Discussion
Inherited deficiency, liver toxicity, thrombocytopenia, hepatic steatosis, TG
THROMBOCYTOPENIA, INJECTION SITE REACTION, HEPATIC STEATOSIS
This first-in-human, proof-of-concept, phase 1 study demonstrated that ARO-ANG3, a therapy that acts through an RNA interference (RNAi) mechanism, resulted in robust and sustained reductions from baseline of up to −92.7% in serum ANGPTL3 concentrations, with concomitant reductions in serum TG and atherogenic lipoproteins (LDL-C, non-HDL-C and VLDL-C) in HP participants. ANGPTL3 is a key regulator of circulating levels of TG and TRL and cholesterol levels (for example, LDL-C) through reversible inhibition of the enzymes LPL and endothelial lipase and, therefore, represents a novel therapeutic target for reducing atherogenic lipoproteinsARO-ANG3 showed durable pharmacologic effects lasting over 3 months after a single dose. This is a consequence of the unique intracellular mechanism of action of RNAi. After hepatic uptake of ARO-ANG3 and cleavage of its passenger RNA strand, the guide strand loads onto the RNA-induced silencing complex (RISC) and pairs with and degrades the Inherited deficiency in ANGPTL3 yields lower serum TG, LDL-C and HDL-C concentrations and is independently protective against coronary diseaseClinical studies with vupanorsen and evinacumab, targeting ANGPTL3, have shown that both can reduce LDL-C and TG. However, vupanorsen appears to increase ALT and risk of hepatic steatosisARO-ANG3 has demonstrated a safety profile supportive of late-stage clinical development. Mild injection site reactions were the most frequently reported TEAEs and are common to all subcutaneous injectables. No thrombocytopenia or liver toxicity was observed, even with repeat dosing. Clinical trials have shown that ASO treatment with vupanorsen was associated with hepatic steatosis and elevations in ALTThis phase 1 study was designed as an evaluation of the safety and efficacy of ARO-ANG3 using a basket of diverse dyslipidemic populations to explore different options for later-stage clinical development. This design is consistent with FDA guidance as a ‘master’ protocol intended to address multiple questions in a single study and is an acceptable approach for early-phase studies with a new therapeutic agent that is directed at a common target across a diverse populationIn summary, results from this early-stage clinical study indicate that siRNA therapy targeting 