Pfizer ends $3B drug dream despite phase 2b success, leaving Regeneron with a clear run at cardiovascular market

A big chunk of Pfizer’s plan to add $15 billion to sales just went up in smoke. Having gone over phase 2b data on cardiovascular drug vupanorsen, Pfizer has decided to return the rights to Ionis Pharmaceuticals, leaving it without a candidate it tipped to deliver peak sales of more than $3 billion.

Pfizer paid Ionis $250 million upfront for vupanorsen in 2019 and put the drug at the heart of the growth plan it unveiled the following year. The belief vupanorsen could rack up big blockbuster sales was built on studies linking loss-of-function variants in the ANGPTL3 gene to low levels of plasma triglycerides and LDL and HDL cholesterol. A hit on the primary endpoint last year validated Ionis’ antisense approach. 

However, while the top-line results in patients with elevated non-HDL cholesterol and triglycerides were positive, a deeper dive into the phase 2b data has exposed weaknesses. All doses of vupanorsen reduced non-HDL cholesterol, but none were particularly impressive.

As Pfizer put it in a statement, “the magnitude of non-HDL-C and [triglycerides] reduction observed did not support” continued clinical research in cardiovascular risk reduction or severe hypertriglyceridemia. Pfizer also highlighted dose-dependent increases in liver fat and elevated liver enzymes at higher doses in its explanation of the decision to dump vupanorsen.

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Ionis and Pfizer shared brief details of the liver toxicity issues when they released the top-line results late  last year. Those issues, coupled to muted comments by Pfizer about the next steps, had already pointed to potential problems for the program. Even so, Ionis’ stock fell 9% to $29 on news of the discontinuation.

Pfizer is returning the rights to Ionis. In theory, Ionis could take the drug forward, but the two companies  jointly announced its discontinuation; Richard Geary, chief development officer at the antisense firm, read the last rites.

“Although this is not the outcome we would have liked, we are grateful for this collaboration with Pfizer whose leadership in the development of vupanorsen has been instrumental in gaining important insights and learnings that will help us continue to deliver potentially life transforming treatments for people impacted by cardiovascular disease,” Geary said in a statement.

The discontinuation eliminates one of the most prominent riders in a blockbuster race. Regeneron is the other big beast of the ANGPTL3 space, and its antibody against the target, Evkeeza, is now approved and looks to be free from the liver toxicity issues that blighted vupanorsen. Other riders include Arrowhead Pharmaceuticals’ ARO-ANG3 and an early-stage program at Verve Therapeutics.