- Pfizer will stop development of an experimental heart-disease drug it paid $250 million to license from Ionis Pharmaceuticals two years ago, saying Monday that it had concluded the effects of treatment to be too modest to merit further testing.
- As a result, Pfizer will hand back rights to the drug, called vupanorsen, to Ionis, likely curtailing the medicine's future. Vupanorsen is designed to target genetic instructions that encode for a protein called ANGPTL3, low levels of which have been linked with decreased amounts of triglycerides and LDL cholesterol in the blood.
- Last November, Pfizer said a Phase 2b study of vupanorsen showed treatment with the drug led to significant reductions in non-HDL cholesterol and triglycerides. However, in Monday's statement the drugmaker noted that the "magnitude" of those reductions "did not support continuation of the clinical development program" for heart-risk reduction and severely high triglycerides.
A year ago, the Food and Drug Administration approved the first drug capable of targeting the ANGPTL3 protein, an antibody treatment from Regeneron called Evkeeza. The regulatory OK offered a stamp of validation for drug-making efforts around ANGPTL3, which had emerged as a promising treatment target following animal studies in the early 2000s and human genome sequencing and genetic risk association studies in the 2010s.
Regeneron's drug won clearance for treatment of people with a rare, inherited form of high cholesterol known as homozygous familial hypercholesterolemia. With vupanorsen, Pfizer and Ionis were exploring ANGPTL3 targeting as an approach for lowering cardiovascular risk and for severe hypertriglyceridemia.
However, the treatment effects they observed in mid-stage testing didn't appear to be significant enough to outweigh some of the safety concerns that emerged in the Phase 2b trial.
While vupanorsen lowered non-HDL cholesterol, triglycerides and ANGPTL3 protein levels by more than placebo after 24 weeks in the study, the drugmaker also said higher doses of the drug were associated with increases in liver enzymes, which sometimes can be a safety concern.
Treatment also was associated with increases in liver fat, according to Pfizer. No cases of drug-induced liver injury were reported, nor were there any treatment-related serious side effects.
Pfizer and Ionis didn't detail specific side-effect rates, nor did they disclose the absolute or relative differences in lipid levels 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," James Rusnak, Pfizer's chief development officer for its internal medicine and hospital division, said in Monday's statement.
The Phase 2 study had enrolled 286 adults over the age of 40 who had elevated non-HDL cholesterol and triglycerides despite stable treatment with statins with or without the drug ezetimibe.
In a Jan. 31 note to clients, SVB Leerink analyst Mani Foroohar noted that the decision and additional information suggest that targeting ANGPTL3 may not be as predictably effective as going after PCSK9, another protein linked with LDL cholesterol and now the target of several approved drugs.
Vupanorsen is known as an antisense therapy and designed to degrade the RNA instructions that allow cells to turn DNA code into proteins. The drug-making approach has led to approved medicines for spinal muscular atrophy, genetically high levels of triglycerides and several rare liver and nerve diseases, many of which were developed by Ionis.
Ionis shares fell as much as 11% Monday morning, before gaining back some of the decline. Pfizer stock dropped 3%.