Randomized, open-label, cross-over, phase-3 study to evaluate efficacy and safety of LIB003 compared with evolocumab in homozygous familial hypercholesterolaemia patients on stable lipid-lowering therapy (liberate-HOFH)

Background and Aims: Lerodalcibep (LIB), a small recombinant fusion protein of a PCSK9‐binding domain (adnectin) and albumin, demonstrated highly effective PCSK9 and LDL‐C suppression in Phase 2 studies. This global Phase 3 trial included India and Turkey, evaluated safety and efficacy of LIB 300 mg SC QM compared to evolocumab (EVO) 420 mg SC QM in genetically confirmed HoFH patients with novel variants on stable lipid lowering therapy not receiving LDL‐apheresis. Methods: Eligible patients (age ≥10 years) were randomized to either LIB or EVO for 24 weeks (Period A) followed by an 8 week ‘washout’ and crossed over to the alternate therapy for the next 24 weeks (Period B). Results: Of 82 HoFH patients screened, 65 entered Period A and 56 completed both Periods (mean age 29; range 10‐58 years; 45% male; mean baseline LDL‐C 401 mg/dL); Mean (SD) reduction in LDL‐C was ‐9.6% (24.3) on LIB and ‐11.7% (27.4) on EVO. LDL‐C reductions were highly variable but were similar with LIB and EVO in individual subjects (r=0.79; p<0.001) ‐ figure. Mean free PCSK9 levels were decreased by 81% at trough on LIB. Both drugs were well tolerated, with no treatment related safety concerns or deaths. [Formula presented] Conclusions: LIBerate‐HoFH is the largest randomized and diverse global trial conducted in genetically confirmed HoFH patients. Despite robust PCSK9 suppression, the LDL‐C response was highly variable but similar with both drugs. PCSK9 inhibitors remain standard of care in HoFH with good residual LDLR activity and worth assessing for those with novel variants but unknown LDLR activity.