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A Double-blind, Randomized, Placebo-controlled Phase 2 Study to Evaluate Efficacy, Safety, and Tolerability of Olpasiran (AMG 890) in Subjects With Elevated Lipoprotein(a)

Olpasiran Trials of Cardiovascular Events And LipoproteiN(a) Reduction - DOSE Finding Study

281

In Study 20180109, 68.0 % of subjects were men, and the mean age was 61.9 years. Most (88.3 %) subjects were white, followed by Asian (8.5 %), black or African American (2.1 %), and other (1.1 %); 2.1 % were Hispanic or Latino.

A total of 281 subjects were enrolled in the study and all 281 subjects received at least 1 dose of investigational product and were included in the full analysis set. Most (96.8 %) subjects completed the study. Nine (3.2 %) subjects (8 subjects, 3.5 %, in the overall olpasiran and 1 subject, 1.9 %, in the placebo group) discontinued the study; the most frequent reasons for discontinuation of study were withdrawal of consent from the study (4 olpasiran subjects, 1.4 %) and lost to follow-up (4 olpasiran subjects, 1.4 %), followed by death (1 placebo subject, 0.4 %).

The subject incidence of adverse events was consistent across olpasiran treatment groups and was similar in the overall olpasiran group (185 [81.5 %] subjects) compared with the placebo group (45 [83.3 %] subjects). The subject incidence of serious adverse events was 16 (7.0 %) subjects in the overall olpasiran group and 8 (14.8 %) subjects in the placebo group. Most adverse events were mild; no specific trend in the incidence of mild, moderate, or severe adverse events per treatment group was observed. The subject incidence of adverse events leading to discontinuation was similar in the overall olpasiran group (4 [1.8 %] subjects) compared with the placebo group (1 [1.9 %] subject). One placebo subject had a fatal adverse event of pneumonia

1. Primary Outcome Statistically significant decreases in change from baseline and percent change from baseline in Lp(a) at week 36 relative to placebo were observed for all olpasiran dose groups (adjusted p < 0.001). At week 36, LS mean decreases in Lp(a) relative to placebo (treatment difference) were 70.5%, 97.4 %, 101.1 %, and 100.5 % for the 10 mg Q12W, 75 mg Q12W, 225 mg Q12W, and 225 mg Q24W olpasiran groups, respectively 2. Secondary Outcome Significant decreases in change from baseline and percent change from baseline in Lp(a) at week 48 relative to placebo were observed for all olpasiran dose groups (nominal p < 0.001). At week 48, LS mean decreases in Lp(a) relative to placebo (treatment difference) were 68.5 %, 96.1 %, 100.9 %, and 85.9 % for the 10 mg Q12W, 75 mg Q12W, 225 mg Q12W, and 225 mg Q24W olpasiran groups, respectively. Significant decreases in percent change from baseline in LDL-C at week 36 and week 48 relative to placebo were observed for all olpasiran dose groups (nominal p < 0.001). At week 36, LS mean decreases in LDL-C relative to placebo (treatment difference) were 23.7 %, 22.5 %, 23.0 %, and 24.7 % for the 10 mg Q12W, 75 mg Q12W, 225 mg Q12W, and 225 mg Q24W olpasiran groups, respectively. At week 48, LS mean decreases in LDL-C relative to placebo (treatment difference) were 24.9 %, 21.6 %, 27.4 %, and 27.0 % for the 10 mg Q12W, 75 mg Q12W, 225 mg Q12W, and 225 mg Q24W olpasiran groups, respectively. Significant decreases in percent change from baseline in ApoB at week 36 and week 48 relative to placebo were observed for all olpasiran dose groups (nominal p < 0.001). At week 36, LS mean decreases in ApoB relative to placebo (treatment difference) were 18.9 %, 16.7 %, 17.6 %, and 18.8 % for the 10 mg Q12W, 75 mg Q12W, 225 mg Q12W, and 225 mg Q24W olpasiran groups, respectively. At week 48, LS mean decreases in ApoB relative to placebo (treatment difference) were 20.0%, 17.1 %, 19.5 %, and 21.8 % for the 10 mg Q12W, 75 mg Q12W, 225 mg Q12W, and 225 mg Q24W olpasiran groups, respectively. Olpasiran was rapidly absorbed and the vast majority was cleared from serum within 2 to 3 days after dosing. Maximum olpasiran concentrations were observed between approximately 3 and 12 hours post-dose based on the available PK data collected in this study. Olpasiran PK exposures did not change with multiple dose administration at any of the 3 dose levels evaluated (10, 75, and 225 mg), indicating that there is no accumulation in serum with Q12W or Q24W dosing. Olpasiran PK parameters were not calculated due to the limited number of PK blood samples which were collected within flexible time windows (eg, 6 to 12 hours post-dose) for this study.

Statistically significant decreases in % change from baseline in Lp(a) at week 36 and 48 relative to placebo were observed for all olpasiran dose groups. Significant decreases in % change from baseline in LDL-C and ApoB at week 36 and 48 relative to placebo were observed for all olpasiran dose groups. Olpasiran was shown to be safe and well tolerated during the treatment period and the extended safety follow-up period. Most AEs were mild. 1 fatal event of pneumonia was reported in the placebo group.

May. 16, 2022

https://pubmed.ncbi.nlm.nih.gov/35588897/

No

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

https://jrct.mhlw.go.jp/latest-detail/jRCT2031200367

Local Contact

Amgen K.K.

Midtown Tower 9-7-1 Akasaka, Minato-ku, Tokyo

clinicaltrials_japan@amgen.com

Local Contact

Amgen K.K.

Midtown Tower 9-7-1 Akasaka, Minato-ku, Tokyo

+81-80-7217-8592

clinicaltrials_japan@amgen.com

Complete

July. 28, 2020

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

- Age 18 to 80 years
- Lipoprotein (a) > 150 nmol/L
- Evidence of atherosclerotic cardiovascular disease

- Severe renal dysfunction
- History or clinical evidence of hepatic dysfunction
- Malignancy within the last 5 years
- Currently receiving, or less than 3 months at Day 1 since receiving > 200 mg/day Niacin

Both

Cardiovascular Disease

- Drug: olpasiran
Dose 1 Dose 2 Dose 3 Dose 4
- Drug: Placebo
Dose 5

1. Percentage Change From Baseline in Lipoprotein(a) (Lp[a]) at Week 36 [ Time Frame: Baseline and Week 36 ]
Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit.

1. Percentage Change From Baseline in Lp(a) at Week 48 [ Time Frame: Baseline and Week 48 ]
Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit.
2. Percentage Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 36 and Week 48 [ Time Frame: Baseline; Week 36 and Week 48 ]
Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit.
3. Percentage Change From Baseline in Apolipoprotein (B) (ApoB) at Week 36 and Week 48 [ Time Frame: Baseline; Week 36 and Week 48 ]
Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit.
4. Mean Serum Olpasiran Concentrations at Day 1, Week 24 and Week 48 [ Time Frame: Pre-dose and 1, 3, 6-12, and 24-72 hours post-dose on Day 1 and Week 24; Week 48 ]
Pharmacokinetic blood draws were collected at one timepoint during the 6-12 and 24-72 hour flexible time windows and at Week 48.
Lower limit of quantification (LLOQ) = 0.400 ng/mL. Values below the LLOQ were set to zero.

July. 03, 2020

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