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A total of 84% of patients who received the 30 mg dose were able to meet AHA-recommended LDL-C levels.\n The highest dose of AstraZeneca’s small molecule halved levels of a type of “bad” cholesterol after 12 weeks, hitting the goal of a phase 2 trial in patients with a lipid disorder.The candidate in question, dubbed AZD0780, is an oral small molecule PCSK9 inhibitor in development for dyslipidemia, a condition characterized by elevated cholesterol in the blood that can progress to clogged arteries, known as atherosclerosis.AstraZeneca used the American College of Cardiology conference today to unveil data from a phase 2 study of 428 patients with the condition who received one of four doses of AZD0780 or placebo, along with standard-of-care statin therapy and, in some cases, the approved high cholesterol drug ezetimibe.The highest daily dose, 30 mg, of AZD0780 was tied to a 50.7% reduction in low-density lipoprotein cholesterol (LDL-C) at 12 weeks. Around this level of efficacy was observed regardless of whether patients were also receiving moderate or high-intensity statin doses alongside AZD0780, AstraZeneca noted.A total of 84% of patients who received the 30 mg dose were able to meet the American Heart Association guidelines of having LDL-C levels under 79 mg/dL, compared to 13% of those on placebo.The rate of adverse events in the combined AZD0780 treatment groups was 38.2%, compared to 32.6% in the placebo cohort. The frequency of treatment discontinuations due to these events was 1.5% for the investigational arm and 2.3% for placebo. “These new data reflect AZD0780’s ability to reduce LDL-cholesterol in patients who need more options to manage their cholesterol and related risks when standard of care therapy is not enough,” Sharon Barr, AstraZeneca\'s executive vice president of biopharmaceuticals R&D, said in a release.“As a novel small molecule oral PCSK9 inhibitor that can be taken without fasting restrictions, AZD0780 has the potential to be a game changer that could offer LDL-C lowering with greater convenience for patients,” Barr added.The phase 2 results echo an early-stage readout for AZD0780 last year that showed a similar 52% reduction in LDL-C.The hypercholesterolemia market is currently dominated by injectable PCSK9 inhibitors in the form of Amgen’s Repatha and Sanofi-Regeneron’s Praluent. Meanwhile, Novartis’ Leqvio uses small-interfering RNA technology to decrease PCSK9 production in the liver.AstraZeneca’s attempt to get an oral option to patients in the form of AZD0780 remains behind Merck & Co.’s own oral PCSK9 inhibitor MK-0616, which is already undergoing a slate of phase 3 trials to confirm its LDL-C-lowering capabilities.In today’s release, Michael Koren, M.D., CEO and medical director of the Jacksonville Center for Clinical Research in Florida, said the results for AZD0780 are “particularly important because the majority of patients with atherosclerotic disease today do not reach their LDL-C goals, despite availability of lipid-lowering therapies such as statins and injectable PCSK9 inhibitors.”

AstraZeneca has great ambitions for its mid-stage oral cholesterol drug, believing that it could reach peak sales of more than $5 billion. Positive data presented Monday at the American College of Cardiology meeting bring that ambition a step closer. The company’s pill is now headed for Phase 3 but is still trailing behind Merck, which has a similar pill already in pivotal trials. Merck’s product might be the more effective of the two, judging by data from their respective mid-stage trials. AstraZeneca’s data come from a Phase 2b trial named PURSUIT, which enrolled more than 400 patients with dyslipidemia. In this condition levels of low-density lipoprotein cholesterol (LDL-C) particles, also called “bad” cholesterol, are elevated, increasing patients’ risk of serious events like heart attacks or strokes. After three months of treatment, AstraZeneca’s pill, AZD0780, cut LDL-C levels by 46.6%. This was at the highest dose tested, 30 mg once daily. Patients in the placebo group saw their LDL-C levels rise by 4.1%, giving a difference of 50.7 percentage points. All the patients in the trial were also on standard anti-cholesterol statin therapy, and AZD0780’s efficacy was unchanged regardless of whether the patients were taking moderate or high-intensity statins. Merck’s rival pill achieved a greater reduction in cholesterol in its mid-stage trial. In March 2023, the US company said that a 30 mg dose of its oral peptide, known as MK-0616, cut LDL-C by 60.9% at just two months. But cross-trial comparisons are imperfect. Merck’s study was conducted in a slightly different form of high cholesterol disease, and not all its subjects were on statins. Data on AZD0780 released Monday also showed that it enabled 84% of trial participants to meet the recommended target levels of LDL-C target, which is less than 70 mg/dL. This was only achieved by 13% of the subjects in the placebo arm. The equivalent finding from Merck’s trial was 90.8% in the MK-0616 30 mg arm versus 9.3% with placebo, but caution should be used with this comparison since the goal was defined differently in Merck’s trial. Rates of side effects were slightly higher with AZD0780, at 38.2% with the pill versus 32.6% with placebo. Discontinuation rates due to adverse events were 1.5% with AstraZeneca’s pill and 2.3% with placebo. The results mean the pill will now move into Phase 3 trials, Mina Makar, AstraZeneca’s SVP, cardiovascular, renal and metabolism, told Endpoints News . “We saw everything that we wanted to see in the Phase 2,” Makar said. “So now it’s just about finalizing the design of the Phase 3 and moving with as much speed as we can.” Late-stage trials should start this year, he added. AstraZeneca’s pill inhibits an enzyme called PCSK9, which degrades the receptor for LDL-C. This means that blocking PCSK9 can cut patients’ cholesterol levels over and above the cuts seen with statins. Several injected drugs, including Sanofi and Regeneron’s Praluent and Amgen’s Repatha, are approved on the basis that they can do just that. But the injected PCSK9s have struggled commercially, failing to make much headway in the 70% or so of patients who can’t hit recommended cholesterol targets with statins alone. Only 4% of these eligible patients take PCSK9 shots. Makar said this was partly due to reimbursement and access challenges but also to their route of administration. Cardiologists and internal medicine specialists say they would consider treating a “much broader population” with a pill, he said, than they would with an injection. “Our intent here is not to focus on the current PCSK9 injectable space,” Makar said. “We intend to compete in the broader statin market, in the broader dyslipidemia treated population, where PCSK9s should have been able to penetrate.” Essentially the company wants to produce a drug that is more potent than a statin and can be as widely used. But Merck wants the same thing, and that company’s oral PSCK9 is ahead of AstraZeneca’s, having entered a major Phase 3 program in 2023. Still, AstraZeneca may have an edge in AZD0780’s chemical structure. “It’s the first time that somebody has actually been able to create a true small molecule, as opposed to a peptide,” Makar said. Small molecules are simpler and cheaper to produce than peptides, and that may have been a factor in Novo Nordisk’s decision to discontinue development of its own PSCK9 pill, a peptide called NNC0385-0434, last year. At the time Novo said the move was “due to portfolio considerations.” AstraZeneca bought AZD0780 from Dogma Therapeutics for an undisclosed sum five years ago.