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Oral Macrocyclic Peptides Are Gaining Quiet Momentum
01、Oral macrocyclic peptides are hitting the spotlight "The rapid warming up of the oral macrocyclic peptide track has a fairly clear underlying driver," Dr. Liu Dan, Managing Partner at Pivotal Bioventure Capital, pointed out to the author. "What has recently drawn market attention is oral cyclic peptides. Their core value lies in the potential to resolve the classic 'molecular dilemma'. Traditional small molecules are orally available yet often lack sufficient affinity and specificity. Macromolecular antibodies boast high targeting precision but can only be administered via injection. Oral macrocyclic peptides aim to combine the strengths of both, breaking through the physical barrier of oral delivery." In addition, macrocyclic peptides are not merely drug molecules; they can also serve as delivery carriers. Such scalability greatly broadens their application scenarios and opens up broader imagination for investors. Macrocyclic peptides are not a new concept. Cyclic peptide antibiotics such as Vancomycin and Daptomycin have long been widely used in clinical practice. Since the 21st century, more macrocyclic peptide drugs have gained regulatory approval. For instance, C5-blocking macrocyclic peptides including Zilucoplan have emerged as a new generation of therapies for autoimmune diseases. However, it should be noted that all previously approved macrocyclic peptide drugs are formulated for injection. The development of oral macrocyclic peptide drugs has long been recognized as a formidable challenge. With a relatively large molecular weight and structural rigidity arising from their cyclic architecture, macrocyclic peptides adopt highly complex three-dimensional conformations that far exceed the computational and simulation capabilities of conventional drug design approaches. "For a macrocyclic peptide small molecule, its size and complexity are four to five times those of a typical small molecule, making scale-up production a bold endeavor," said David Thaisrivongs, Chief Chemistry Director at Merck. However, several recent cases have demonstrated the feasibility of oral macrocyclic peptides. Recently, at the Annual Scientific Session of the American College of Cardiology (ACC), Merck unveiled the latest Phase III clinical data for enlicitide (MK-0616), an oral macrocyclic peptide PCSK9 inhibitor. The results showed that among patients already on statin therapy, enlicitide reduced levels of LDL-C, the so-called "bad cholesterol", by more than 64%, a far greater reduction than that achieved by existing oral lipid-lowering medications. This marks the third successful Phase III trial of enlicitide. Previously, it achieved an LDL-C reduction of 58.2% in patients with heterozygous familial hypercholesterolemia and a 57.1% reduction in the broader high-risk cardiovascular population. On March 18, 2026, Johnson & Johnson announced that the FDA has approved Icotyde (icotrokinra) for the treatment of moderate to severe plaque psoriasis in adults and pediatric patients aged 12 years and older weighing at least 40 kilograms who are candidates for systemic therapy or phototherapy. This is an oral IL-23R cyclic peptide antagonist. In the prior Phase III ICONIC-LEAD trial, 74% of patients achieved almost complete skin lesion clearance (IGA 0/1) at week 24, while nearly half, or 46%, attained complete skin lesion clearance (IGA 0). Although preclinical studies have shown that the oral bioavailability of Icotyde is only 0.1%–0.3%, it still delivers definite pharmacological activity without the use of absorption enhancers. The compound exhibits high stability in plasma, gastrointestinal contents and hepatocytes, with a relatively low protein binding rate of approximately 50%. It can be widely distributed to target tissues such as the skin and joints. No serious adverse events were observed in the first-in-human trial. These two cases prove that oral macrocyclic peptides are now commercially viable, undoubtedly boosting confidence across the entire industry track. 02、Oral bioavailability remains a major challenge. Strictly speaking, the core challenge of oral macrocyclic peptides has not yet been truly overcome. Many investors hold the view that the market is currently still paying a premium for the concept alone. Liu Dan stated: "There have indeed been some positive signs recently, but the problem is far from being solved." He believes oral bioavailability is the most critical metric in this track. "Whoever can stably lift the oral bioavailability of cyclic peptides above 5% will truly secure the admission ticket to this field." Oral macrocyclic peptides need to avoid degradation by gastric acid and intestinal enzymes, while also penetrating intestinal epithelial cells to enter the bloodstream—a highly challenging process. In addition, oral macrocyclic peptides exhibit low and non-linear absorption rates, making it difficult to maintain stable plasma