Pfizer has licensed exclusive global rights to Akcea Therapeutics’ Phase II cardiovascular and metabolic disease candidate AKCEA-ANGPTL3-LRx, through an agreement that could generate up to $1.5 billion-plus for Akcea and its corporate parent Ionis Pharmaceuticals, the companies said today.

AKCEA-ANGPTL3-LRx is an antisense therapy designed to reduce the production of angiopoietin-like 3 (ANGPTL3) protein in the liver, a key regulator of triglycerides, cholesterol, glucose, and energy metabolism.

AKCEA-ANGPTL3-LRx was developed using Ionis’ advanced Ligand Conjugated Antisense (LICA) technology platform. According to Ionis, LICA is a chemical modification that combines with its antisense therapies, targeting them to specific tissues, increasing the efficiency of drug uptake. Ionis says it aims to apply LICA in order to develop an emerging class of antisense medicines that can treat conditions, with both large and small patient populations, with less frequent and smaller doses.

According to Akcea and Ionis, 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 triglycerides, and a decreased risk of diabetes and cardiovascular disease—the finding of a 2018 study published in JAMA Cardiology.

AKCEA-ANGPTL3-LRx is being assessed in a Phase II study (NCT03371355) in patients with type 2 diabetes, hypertriglyceridemia, and non-alcoholic fatty liver disease (NAFLD). The 144-participant trial is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study designed to evaluate the safety, including tolerability, of AKCEA-ANGPTL3-LRx—also known as ISIS 703802—and assess the efficacy of different doses and dosing regimens of the antisense therapy candidate.

The study had an estimated primary completion date of November 29, 2019, and was active but not recruiting patients as of the most recent update on, dated September 27.

“Given the unmet medical need for this patient population and the broad market potential, we believe Pfizer’s expertise and breadth of experience in cardiovascular and metabolic diseases makes it well suited to accelerate clinical development of AKCEA-ANGPTL3-LRx, and to deliver it to patients in need of additional therapies for these life-threatening diseases,” Damien McDevitt, PhD, Akcea’s interim CEO, said in a statement.

McDevitt, who remains a member of Akcea’s board, became interim CEO two weeks ago. He succeeded Paula Soteropoulos, who left Akcea immediately along with two other top executives, president Sarah Boyce and COO Jeff Goldberg, the company stated on September 23. McDevitt joined Akcea from Ionis, where he was the chief business officer responsible for leading Ionis’ corporate development activities, including corporate communications, investor relations, business development, competitive intelligence, and alliance management.

Core therapeutic area

Pfizer reasons that AKCEA-ANGPTL3-LRx will strengthen one of its core therapeutic areas, cardiovascular and metabolic diseases. According to its website: “Pfizer is interested in partnering to develop therapeutics, expand our understanding of disease biology, and identify biomarkers” for treating four conditions:

  • CVD (Heart failure, dislipidemia, and atherosclerosis)
  • Diabetes and related co-morbidities
  • Non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and cirrhosis
  • Obesity and related co-morbidities

In May, Pfizer expanded its cardiovascular offerings when the FDA approved its Vyndaqel® (tafamidis meglumine) and Vyndamax (tafamidis) for treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization. Vyndaqel and Vyndamax are two oral formulations of the first-in-class transthyretin stabilizer tafamidis, and Pfizer has noted they are the first and only FDA-approved treatments for ATTR-CM.

“AKCEA-ANGPTL3-LRx is a novel therapy that will complement our clinical mid-stage internal medicine pipeline,” Mikael Dolsten, CSO and president, worldwide research & development and medical, Pfizer, said in a statement. “We believe that our deep expertise in cardiovascular and metabolic diseases will help allow this program to reach its maximum potential for patients.”

Pfizer agreed to pay Akcea and Ionis a $250 million upfront “license fee” that both companies have agreed to split evenly. Akcea plans to use the upfront payment to settle a $125 million obligation to Ionis in Akcea common stock, the companies said.

In addition, Pfizer agreed to pay Akcea and Ionis up to $1.3 billion in payments tied to achieving development, regulatory, and sales milestones, as well as tiered, double-digit royalties on annual worldwide net sales of AKCEA-ANGPTL3-LRx following marketing approval.

Pfizer is responsible for all development and regulatory activities and costs beyond those associated with the ongoing Phase II study. Before regulatory filing for marketing approval, Akcea has the option to participate in commercialization activities with Pfizer in the United States and certain additional markets on predefined terms and based on meeting predefined criteria.

Akcea and Ionis also agreed to split future milestone payments and royalties on a 50-50 basis.

The licensing agreement is subject to clearance under the Hart-Scott Rodino Antitrust Improvements Act and other customary closing conditions, Pfizer and Akcea/Ionis said.

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