Amgen, Inc.

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.

Phase 2 results on Eli Lilly’s experimental heart disease drug showed it could be dosed far less frequently than competing treatments in development from Novartis and Amgen, giving Lilly a way into an intense competition to make a new class of heart drug where it’s currently years behind. The mid-stage study tested lepodisiran, an RNA drug that’s meant to lower levels of a heart disease risk factor called lipoprotein(a). Lilly’s study showed its drug could be dosed once or twice per year, while experimental drugs from Novartis and Amgen are given monthly and once every three months, respectively. The clinical trial included 320 adults 40 years or older with elevated lipoprotein(a) levels and split them into five study arms. In four of the study arms, participants received either a 16 mg dose, 96 mg, 400 mg or placebo to start, and again at six months. In a fifth study arm, participants received 400 mg to start, and then a placebo shot at six months. At the highest dose (the group that received 400 mg twice), the drug cut lipoprotein(a) concentrations by 94.8% at one year. For the group that received 400 mg once, the drug cut Lp(a) concentrations by 88.5%. Meanwhile, in the two lower doses of 96 mg and 16 mg, lepodisiran cut Lp(a) levels by 77.2% and 41.2% at one year, respectively. Lilly’s Phase 2 results were presented at the annual American College of Cardiology conference and published in the New England Journal of Medicine on Sunday. “How much lipoprotein(a) reduction is necessary to produce clinical benefits remains uncertain and has been debated,” the authors of the NEJM study wrote. Lilly shared initial results from lepodisiran in 2023, and researchers then also remarked on the long durability of its effect. Lepodisiran came from Lilly’s partnership with Dicerna Pharmaceuticals, a company Novo Nordisk bought for $3.3 billion in 2021. Lilly is currently studying lepodisiran in a Phase 3 trial called ACCLAIM-Lp(a) that’s expected to enroll around 12,500 people. The company has not yet said what dose it plans to move forward with. “The dosing schedule for lepodisiran is still under evaluation to determine the optimal regimen. The significant and sustained Lp(a) reductions in the ALPACA trial are encouraging and results suggest that lepodisiran may potentially offer durable Lp(a)-lowering benefits with very infrequent dosing,” a Lilly spokesperson said in an email. That study is expected to complete in 2029, according to a federal clinical trials database . Treatments targeting Lp(a) could represent a potential new class of heart drug. Elevated levels of Lp(a) have been associated with a higher risk of heart disease, heart attack and stroke. Novartis is expected to share pivotal results on its Lp(a) therapy next year — one of the most highly anticipated readouts of 2026 — while Amgen’s study is expected to complete at the end of next year, according to clinicaltrials.gov . Lilly is simultaneously developing a once-daily pill called muvalaplin targeting Lp(a). It’s not yet clear what next steps are for the experimental pill, for which Lilly shared Phase 2 results in November. “Lilly is engaged with regulatory authorities on the next steps for muvalaplin for the treatment of cardiovascular events,” the spokesperson told Endpoints.

Taylor Tieden for BioSpace In the coming two weeks, the FDA is expected to announce three big decisions, including one for a dry eye disease therapy. After a hectic March, the FDA seems to be slowing down a bit in April. The regulator has three big milestones set for the coming weeks, two of which could expand the applications for already-established drugs and help them push into new markets. Read below for more. Aldeyra Sets Sights on Dry Eye Disease with Reproxalap By April 2, the FDA will release its decision on Aldeyra Therapeutics’ RASP modulator reproxalap, which the Massachusetts biotech is developing for dry eye disease. To support the drug application, Aldeyra filed Phase III data, which in August 2024 showed that a 0.25% dose of reproxalap ophthalmic solution significantly eased eye discomfort versus a vehicle comparator. CEO Todd Brady at the time said these findings are “supportive of the potential rapid clinical effect of reproxalap on reducing the ocular discomfort associated with dry eye disease.” Designed as a topical eye therapy, reproxalap is a small molecule that targets and inhibits reactive aldehyde species, chemicals that are typically present in high concentrations during eye inflammation. Aldeyra first tried for regulatory approval of reproxalap in 2023, but in October of that year announced it was anticipating a rejection after a late-cycle review surfaced “substantive new issues” with its application at the time. The rebuff formally came a few weeks later , with the FDA citing a lack of evidence to support reproxalap’s efficacy and pointing to the need for “at least one additional adequate and well-controlled study.” Amgen Files for Expansion of Uplizna Amgen is proposing to use its anti-CD19 antibody Uplizna in IgG4-related disease. The FDA is currently reviewing the pharma’s supplemental application and is scheduled to release its verdict by April 3. Approved in 2020 for neuromyelitis optica spectrum disorder, Uplizna is a humanized monoclonal antibody that targets CD19, a surface protein found on B lymphocytes. This mechanism of action allows Uplizna to trigger death, depleting both mature and immature B cells. Amgen is leveraging this activity for IgG4-related disease , which arises when antibody-producing B cells infiltrate tissues at high volumes, ultimately causing organ damage. Symptoms vary depending on the affected organs, but commonly include fatigue, weight loss, headaches and shortness of breath. Uplizna’s bid for IgG4-related disease is backed by data from the Phase III MITIGATE trial. A readout in November 2024 showed that the therapeutic antibody can reduce the risk of disease-related flares by 84% relative to placebo—an effect that Amgen at the time labelled clinically meaningful. Nearly 60% of Uplizna-treated patients in MITIGATE achieved flare-free, corticosteroid-free complete remission at 52 weeks, as opposed to just over 20% of placebo comparators. Amgen is also advancing Uplizna for generalized myasthenia gravis, for which the FDA has granted it Orphan Drug Designation. A regulatory filing in this indication is planned for the first half of 2025. Argenx Awaits Approval of Prefilled Vyvgart Syringe Argenx has developed a prefilled syringe product for Vyvgart and is proposing it for use in patients with generalized myasthenia gravis and chronic inflammatory demyelinating polyneuropathy (CIDP). The FDA is scheduled to release its regulatory verdict for the product on April 10. First approved in 2021, Vyvgart is a human IgG1 antibody fragment that works by binding to the neonatal Fc receptor, lowering the circulating levels of IgG. Initially, the drug was indicated for intravenous infusion, but in June 2023, argenx won an FDA nod for a formulation that can be injected under the skin. This subcutaneous product is marketed as Vyvgart Hytrulo . In an interview with Fierce Pharma in February, argenx Chief Operating Officer Karen Massey said the prefilled syringe is the next stage in Vyvgart’s development and would help the company push the drug into earlier lines of therapy in generalized myasthenia gravis, while also helping support its current rollout in CIDP. As with Vyvgart Hytrulo, the prefilled syringe, if approved, could potentially boost product sales by attracting new prescribers, Massey added.