drug concentrations. Excessively low bioavailability gives rise to multiple issues. For one thing, most of the drug is wasted, placing substantial pressure on production costs. For another, raising the dosage to compensate for low absorption rates may trigger more severe gastrointestinal side effects. Moreover, extremely low bioavailability is often accompanied by high pharmacokinetic variability. Drug absorption varies greatly among individuals and under different feeding states, making therapeutic efficacy difficult to control. Over the past few years, GLP-1 drugs have dominated the industry’s attention. With the launch of Novo Nordisk’s oral Wegovy and Eli Lilly’s small-molecule GLP-1 receptor agonist Orforglipron, the competition in weight-loss medications has officially entered the oral era. Data shows that there are currently 84 novel oral small-molecule GLP-1 drugs under global research and development, among which 52 have entered clinical stages. Amid such fierce competition, the requirement for oral bioavailability of peptides has also been driven to a higher standard, laying valuable experience for the development of oral macrocyclic peptides. According to data from Novo Nordisk, the bioavailability of oral semaglutide tablets is only 0.4%–1%. As a non-peptide molecule, Orforglipron boasts a much higher bioavailability of approximately 30%–40%. In November 2025, Ascletis Pharma announced that ASC37 oral tablets, developed leveraging its Peptide Oral Transport Enhancement Technology (POTENT), achieved an average absolute oral bioavailability of 4.2% in head-to-head non-human primate (NHP) studies. Overall, oral bioavailability remains an unsolved challenge for cyclic peptides with no mature solutions available. Most candidates with promising preclinical data are still confined to animal trial stages. Liu Dan also stated that he has not yet seen any platform technology capable of systematically solving this problem. "For example, even if a company manages to raise the oral bioavailability of a single pipeline candidate above 5%, such capability cannot be directly transferred to another pipeline to guarantee the same outcome. At present, most companies’ data remain limited to the optimization of individual molecular candidates, still far from forming a versatile, scalable platform. Even so, every player in the field is working hard toward this goal." 03、AI Becomes the Core Betting Focus Although bioavailability stands as the core metric, given that no player has yet delivered a comprehensive solution, it is still impossible to screen investment targets based on tangible outcomes from an investment perspective. "No one can achieve this in a stable and mature manner. If we screen candidates by the benchmark of stably achieving an oral bioavailability above 5%, not a single company can meet the requirement," an investor commented. Since what investors truly want to see remains unattainable, they have no choice but to adopt a different line of reasoning. "Investors have to settle for the next best thing: looking into whether a team has prior experience in cyclic peptide development, built up expertise in peptide drug research, or established solid analytical capabilities and data reserves via AI design in this field," the aforementioned investor said. Liu Dan shares this view. He points out that current investment decisions rely heavily on tools and experience for judgment. "Since the outcomes everyone hopes to see — especially clinical data — have not yet materialized, investors can only evaluate which companies possess capable technical tools and which teams have long-standing experience deeply rooted in this field. Most investors are currently making judgments based on this logic." In the past, the screening and optimization of macrocyclic peptides mainly relied on high-throughput experiments, which suffered from long cycles, high costs, and a high failure rate. The emergence of AI has opened up new possibilities for the industry: AI can be used to design peptide chain combinations and spatial conformations, as well as predict their oral absorption properties. Consequently, AI-aided design and development have become a major focal point in the oral macrocyclic peptide track. For example, as mentioned earlier, YuanSi Peptide's Synova platform integrates AI, data science and high-throughput screening, aiming to discover macrocyclic peptide drugs that combine the specificity of biological drugs with the druggability characteristics of small molecules. In March 2025, AstraZeneca entered into a strategic cooperation with YuanSi Peptide to jointly develop first-in-class macrocyclic peptide drugs for chronic diseases, granting AstraZeneca access to the Synova technology platform. Under the terms of the agreement, AstraZeneca will pay a $75 million upfront payment plus near-term milestone payments, as well as research, development and commercialization milestone payments of up to $3.4 billion in total, together with tiered royalties based on