Anti-ANGPTL3 Antibody SHR-1918 for Homozygous Familial Hypercholesterolemia

Importance: Homozygous familial hypercholesterolemia (HoFH) is a rare, life-threatening genetic disorder. Patients with HoFH have markedly elevated low-density lipoprotein cholesterol (LDL-C) levels from birth, and their activity of LDL receptor (LDLR) is typically absent or severely impaired. However, efficacy of traditional lipid-regulating agents relies on residual LDLR function. Angiopoietinlike 3 (ANGPTL3)-directed therapies could reduce lipid levels through an LDLR-independent pathway. Objective: To evaluate SHR-1918, a fully human monoclonal antibody targeting ANGPTL3, in adults with HoFH taking stable lipid-lowering therapy. Design, Setting, and Participants: This was a multicenter, single-arm, phase 2 nonrandomized clinical trial conducted at 8 sites in China between December 19, 2023, and April 2, 2024. Included were participants with HoFH taking stable lipid-lowering therapy. Interventions: Patients were given subcutaneous SHR-1918 at 600 mg every 4 weeks for 12 weeks, followed by an 8-week follow-up. Main Outcomes and Measures: The primary end point was the percent change in serum LDL-C level from baseline to week 12. Results: A total of 26 patients (mean [SD] age, 36.1 [12.2] years; 16 female [61.5%]) were included in this analysis. The mean (SD) baseline LDL-C level was 433.59 (173.74) mg/dL. At week 12, the mean percent change in LDL-C level was -59.09% (SD, 11.71%; 95% CI, -63.81% to -54.36%). The reduction was observed throughout the entire 8-week follow-up period. SHR-1918 suggested similar LDL-C reduction across HoFH genotypes, with a percent change from baseline to week 12 of -61.32% for homozygous, -56.40% for compound heterozygous, and -72.21% for double heterozygous. Overall, 16 patients (61.5%) had at least 1 treatment-emergent adverse event, with the most common being proteinuria (4 [15.4%]). Injection site reaction occurred in only 1 patient (3.8%) and included pain and rash or erythema (both grade 1). Conclusions and Relevance: Results show that SHR-1918 was associated with a substantial reduction in LDL-C level and favorable safety profile among patients with HoFH taking stable lipid-lowering therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT06009393.