – review & editing. A.N. (Nield): Conceptualization, Methodology, Project administration, Funding Acquisition, Writing – review & editing. M.R.D.: Writing – Original Draft, Writing – Review & Editing. A.N. (Nakata): Investigation, Supervision, Project administration. A.S.: Investigation, Supervision, Project administration. S.K.: Investigation, Supervision, Project administration. J.J.P.K.: Conceptualization, Methodology, Funding Acquisition, Writing – Review & Editing.