global sales. In addition, AstraZeneca will make an equity investment in YuanSi Peptide. The company also plans to expand its R&D center in Beijing through this collaboration. UNP has also garnered favor from multiple multinational pharmaceutical companies. In 2024, UNP sealed a $220 million collaboration with Merck. This February, Novartis obtained access to its AI-driven macrocyclic peptide discovery platform with a $100 million upfront payment and total deal value exceeding $1.7 billion, to jointly develop therapeutics for cardiovascular diseases. UNP’s integrated discovery engine combines AI-guided molecular design, massively parallel synthesis and direct biological screening, enabling the rapid generation of potent and highly selective macrocyclic compounds suitable for both oral and injectable administration routes. According to UNP, the platform integrates digital and wet-lab technologies through continuous macrocycle optimization cycles. Each cycle rapidly iterates toward more drug-like macrocyclic peptide molecules. Liu Dan believes that although no company has yet truly leveraged AI to specifically tackle the core challenge of oral bioavailability, having an additional tool is always worth a try. "Many VC investors are willing to bet on this tool. In drug R&D, any new method that can boost efficiency and cut trial-and-error costs will attract institutional investment. I also hold positive expectations for this direction." 04、Conclusion The maturation of every new drug modality has always followed a long journey from widespread skepticism to preliminary validation, and eventually to broad industry acceptance. This holds true for monoclonal antibodies, bispecific antibodies, and ADCs alike. Today, oral macrocyclic peptides stand at precisely the same inflection point. Multinational pharmaceutical companies have locked in technology platform licensing with substantial capital, and clinical data have initially validated the underlying concept. Nevertheless, there is still a long way to go before genuine technological maturity is achieved. Is the current boom in oral macrocyclic peptides merely a bubble, or a genuine starting point? Only time and data will tell. Disclaimer： Reposted from: https://news.yaozh.com/ All images and texts are copyrighted by their original authors. This repost is for the purpose of disseminating more information and does not represent the views of this platform. If you have any issues concerning content, copyright, or other related matters, please leave a message on this platform, and we will remove the relevant content promptly.
2026.06.08
Clinical Application and Research Progress of PCSK9 Inhibitors in Ischemic Stroke Complicated with Dyslipidemia
Abstract As a novel class of lipid-lowering agents, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors specifically block the binding of PCSK9 to low-density lipoprotein (LDL) receptors, inhibit the degradation of LDL receptors, and enhance the hepatic uptake and metabolism of circulating LDL-C, thereby exerting potent lipid-lowering effects. For patients with ischemic stroke (IS) complicated by dyslipidemia, especially those at extremely high risk who fail to achieve lipid targets with statin monotherapy or statin combined with ezetimibe, as well as statin-intolerant individuals,PCSK9 inhibitors offer a new therapeutic option. This article systematically elaborates on the mechanism of action and clinical efficacy characteristics of PCSK9 inhibitors, and comprehensively discusses their clinical application strategies, safety profiles and long-term benefits in different subgroups of IS patients with dyslipidemia. It also summarizes the latest research advances and future application prospects, aiming to provide a reference for clinicians to optimize lipid-lowering regimens and implement precise prevention and treatment strategies. Keywords Ischemic stroke; Dyslipidemia; PCSK9 inhibitors; Lipid-lowering therapy; Extremely high-risk population; Drug safety 1、Introduction Patients at extremely high risk of ischemic stroke complicated with dyslipidemia require strict control of LDL‑C levels to reduce the risks of disease recurrence and cardiovascular events. However, a considerable number of patients still face difficulties in lipid management in clinical practice. Approximately 20%–30% of patients fail to achieve the LDL‑C target of below 1.8 mmol/L even after treatment with moderate-to-high intensity statins combined with ezetimibe. In addition, 5%–10% of patients cannot receive conventional statin therapy due to severe statin intolerance, resulting in poor lipid control and persistently elevated recurrence risk. The advent of PCSK9 inhibitors has broken through the limitations of traditional lipid-lowering drugs. Featuring powerful lipid-lowering potency, favorable safety profile, and independence from hepatic metabolic enzyme systems, they provide an effective approach to addressing the above clinical dilemmas. In recent years, multiple large-scale clinical studies have confirmed the remarkable efficacy of PCSK9 inhibitors in lowering LDL-C and reducing the risk of cardiovascular events, with clear benefits demonstrated particularly in the secondary prevention of ischemic stroke. Based on the latest clinical guidelines and research evidence, this article systematically reviews the mechanism of action, clinical application, safety profile, and research progress of PCSK9 inhibitors. It aims to provide new insights into individualized lipid-lowering therapy for patients with ischemic stroke complicated by dyslipidemia, and promote the development of clinical lipid-lowering treatment toward precision and high efficacy. 