Introduction
The management of homozygous familial hypercholesterolemia (HoFH) has long represented one of the most significant challenges in lipidology. As a rare and life-threatening genetic disorder, HoFH is characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels from birth, leading to premature and aggressive cardiovascular disease. The fundamental pathophysiological hurdle in HoFH is the severe impairment or total absence of LDL receptor (LDLR) activity. Because traditional potent therapies, such as statins and PCSK9 inhibitors, rely heavily on the upregulation of residual LDLRs, their efficacy is often profoundly limited in this population. However, the emergence of angiopoietin-like 3 (ANGPTL3) inhibitors has shifted the paradigm, offering a potent lipid-lowering mechanism that operates independently of the LDL receptor.
The Mechanistic Advantage of ANGPTL3 Inhibition
ANGPTL3 is a protein primarily secreted by the liver that acts as a key regulator of lipoprotein metabolism. It functions by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL). By inhibiting ANGPTL3, either through monoclonal antibodies or RNA interference (RNAi), these enzymes are disinhibited. This leads to increased processing of triglyceride-rich lipoproteins and a significant reduction in LDL-C through pathways that do not require a functional LDL receptor. This ‘receptor-independent’ mechanism is precisely why ANGPTL3 directed therapies are uniquely suited for HoFH patients, especially those with ‘null/null’ genotypes who have zero receptor function.
The SHR-1918 Phase 2 Trial: Potency of Monoclonal Antibodies
Recent data from a multicenter, single-arm, phase 2 trial conducted in China evaluated SHR-1918, a fully human monoclonal antibody targeting ANGPTL3. The study included 26 adults with HoFH who were already on stable, high-intensity lipid-lowering therapy. Participants received 600 mg of SHR-1918 subcutaneously every four weeks for 12 weeks.
The results were striking. At week 12, the mean percent change in serum LDL-C from baseline was -59.09% (95% CI, -63.81% to -54.36%). This reduction was not only substantial but also remarkably consistent across different genetic subtypes. Patients with homozygous genotypes saw a reduction of -61.32%, while compound heterozygous and double heterozygous patients saw -56.40% and -72.21%, respectively. Safety was also favorable; while 61.5% of patients experienced at least one treatment-emergent adverse event, most were mild, with the most common being proteinuria (15.4%) and minimal injection site reactions. These findings underscore the potential of SHR-1918 as a transformative therapeutic option for patients who have plateaued on conventional regimens.
Zodasiran and the GATEWAY Trial: The RNAi Approach
While monoclonal antibodies block the protein directly in circulation, RNA interference (RNAi) therapies like zodasiran target the production of ANGPTL3 at its source in the liver. The GATEWAY trial, an open-label, randomized, phase 2 study, evaluated zodasiran in patients with documented HoFH. Patients were assigned to receive either 200 mg or 300 mg of zodasiran on day 1 and month 3.
At month 6, patients achieved dose-responsive reductions in fasting LDL-C, with the 200 mg group seeing a -35.7% reduction and the 300 mg group seeing a -39.9% reduction. Interestingly, in a subset of patients who were also receiving a PCSK9 inhibitor, the reduction was even more pronounced, reaching -55.8% at month 6. The long-term open-label extension showed sustained efficacy over 12 months, with a pooled reduction of -40.7%. Zodasiran demonstrated a favorable safety profile with no drug-related serious adverse events or discontinuations. The quarterly dosing schedule of RNAi therapeutics offers a significant advantage in terms of patient adherence compared to more frequent injections.
Comparative Efficacy: ANGPTL3i vs. PCSK9i
A comprehensive meta-analysis involving 12 trials and 392 patients has provided the most definitive comparison to date between ANGPTL3 inhibitors and PCSK9 inhibitors in the HoFH population. The analysis revealed a clear superiority for ANGPTL3 inhibition across almost all lipid parameters.
