USA – Pfizer has terminated its collaboration with Ionis for the cholesterol-lowering therapy vupanorsen, following a review of phase 2b data that raised concerns about the antisense drug’s efficacy and safety.

It’s a setback for Pfizer’s late-stage pipeline, given that the company had projected US$3 billion in potential sales for vupanorsen, which targets the ANGPTL3 protein and is competing in the category with Regeneron’s already-marketed Evkeeza (evinacumab).

The big pharma’s commitment to the program had already been called into question after it issued a somewhat evasive response to the trial data last November, despite vupanorsen exceeding its efficacy targets in the TRANSLATE-TIMI 70 study.

Subsequently, Pfizer has announced that it was discontinuing the program, stating that the magnitude of response seen in the trial “did not support continuation of…clinical development” in cardiovascular (CV) risk reduction and severe hypertriglyceridemia (SHTG).

While vupanorsen reduced non-HDL cholesterol, triglycerides, and ANGPTL3 protein levels more than placebo after 24 weeks, the drugmaker also reported that higher doses of the drug were associated with increases in liver enzymes, which can sometimes be a safety concern.

According to Pfizer, treatment was also linked to an increase in liver fat. There were no reports of drug-induced liver damage or treatment-related serious side effects.

Pfizer and Ionis did not provide specific side-effect rates, nor did they provide absolute or relative lipid levels differences between the drug and placebo groups.

While this outcome is disappointing, the clinical and scientific knowledge derived from the vupanorsen program will hopefully contribute to a greater understanding of cardiovascular risk reduction and severe hypertriglyceridemia and the current gaps in treating these conditions,” said James Rusnak, Pfizer’s chief development officer for internal medicine and hospital products.

Pfizer paid US$250 million upfront for vupanorsen rights in 2019, as part of a deal that included another US$1.3 billion in milestone payments, but will now return rights to Ionis.

The FDA approved Regeneron’s rival antibody product to treat a genetic form of elevated cholesterol – homozygous familial hypercholesterolemia (HoFH) – and the company is also testing it in other, more common forms of dyslipidemia and acute pancreatitis prevention.

Meanwhile, Arrowhead Pharmaceuticals and Verve Therapeutics are two other companies working in the ANGPTL3 space.

With the help of its oral COVID-19 antiviral Paxlovid (nirmatrelvir/ritonavir), Pfizer’s windfall revenues and profits from its BioNTech-partnered COVID-19 vaccine will soften the blow, but it still needs to bring other drugs to market in preparation for a post-pandemic world.

Vupanorsen was a key component of the company’s plans to add $15 billion in revenue with new products by 2025, which were announced in 2020, along with JAK inhibitor abrocitinib – which was delayed due to FDA concerns about the class – and the 20-valent pneumococcal vaccine Prevnar 20.

The setback comes after a string of pipeline disappointments for Ionis, including failed phase 3 trials for Biogen-partnered amyotrophic lateral sclerosis (ALS) therapy tofersen and tominersen for Huntington’s disease, both of which are licensed to Roche.

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