Determinants of short term Lp(a) variability in phase 3 obicetrapib trials

Introduction In the BROADWAY and BROOKLYN studies, obicetrapib reduced lipoprotein(a) (Lp(a)) in participants with a range of elevated concentrations below those studied in phase 3 trials of RNA targeted Lp(a) lowering therapeutics. Although repeated testing of lipoprotein(a) (Lp(a)) is generally viewed as unnecessary due to the genetically-determined nature of levels, there are limited data on the variability in Lp(a) measurements over time, which might impact the ability to identify individuals who might benefit from Lp(a) lowering with obicetrapib and therefore justify repeated testing. Purpose To document predictors of short-term variability in Lp(a) assessments in phase 3 studies of obicetrapib. Methods The analysis cohort comprised participants from the placebo arms of the BROADWAY and BROOKLYN studies with Lp(a) measurements at randomization and week 12. A Bland-Altman plot summarized variability of the two assessments. The per-participant absolute value of the difference in assessments was related to baseline characteristics in linear regression models overall and among those with elevated concentrations who were not necessarily eligible for studies of targeted Lp(a) lowering agents. Results Among 920 participants, median (IQR) Lp(a) concentrations were 38.6 (11.9, 161.7) and 38.4 (10.9, 156.2) at baseline and week 12, respectively. Bland-Altman analysis demonstrated that the overall bias was small (0.6 nmol/L), but 95% limits of agreement were relatively wide (−64.8 to 66.0 nmol/L; Figure). Although the assessments were strongly correlated (Spearman r=0.96), variability increased with average concentration (Figure). Among 95 participants with baseline Lp(a) 30 to <50 nmol/L, 11 (11.6%) had week 12 Lp(a) 50 to <150 nmol/L, while among 249 with baseline Lp(a) 150 nmol/L ,15 (6.0%) were 50 to <150 nmol/L at week 12. Only baseline Lp(a) explained a meaningful proportion of the variance in the difference in assessments (Table). Conclusion Over 12 weeks in obicetrapib phase 3 studies, a meaningful subset of participants unselected for Lp(a) shifted into a range where obicetrapib has demonstrated >40% reductions in Lp(a) — 50 to <150 nmol/L — while baseline levels explained a significant proportion of the variability in concentrations. These findings suggest that if Lp(a) lowering is proven to reduce cardiovascular risk, repeated testing may be warranted to determine if individuals who otherwise would not be eligible for treatment with a targeted Lp(a) lowering agent may benefit from such lowering with obicetrapib.