Pfizer Enters $1.5 Billion Licensing Deal for RNA-Targeted Therapy AKCEA-ANGPTL3-LRx

Today, Akcea Therapeutics, a subsidiary of Ionis Pharmaceuticals, announced that it has entered into a global exclusive license agreement with Pfizer for its investigational antisense oligonucleotide drug, AKCEA-ANGPTL3-LRx, for the treatment of specific cardiovascular and metabolic diseases.

Previous research findings indicate that loss-of-function mutations in angiopoietin-like protein 3 (ANGPTL3) are associated with reduced low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels, as well as increased insulin sensitivity, thereby holding the potential to lower the risk of diabetes and cardiovascular disease.

▲ANGPTL3 antisense oligonucleotides can inhibit the production of ANGPTL3 (Image source: Reference [2])

Ionis Pharmaceuticals’ ligand-conjugated antisense (LICA) technology conjugates an N-acetylgalactosamine trimer (GalNAc3) to an antisense oligonucleotide targeting ANGPTL3 mRNA, forming the conjugate AKCEA-ANGPTL3-LRx. This modification enables targeted delivery of the antisense oligonucleotide therapeutic to hepatocytes, thereby increasing its hepatic potency by more than 10-fold.

▲Inhibiting ANGPTL3 production exerts multiple beneficial effects on lipoprotein metabolism (Image source: Reference [2])

Results from the Phase 1/2 trial demonstrated that AKCEA-ANGPTL3-LRx reduced plasma ANGPTL3 levels by 83%, with significant reductions in triglycerides (TGs; -66%), apolipoprotein C-III (apoC-III; -68%), low-density lipoprotein cholesterol (LDL-C; -35%), total cholesterol (-36%), high-density lipoprotein cholesterol (HDL-C; -25%), and non-HDL cholesterol (non-HDL-C; -40%). Furthermore, AKCEA-ANGPTL3-LRx exhibited a favorable tolerability and safety profile. AKCEA-ANGPTL3-LRx is currently being evaluated in a Phase 2 study in patients with type 2 diabetes, hypertriglyceridemia, and non-alcoholic fatty liver disease (NAFLD). AKCEA-ANGPTL3-LRx has the potential to become a unique therapeutic agent for lowering atherogenic lipoproteins, making it an ideal option for patients with poorly controlled LDL-C, elevated TGs, and possibly hepatic steatosis or NAFLD.

Under the terms of the agreement, Akcea and Ionis will receive a $250 million upfront payment and are eligible to receive up to $1.3 billion in development, regulatory, and sales milestone payments. Pfizer will be responsible for the continued development of AKCEA-ANGPTL3-LRx.

Mikael Dolsten, M.D., Chief Scientific Officer and President of Global Research, Development and Medical at Pfizer, stated: “Pfizer is committed to delivering breakthrough medicines for patients with unmet medical needs. AKCEA-ANGPTL3-LRx is a novel therapy, and Pfizer believes that its deep expertise in cardiovascular and metabolic diseases will help maximize the potential of this investigational drug in the future.”

References:

[1]. Akcea and Pfizer Inc. Announce Licensing Agreement for investigative antisense therapy AKCEA-ANGPTL3-LRx. Retrieved Oct. 7, 2019, from https://www.pfizer.com/news/press-release/press-release-detail/akcea_and_pfizer_inc_announce_licensing_agreement_for_investigative_antisense_therapy_akcea_angptl3_lrx

[2]. IONIS-ANGPTL3-LRx. Retrieved Oct. 7, 2019, from http://clinicaltrialresults.org/Slides/AHA2016/Tsimikas_IONIS-ANGPTL3.pdf

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