NNC0385-0434

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.

Every minute, somewhere in the world, someone suffers a heart attack or stroke. The common culprit? Elevated levels of low-density lipoprotein cholesterol (LDL-C)—more popularly known as “bad cholesterol.” Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, and while the importance of healthy eating and physical activity cannot be overstated, sometimes they aren’t enough. For millions, effective medication becomes the most vital line of defense. And now, in a field long dominated by statins and injections, a new class of drugs is on the horizon—oral PCSK9 inhibitors—bringing hope to patients and physicians alike. Cholesterol gets a bad rap, but it’s not all villainy. This fat-like substance is essential for life: it stabilizes cell membranes, helps synthesize hormones (like estrogen, testosterone, and cortisol), and is even involved in vitamin D production. But when cholesterol—especially LDL-C—builds up in the blood, it sticks to artery walls, forming plaques that can block blood flow. This process, called atherosclerosis, is the ticking time bomb behind heart attacks and strokes. That’s why managing cholesterol—especially LDL-C—is a non-negotiable aspect of long-term health Since the 1980s, statins have been the gold standard in cholesterol-lowering therapy. They work by inhibiting HMG-CoA reductase, an enzyme involved in cholesterol production in the liver. They’re widely prescribed, orally administered, and affordable. But statins aren’t for everyone. Roughly 10% of patients experience side effects, including: muscle pain and weakness (rhabdomyolysis), liver enzyme elevation, increased risk of type 2 diabetes, fatigue and memory fog. For those patients or for those who need more aggressive cholesterol control, other options are needed. Enter PCSK9: The New Target in Cholesterol Control In 2003, scientists discovered a new protein called PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9). Its role? Regulating the number of LDL receptors on liver cells—the same receptors responsible for clearing LDL from the bloodstream. Here’s the catch: More PCSK9 = fewer LDL receptors = more LDL-C in your blood. This insight transformed PCSK9 into a superstar target for cholesterol-lowering drug development. The power of PCSK9 inhibitors, but at a cost Today, three PCSK9 inhibitors are approved and on the market: Alirocumab (Praluent) Evolocumab (Repatha) Inclisiran (Leqvio) Alirocumab (Praluent) Evolocumab (Repatha) Inclisiran (Leqvio) These drugs are incredibly effective—able to reduce LDL-C by 50–70%. But they all come with two major downsides: They’re injectable—requiring subcutaneous injections every 2–4 weeks or biannually. They’re expensive, costing thousands of dollars annually. For many patients, this makes them impractical despite their effectiveness. Imagine achieving the power of a PCSK9 inhibitor with the convenience of a once-daily pill. No needles. No clinic visits. Lower costs. Better patient adherence. No needles. No clinic visits. Lower costs. Better patient adherence. That’s the promise of oral PCSK9 inhibitors—and pharmaceutical companies are racing to deliver. Oral PCSK9 Drugs in Development: Who’s Leading the Race? Several compounds are in various stages of development, with some already showing powerful results in clinical trials: 🔹 MK-0616 (Merck) Status: Phase III trials Effectiveness: Up to 60% LDL-C reduction Delivery: Daily oral tablet Fun fact: Called the “molecule of the year” in 2023 for its potential to reshape cholesterol therapy Status: Phase III trials Effectiveness: Up to 60% LDL-C reduction Delivery: Daily oral tablet Fun fact: Called the “molecule of the year” in 2023 for its potential to reshape cholesterol therapy 🔹 AZD0780 (AstraZeneca) Status: Phase II trials Key advantage: Demonstrated 78% LDL-C reduction when used with statins Mechanism: Small molecule that enhances LDL-receptor recycling by inhibiting PCSK9 Status: Phase II trials Key advantage: Demonstrated 78% LDL-C reduction when used with statins Mechanism: Small molecule that enhances LDL-receptor recycling by inhibiting PCSK9 🔹 NNC0385-0434 (Novo Nordisk) Status: Completed Phase II trial Innovation: Uses SNAC technology to survive stomach acid Limitation: Discontinued for strategic reasons, despite promising results Status: Completed Phase II trial Innovation: Uses SNAC technology to survive stomach acid Limitation: Discontinued for strategic reasons, despite promising results 🔹 CVI-LM001 & DC371739 Origin: Derived from natural plant compounds (e.g., Corydalis ambigua) Promise: Modulate PCSK9 expression with minimal side effects Status: Early-phase trials showing significant LDL-C reductions Origin: Derived from natural plant compounds (e.g., Corydalis ambigua) Promise: Modulate PCSK9 expression with minimal side effects Status: Early-phase trials showing significant LDL-C reductions 🔹 AZD8233 (Antisense Therapy) Status: Discontinued Challenge: Did not meet efficacy thresholds, highlighting the difficulty of drug delivery to the liver via oral routes Status: Discontinued Challenge: Did not meet efficacy thresholds, highlighting the difficulty of drug delivery to the liver via oral routes PCSK9 inhibitors traditionally work by blocking the protein’s interaction with LDL receptors, preventing their degradation. Oral versions aim to do the same, but with small molecules or macrocyclic peptides instead of large injectable antibodies. The biggest challenge? Surviving the stomach and being absorbed effectively—a feat that technologies like macrocyclic design and permeation enhancers are helping solve. While not nearly as powerful, plant sterols like sitosterol and sitostanol have shown modest cholesterol-lowering effects, especially in children with familial hypercholesterolemia. These natural compounds block cholesterol absorption in the intestine and are being explored for complementary therapies. The future is promising: MK-0616 may hit the market as early as 2026 Oral therapies will likely become first-line options for statin-intolerant patients Prices are expected to fall as competition and innovation increase MK-0616 may hit the market as early as 2026 Oral therapies will likely become first-line options for statin-intolerant patients Prices are expected to fall as competition and innovation increase Meanwhile, injectable PCSK9 inhibitors are evolving too—offering longer-lasting effects and improved safety profiles. But for most people, a daily pill still feels far more approachable. Final Thoughts: A Pill That Could Change Lives The movement toward oral PCSK9 inhibitors reflects more than just scientific innovation—it reflects a shift toward patient-centered care. A treatment only works if people are willing (and able) to take it. If oral PCSK9 inhibitors deliver on their promise, they won’t just change cholesterol numbers. They’ll change lives. 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