Pfizer And Ionis’s Antisense Cholesterol Candidate Sparks Safety Worries
Concerns Despite Phase IIb Win
Executive Summary
Increases in liver enzymes and fat could dampen approval prospects despite vupanorsen meeting its mid-stage primary endpoint, some analysts have said.
Pfizer Inc. and Ionis Pharmaceuticals, Inc.’s antisense candidate vupanorsen has left experts cautious on safety even as it met the primary endpoint in a Phase IIb cholesterol study.
Although vupanorsen lowered its target protein in patients with dyslipidemia, Biomedtracker analysts noted topline data from the dose-finding study were obscure. The lack of efficacy details combined with the statement that Pfizer was continuing to review findings suggest side effects could have proved troublesome. Reported liver enzyme and fat events are of particular concern, the analysts explained.
Vupanorsen is designed to reduce the liver’s production of angiopoietin-like protein 3 (ANGPTL3), which is a key regulator of triglyceride (TG) and cholesterol metabolism. It is in development for indications related to cardiovascular risk reduction and for severe hypertriglyceridemia, where patients have high levels of plasma TG.
Despite the analyst's criticism, Ionis’s head of global cardiovascular development, Sotirios Tsimikas, said he was pleased with the efficacy data.
The 286-patient Phase IIb trial studied vupanorsen in dyslipidemia patients with elevated non-high density lipoprotein cholesterol (non-HDL-C) and TG who were receiving a stable dose of a statin. Subcutaneous vupanorsen was dosed at 60mg, 80mg, 120mg and 160mg on varying schedules.
Vupanorsen achieved a significant reduction in the non-HDL-C change primary endpoint at week 24, topline data show. However, common abnormalities included increases in liver enzymes, alanine aminotransferase and aspartate aminotransferase, mostly seen at higher doses, while some doses were also associated with increases in hepatic fat fraction.
As for secondary endpoints, vupanorsen attained significant reductions in ANGPTL3 and TG at week 24. Full data will be presented at a medical meeting next year.
More Data Needed
Only one drug targeting ANGPTL3 has been approved. In February, the US Food and Drug Administration gave Regeneron Pharmaceuticals, Inc.’s monoclonal antibody Evkeeza (evinacumab) the green light for rare disease homozygous familial hypercholesterolemia (HoFH). (Also see "Regeneron's Evkeeza Approved For Ultra-Rare Genetic High Cholesterol – And Priced To Match" - Scrip, 11 Feb, 2021.)
Just 1,300 patients in the US are estimated to have HoFH, but Pfizer has high hopes that vupanorsen could treat the broader high cholesterol population. The US giant had been planning a Phase III program for vupanorsen, which could have included a cardiovascular outcomes trial. (Also see "Regeneron's Evkeeza Approved For Ultra-Rare Genetic High Cholesterol – And Priced To Match" - Scrip, 11 Feb, 2021.) If Pfizer does go ahead with a late-stage study, the candidate could attain $3bn peak sales, according to BMO Capital Markets analysts.
However, Biomedtracker analyst predictions for approval likelihood have dropped by 8% to a measly 3%. The analysts cited trial size as a potential issue, noting that while there were no cases of Hy’s law, which indicates of severe liver toxicity, these may not show up outside of large studies.
Even in the absence of toxicity, observed increases in liver fat are concerning given that vupanorsen is supposed to reduce cardiovascular risk. However, the company noted that increases in liver fat could potentially be related to the biology of certain patients, such as diagnoses of diabetes, the BMO analysts said.
Nonetheless, further details are needed to ascertain whether there are efficacious doses without troubling side effects, Biomedtracker analysts asserted. Competition-wise, Arrowhead Pharmaceuticals, Inc.’s Phase II RNAi candidate ARO-ANG3 for hypertriglyceridaemia, which also targets ANGPTL3, has a 4% likelihood of approval, according to Biomedtracker.
Kynmaro Is Not a Blueprint
Interestingly, Ionis’s antisense product Kynamro (mipomersen) received US approval for HoFh in 2013 despite observed increases in liver enzymes and liver fat. However, HoFH is a high-need orphan indication and drug candidates with significant liver side effects would face greater difficulty getting the green light for broader dyslipidemia indications, Biomedtracker claimed.