At a median follow-up of 12 months, ANGPTL3 inhibitors achieved a mean LDL-C reduction of -50.77%, compared to only -17.88% for PCSK9 inhibitors (p < 0.001). The disparity was even more pronounced when looking at specific genotypes. In patients with the negative LDLR genotype (null-receptor), ANGPTL3 inhibitors produced a 34.5% greater reduction in LDL-C than PCSK9 inhibitors. Furthermore, ANGPTL3 inhibitors were significantly more effective at reducing total cholesterol (-49.9% vs -21.2%) and triglycerides (-48.9% vs -8.2%).
However, the meta-analysis noted a distinct difference in the impact on high-density lipoprotein cholesterol (HDL-C). While PCSK9 inhibitors slightly increased HDL-C (+5.2%), ANGPTL3 inhibitors were associated with a significant decrease (-28.9%). While the clinical significance of lowering HDL-C in the context of massive LDL-C reduction remains a topic of debate, the overall reduction in atherogenic burden (Apolipoprotein B) was significantly greater with ANGPTL3 inhibitors (-26.9% vs -13.2%).
Expert Commentary and Clinical Implications
The clinical implications of these findings are profound. For decades, the ‘null/null’ HoFH patient was considered largely untreatable outside of liver transplantation or lifelong LDL apheresis. The data from SHR-1918, zodasiran, and the recent meta-analysis suggest that ANGPTL3 inhibition is not merely an ‘add-on’ therapy but a primary pillar of management for HoFH.
From a clinical decision-making perspective, the choice between a monoclonal antibody (like SHR-1918 or evinacumab) and an RNAi (like zodasiran) may eventually come down to dosing frequency and patient preference. Monoclonal antibodies offer a rapid onset of action, while RNAi provides a more stable, long-term suppression of ANGPTL3 with less frequent administration.
Clinicians should also be aware of the safety nuances. While ANGPTL3 inhibitors are generally well-tolerated, the observation of proteinuria in the SHR-1918 trial and the reduction in HDL-C across the class warrant ongoing monitoring. Nevertheless, when compared to the catastrophic risk of untreated HoFH, the benefit-to-risk ratio of these agents appears exceptionally favorable.
Summary and Future Directions
The therapeutic landscape for HoFH has been revolutionized by the validation of the ANGPTL3 pathway. The superior efficacy of ANGPTL3 inhibitors over PCSK9 inhibitors—particularly in receptor-negative patients—establishes them as the preferred biologic therapy for this high-risk population. As we move toward Phase 3 results for many of these agents, the focus will likely shift toward earlier intervention and the potential for these therapies to be used in broader populations with refractory hypercholesterolemia. For now, the evidence is clear: for the patient with HoFH, ANGPTL3 inhibition offers a level of LDL-C control that was previously thought impossible.
Funding and Trial Information
The SHR-1918 study was supported by Jiangsu Hengrui Pharmaceuticals (ClinicalTrials.gov: NCT06009393). The GATEWAY trial was funded by Arrowhead Pharmaceuticals (ClinicalTrials.gov: NCT05217667). No external funding was declared for the meta-analysis by Bytyçi et al.
References
1. Peng D, Wang L, Pi L, et al. Anti-ANGPTL3 Antibody SHR-1918 for Homozygous Familial Hypercholesterolemia: A Nonrandomized Clinical Trial. JAMA Cardiol. 2026; doi:10.1001/jamacardio.2025.4878.
2. Raal FJ, Bergeron J, Gaudet D, et al. Zodasiran, an RNAi therapeutic targeting ANGPTL3, for treating patients with homozygous familial hypercholesterolaemia (GATEWAY): an open-label, randomised, phase 2 trial. Lancet Diabetes Endocrinol. 2026;14(2):123-136.
3. Bytyçi I, Henein MY, Bytyqi S, et al. PCSK9 and ANGPTL3 Inhibitors in Homozygous Familial Hypercholesterolemia: A Meta-analysis of Randomized Clinical Trials. Drugs. 2026; doi:10.1007/s40265-025-02272-z.
