While drugs are available that reduce levels of a lipoprotein (a), a protein associated with cardiovascular disease, no currently available therapies target this protein directly. Several companies are in various stages of clinical development with drugs that could tackle this protein, and AstraZeneca is paying $100 million to license a preclinical drug gives it a contender in the chase.
AstraZeneca’s new cardiovascular asset comes from Hong Kong-based CSPC Pharmaceutical Group. Beyond the upfront payment, the pharmaceutical giant could pay out up to $1.92 billion if the drug achieves development and commercialization milestones, according to deal terms announced Monday. CSPC will also receive royalties from sales of a commercialized product.
The CSPC drug, named YS2302018, is in development for dyslipidemia, which is abnormally high levels of cholesterol in the blood. One biological indicator of this condition is high levels of lipoprotein (a), or Lp(a), a type of protein that transports cholesterol through the blood. High Lp(a) levels increase the likelihood of cholesterol buildup in the walls of blood vessels and this protein is a known risk factor for cardiovascular disease, including coronary artery disease and stroke.
Lp(a) levels can already be reduced by therapies addressing PCSK9, a liver protein that regulates cholesterol. Studies of the approved PCSK9 inhibitors Repatha from Amgen, and Praluent from Regeneron Pharmaceuticals, showed reductions in Lp(a) levels. Novartis’s approved small interfering RNA (siRNA) therapy Leqvio takes a different approach by silencing the gene that produces PCSK9. That drug also reduces Lp(a). But these therapies do not address Lp(a) directly and they are all administered as injections.
AstraZeneca describes CSPC’s YS2302018 as an oral Lp(a) disruptor. Compared to the available injectable therapies addressing PCSK9, the CSPC drug offers the convenience of once-daily oral dosing. That formulation gives AstraZeneca a way to catch up to and potentially compete with Eli Lilly in the treatment of dyslipidemia. Lilly’s muvalaplin is an oral small molecule disrupter of Lp(a) currently in Phase 2 testing.
Lilly is also part of a group of companies developing siRNA therapies that reduce Lp(a) levels. The Indianapolis-based pharma giant’s lepodisiran earlier this year began a Phase 3 clinical trial in atherosclerotic cardiovascular disease. Amgen’s olpasiran is in Phase 3 testing in the same indication while Silence Therapeutics is preparing to enter pivotal testing with its Lp(a)-reducing drug candidate, zerlasiran. Pelacarsen, an Ionis Pharmaceuticals antisense oligonucleotide intended to reduce Lp(a) production, is in Phase 3 testing under a partnership with Novartis.
Lilly is taking a third approach to cardiovascular disease with potential one-time treatments. Last year, Lilly struck deals enabling it to share in the development of preclinical gene-editing therapies from Verve Therapeutics. The three disclosed targets are PCSK9, Lp(a), and ANGPTL3.
AstraZeneca’s cardiovascular, renal, and metabolism drug lineup is anchored by the blockbuster products Farxiga (approved for type 2 diabetes, heart failure, and chronic kidney disease) and Brilinta (approved for coronary acute syndromes). The company says the CSPC drug has potential uses in a range of cardiovascular disease indications as a standalone treatment or in combination with other therapies.
One potential combination could pair the CSPC drug with AstraZeneca’s own PCSK9 inhibitor, AZD0780. In May, the pharma giant reported Phase 1 results showing once-daily oral doses of AZD0780 on top of statin therapy led to a statistically significant 52% reduction in levels of LDL cholesterol. The drug was well tolerated and no serious adverse events were reported. AstraZeneca is currently testing the pill in a Phase 2 clinical trial with a targeted enrollment of 428 participants.
“Given the scale of unmet need, with cardiovascular disease being a leading cause of death globally, advancing novel therapies that can be used alone or in combination to effectively address known risk factors and advance patient care is particularly important and a key part of our strategy,” Sharon Barr, AstraZeneca executive vice president and head of biopharmaceuticals R&D, said in a prepared statement.
[Updated to add the following three paragraphs with analyst comment.] In a note sent to investors Monday, William Blair analyst Myles Minter said big pharma is taking several strategies to combine Lp(a) and PCSK9 inhibition as a lipid-lowering regimen. Both Pfizer and Merck have small molecule oral PCSK9 inhibitors but have yet to formally enter the Lp(a)-lowering space before the expected 2025 cardiovascular outcomes data readout of Ionis and Novartis’s pelacarsen, he added.
The American Heart Association’s Scientific Sessions meeting next month will bring details that help shape this landscape of potential cardiovascular therapies. The presentation of Phase 2 data for Lilly’s muvalaplin will be important for setting the Lp(a)-lowering bar for oral therapies, Minter said. Silence will have a presentation for zerlasiran’s Phase 2 results. That therapy could be the target of a big pharma deal based on preliminary Phase 2 results that showed 90% Lp(a) reduction and the potential for dosing every three months.
“Given the competitive profile of zerlasiran in the broader RNA-targeted therapeutics space for Lp(a) lowering and that small molecules such as muvalaplin have demonstrated less potent Lp(a) lowering than siRNAs, we continue to view zerlasiran as an attractive partnering, licensing, or acquisition target and do not believe today’s announcement rules out AstraZeneca’s potential interest,” Minter said.
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