Pfizer's Vupanorsen Injection Receives First Clinical Trial Approval in China

On February 23, the CDE website showed that Pfizer's "Vupanorsen Injection" was approved for clinical trials in China for the first time. This drug is an antisense oligonucleotide therapy for lowering lipids. In 2019, Pfizer obtained the global exclusive licensing rights to this drug from Akcea and Ionis Pharmaceuticals with an upfront payment plus milestone payments totaling up to $1.55 billion.

Vupanorsen, initially discovered by Ionis Pharmaceuticals, is an RNAi therapeutic developed based on Ionis’s Ligand-Conjugated Antisense (LICA) technology platform. It targets hepatic angiopoietin-like protein 3 (ANGPTL3) and is indicated for reducing the risk of cardiovascular disease and treating severe hypertriglyceridemia.

ANGPTL3 is a key regulator of triglyceride and cholesterol metabolism. It not only reduces levels of triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL), but also enhances insulin sensitivity and lowers the incidence of coronary heart disease. Vupanorsen has the potential to become a first-in-class therapy that inhibits ANGPTL3 to reduce cardiovascular risk.

In October 2019, Pfizer entered into a global exclusive licensing agreement with Akcea and Ionis for vupanorsen, based on its optimism about the drug’s potential. Under the terms of the agreement, Akcea and Ionis received a $250 million upfront payment and are eligible to receive up to $1.3 billion in milestone payments, while Pfizer will continue the development of vupanorsen.

At the 2020 European Society of Cardiology (ESC) Annual Congress, held online, Akcea presented Phase 2a clinical data on vupanorsen for the treatment of cardiovascular disease. The results demonstrated that, compared with placebo, vupanorsen met the primary endpoint of significantly reducing triglyceride (TG) levels as well as multiple secondary endpoints, and exhibited a favorable safety and tolerability profile.

This trial is a randomized, double-blind, multicenter, placebo-controlled Phase 2 study that enrolled 105 patients with hypertriglyceridemia, type 2 diabetes, and hepatic steatosis. The primary endpoint was the percent change from baseline in fasting triglycerides at 6 months. Secondary endpoints primarily included changes in ANGPTL3, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and other lipid components, glycated hemoglobin (HbA1c), and liver fat fraction.

In the three cohorts receiving vupanorsen 40 mg every 4 weeks (Q4W), 80 mg every 4 weeks (Q4W), and 20 mg weekly (QW), triglyceride levels were reduced by 36%, 53%, and 47%, respectively, whereas the placebo group exhibited only a 16% reduction.

Compared with the placebo group, the Vupanorsen 80 mg Q4W group significantly reduced ANGPTL3 (62%), apolipoprotein CIII (58%), total cholesterol (19%), non-HDL cholesterol (18%), HDL cholesterol (24%), and apolipoprotein B (9%), with statistically significant differences.

Currently, Pfizer has initiated a Phase IIb clinical trial abroad. The trial will explore different dosing regimens and evaluate the efficacy, safety, tolerability, and pharmacokinetics of vupanorsen. Its primary endpoint is the percentage change from baseline in non-high-density lipoprotein cholesterol (non-HDL-C) at Week 24.

Antisense RNA therapy has emerged as a significant area of considerable interest in recent years. Initially, this class of therapeutics was primarily employed for the treatment of rare and genetic diseases; however, cardiovascular diseases have recently become a key area of breakthrough.

In 2019, Novartis acquired The Medicines Company for $9.7 billion, gaining access to inclisiran, an antisense RNA therapy targeting PCSK9. The drug has already been approved in Europe, with US approval imminent. In China, inclisiran was included in the Breakthrough Therapy Designation by the Center for Drug Evaluation (CDE) in November 2020, and its Phase III clinical trials have been initiated. Meanwhile, vupanorsen, which recently received clinical trial approval, represents another promising candidate; Pfizer secured global rights to this asset in 2019 through a $250 million upfront payment and $1.3 billion in milestone payments, making its development highly anticipated.