AZD0780, a novel, oral PCSK9 inhibitor with properties allowing for broad use, food-intake independency and co-administration with other lipid lowering therapies

Abstract Introduction Even with a variety of lipid lowering therapies available, many patients do not reach LDL-C targets, leaving them at an increased risk of CV events. AZD0780, an oral, small molecule PCSK9 inhibitor has demonstrated meaningful LDL-C reduction in clinical studies supporting advancement to phase 3. Purpose To present an integrated profile of select key pharmacokinetic (PK) and absorption, metabolism, distribution and elimination (ADME) properties of AZD0780 relevant for investigators and prescribers evaluating potential future therapies. Methods The PK and ADME properties were characterized through in vitro experiments and multiple clinical studies involving healthy volunteers and participants with elevated LDL-C. Phase 1 studies included single doses (10-400mg) and multiple doses (1-60mg) with or without rosuvastatin, plus a single 10mg dose with itraconazole. Phase 2 examined 1-30mg doses on top of moderate and high-intensity statin therapy. Additionally, a two-part single dose ADME study in healthy male volunteers assessed oral bioavailability (Part A, 100µg IV [14C]AZD0780 microdose with AZD0780 60mg oral tablets) and drug disposition using mass balance (Part B, 60mg dose of [14C]AZD0780 oral solution). Population PK modeling explored predictors of AZD0780 exposure, including demographics, ezetimibe concomitant use, and statin-intensity. Metabolite enzyme identification was studied using spheroids of primary human hepatocytes. Results The half-life of AZD0780 is approximately 40 hours and consistent between doses. It is rapidly absorbed (1-4 hours Tmax) with high oral bioavailability (78.4%) and dose-proportional, time independent exposure. Variability in exposure is typical for a small molecule with 24% CV of AUCtau at a 30mg QD dose. No clinically relevant food effect was observed, and exposure was similar with or without rosuvastatin (AUCtau=67 vs 66 µM*h, respectively). In vitro data show AZD0780 is primarily metabolized by CYP3A4, but preliminary DDI results suggest no dose adjustment is needed with strong CYP3A4 inhibitor coadministration. The human ADME study showed 14% and 6% elimination as parent drug in urine and faeces, indicating limited impact of renal impairment on AZD0780 PK. No major circulating metabolites were identified. Population PK analysis from phase 1 and 2 data found no significant intrinsic or extrinsic factors which impact exposure to a clinically significant extent. Conclusion The PK and ADME properties of AZD0780 suggest it can be widely used without dose adjustment across patient subpopulations, including those with co-morbidities such as renal impairment or obesity. AZD0780 may offer a convenient once-daily oral therapy that could be co-administered with other oral lipid lowering treatments, such as statins, to help a large majority of patients reach guideline recommended LDL-C goals.