Presenter of 3 Presentations
Therapeutic strategies for homozygous familial hypercholesterolaemia: a review of the clinical trial data (ID 1631)
O044 - EVOLOCUMAB TREATMENT IN PAEDIATRIC PATIENTS WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA: DATA FROM THREE POOLED OPEN-LABEL STUDIES (ID 165)
Abstract
Background and Aims
Patients with homozygous familial hypercholesterolaemia (HoFH) have a premature, high risk for ASCVD, and treatment should be initiated as early as possible. We evaluated paediatric HoFH patients from three pooled trials to describe safety and efficacy of evolocumab (a proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitor monoclonal antibody) and the relationship between LDL-C lowering and genetic mutations.
Methods
HoFH patients (aged 10-17 years) participated in the TAUSSIG, RAMAN, or HAUSER-OLE studies and received open-label subcutaneous evolocumab (420 mg QM or Q2W) with background lipid-lowering therapy for 12 to 260 weeks. Patients receiving lipoprotein apheresis (n=4) were analyzed separately. The primary endpoint for this analysis was TEAEs, analyzed per 100 patient-years. Efficacy endpoints were percent change in lipids at week 12 and LDL-C change by LDLR mutation type.
Results
Of 39 patients in the pooled analysis set, 69% were male, mean age was 13.5 (SD=1.8) years, and 82% had genotyped HoFH (Table). Overall, median (Q1, Q3) evolocumab exposure was 18.2 months (3.0, 18.5). TEAEs with exposure-adjusted incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%). The rate for serious TEAEs was 13.3%. At week 12, mean percent change from baseline LDL-C was –10.0% (SD=21.2) in non-apheresis patients, with high variability depending on residual LDLR activity (Figure).
Conclusions
In paediatric patients with HoFH, LDL-C reduction achieved during 12 weeks of PCSK9 inhibitor therapy was variable, depending on residual LDLR activity. However, several patients achieved a clinically meaningful reduction in LDL-C. Safety findings were consistent with previous studies of evolocumab.
O066 - 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) (ID 1562)
Abstract
Background and Aims
Background: 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
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
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.
Conclusions
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.