Pfizer Initiates Study of Vupanorsen

Ionis Pharmaceuticals and its wholly owned subsidiary Akcea Therapeutics announced Pfizer has initiated a Phase 2b study of vupanorsen (AKCEA-ANGPTL3-LRx) in statin-treated patients with elevated non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TGs). The study, Targeting ANGPTL3 with an antisense oligonucleotide in adults with dyslipidemia (TRANSLATE-TIMI 70), will evaluate various doses of vupanorsen to inform potential future development.

In the Phase 2a study, vupanorsen met the primary endpoint of significant reductions in TG levels and multiple secondary endpoints compared to placebo, with a favorable safety and tolerability profile.

"Results from the Phase 2a study recently presented at the ESC Congress and published in the European Heart Journal, showed that antisense-mediated reduction of ANGPTL3 has the potential to address unmet needs in patients with atherosclerotic cardiovascular diseases, and adds to the growing body of evidence supporting our LICA antisense technology," said Sam Tsimikas, vice president of global cardiovascular development at Ionis. "We look forward to seeing Pfizer advance the Phase 2b study and report results on this clinical program."

The first patient has been treated in the multicenter, double-blind, placebo-controlled, dose-ranging Phase 2b study. TRANSLATE-TIMI 70 has an estimated total enrollment of 260 participants (≥ 40 years old) with elevated non-HDL-C (≥ 100 mg/dL) and triglycerides (150-500 mg/dL) who are receiving a stable dose of a statin. The study will explore different doses and dose regimens versus placebo, with patients receiving either 80 mg, 120 mg or 160 mg every 4 weeks, or 60 mg, 80 mg, 120 mg or 160 mg every two weeks via subcutaneous injection. The study (NCT04516291) will assess the efficacy, safety, tolerability and pharmacokinetics of vupanorsen, and the primary endpoint is percent change from baseline in non-HDL-C at week 24.

In November 2019, Akcea and Ionis announced the closing of a worldwide exclusive licensing agreement with Pfizer for vupanorsen. Pfizer is responsible for all development and regulatory activities and costs for vupanorsen beyond those associated with the Phase 2a study. Under the terms of the licensing agreement, the initiation of the Phase 2b study triggered a milestone payment of $75 million from Pfizer.

Vupanorsen is an investigational antisense therapy being developed for potential indications in cardiovascular risk reduction and severe hypertriglyceridemia. Vupanorsen is designed to reduce the production of angiopoietin-like 3 (ANGPTL3) protein, a key regulator of triglyceride and cholesterol metabolism, in the liver. This antisense therapy was developed using Ionis' advanced LIgand Conjugated Antisense (LICA) technology platform. The potential therapeutic benefits of ANGPTL3 reduction are supported by the discovery that people with a genetic deficiency in ANGPTL3 have reduced levels of low-density lipoprotein cholesterol (LDL-C) and TG, and a decreased risk of diabetes and cardiovascular disease.1 In a Phase 1 study, subjects treated with vupanorsen achieved robust, dose-dependent reductions in ANGPTL3, TG, LDL-C, non-HDL-C and total cholesterol with a favorable safety and tolerability profile.2 In a Phase 2a study, vupanorsen met the primary endpoint of significant reductions in TG levels and multiple secondary endpoints compared to placebo, with a favorable safety and tolerability profile.