PCSK9 antagonists (Ensemble Therapeutics)

A genetic medicine from Ionis Pharmaceuticals designed to reduce high levels of cholesterol has achieved the main goal of a Phase 2 study, but the results are short of what partner AstraZeneca hoped for, leading the pharmaceutical giant to abandon plans to continue clinical testing. Ionis and AstraZeneca had been vying to compete among a relatively new class of therapies that interfere with PCSK9. In high amounts, that liver protein makes it harder for the body to clear low-density lipoprotein (LDL) cholesterol. Drug developers have been coming up with different ways to lower levels of PCSK9. Amgen and Regeneron Pharmaceuticals have each commercialized antibody drugs that block PCSK9. Last year, Novartis won FDA approval for Leqvio, a genetic medicine that employs an approach called RNA interference to stop production of PCSK9. The Ionis drug, ION449, is a type of genetic medicine called an antisense oligonucleotide. The therapy is designed to bind to messenger RNA, preventing it from producing PCSK9 in the liver, which in turn lowers levels of that protein in the blood. Carlsbad, California-based Ionis said Friday that compared with a placebo, preliminary Phase 2 data showed its drug led to a statistically significant 62.3% reduction in LDL cholesterol after 28 weeks in patients with hypercholesterolemia, or high cholesterol. Other than stating that the therapy did not achieve AstraZeneca’s pre-specified efficacy criteria, the companies provided no additional details about results. William Blair analyst Myles Minter spoke with Ionis executives on Friday. In a research note sent to investors, Minter said they told him AstraZeneca set a goal of 70% reduction in LDL cholesterol, a bar that would differentiate the therapy from Novartis’s Leqvio. In Leqvio’s Phase 3 study, the therapy showed a 52% reduction in LDL cholesterol. But compared to other PCSK9 drugs, Leqvio offers a dosing advantage of one injection every six months. The injectable Amgen and Regeneron drugs are given every two weeks or monthly. ION449 is a once-monthly injectable drug. Despite posting a higher reduction in PCSK9 levels, Ionis told Minter that the results did not give AstraZeneca the confidence to proceed to a larger, resource-intensive Phase 3 test of the therapy. Minter added that Ionis executives noted that the 60 mg dose tested in Phase 2 led to no signs of elevated liver enzymes or changes in platelet counts—potential indicators of safety problems that could prevent further clinical development. Ionis plans to present the clinical trial data at a future medical conference, but Minter doesn’t see Ionis picking up the clinical trial plans that AstraZeneca abandoned. “AstraZeneca is contractually obligated to return the asset to Ionis with no financial obligation if not pursuing future development, but we do not see Ionis electing to run a large [cardiovascular] outcomes study (capital intensive), leaving Leqvio the only RNA-targeted therapeutic for PCSK9 inhibition on the market for at least the near future,” Minter wrote. Ionis has been working with AstraZeneca since 2012, when the companies started a cancer R&D alliance. Three years later, the two companies began an additional collaboration focused on the development of drugs for cardiovascular, renal, and metabolic diseases. ION449 is part of the latter collaboration, one of five medicines that AstraZeneca licensed under the deal. According to the financial terms of the pact, Ionis received $65 million up front and is eligible to earn up to $6.6 billion more tied to the achievement of regulatory and commercial milestones. In its 2021 annual report, Ionis said it has received more than $282 million from AstraZeneca through this collaboration. Image: Magicmine, Getty Images