2、Mechanism of Action and Classification of PCSK9 Inhibitors 2.1 Core Mechanism of Action PCSK9 is a serine protease synthesized and secreted by the liver. Its physiological function is to bind to LDL receptors on the surface of hepatocytes, mediate the endocytosis and degradation of LDL receptors, thereby reducing the hepatic uptake of circulating LDL-C and maintaining cholesterol homeostasis in the body. In patients with dyslipidemia, elevated PCSK9 levels can markedly reduce the number of LDL receptors and impair the liver’s capacity to clear LDL-C. This consequently raises serum LDL-C levels and accelerates the progression of atherosclerosis. PCSK9 inhibitors specifically bind to circulating PCSK9 and block its interaction with LDL receptors, thereby inhibiting the degradation of LDL receptors. This increases the quantity and activity of LDL receptors on the surface of hepatocytes, markedly improves the liver’s efficiency in uptake and metabolism of circulating LDL‑C, and achieves potent lipid‑lowering effects. Compared with statins and ezetimibe, PCSK9 inhibitors exert a more direct mechanism of action. Instead of affecting cholesterol synthesis and absorption, they function by regulating the metabolic pathway of LDL receptors. The three types of agents have complementary action targets, providing a mechanistic basis for combined lipid‑lowering therapy. In addition, several studies have indicated that PCSK9 inhibitors may further reduce the risk of cardiovascular events through lipid‑independent effects, such as suppressing inflammatory responses, improving vascular endothelial function, and stabilizing atherosclerotic plaques. Their pleiotropic effects remain under in‑depth investigation. 2.2 Classification and Administration of Drugs Currently, clinically available PCSK9 inhibitors are mainly divided into two categories: monoclonal antibodies and small interfering RNA (siRNA) agents. Both are formulated for injection, featuring convenient administration and satisfactory patient compliance. Monoclonal antibodies are the most widely used type in clinical practice, with representative drugs including evolocumab and alirocumab. They bind specifically to the active site of human PCSK9, block its combination with LDL receptors, and exert a rapid and remarkable lipid-lowering effect. The recommended regimen of evolocumab is 140 mg subcutaneously every two weeks, or 420 mg subcutaneously once monthly. For alirocumab, the standard dose is 75 mg or 150 mg via subcutaneous injection every two weeks, with dosage adjustable according to the patient’s lipid levels. The small interfering RNA (siRNA) class of PCSK9 inhibitors is represented by inclisiran. By adopting RNA interference technology, it suppresses the expression of the hepatic PCSK9 gene and reduces PCSK9 synthesis at the source, exhibiting long-acting lipid-lowering characteristics. The recommended administration regimen of inclisiran is a subcutaneous injection of 284 mg for the first dose, followed by a second dose after 3 months, and subsequent maintenance doses once every 6 months. This regimen greatly reduces the frequency of administration, making it particularly suitable for patients requiring long-term treatment who are unable to receive frequent injections. The two categories of PCSK9 inhibitors deliver comparable lipid-lowering potency, while the siRNA agents boast superior long-acting properties, offering more individualized therapeutic options for clinical practice. 3、Clinical Efficacy of PCSK9 Inhibitors 3.1 Lipid-lowering Efficacy PCSK9 inhibitors exhibit significantly stronger lipid-lowering potency than traditional lipid-lowering drugs and can achieve a substantial reduction in LDL-C levels. Clinical studies have shown that monotherapy with monoclonal antibody-based PCSK9 inhibitors (evolocumab and alirocumab) can reduce serum LDL-C levels by 50%–60%. When combined with statins, they can further lower LDL-C by an additional 40%–50% on the basis of statin treatment. Even in patients who fail to reach lipid targets after moderate-to-high intensity statin combined with ezetimibe therapy, the addition of PCSK9 inhibitors can raise the LDL-C attainment rate (<1.8 mmol/L) to more than 90%. The lipid-lowering efficacy of small interfering RNA PCSK9 inhibitors (inclisiran) is equally remarkable. The initial injection reduces LDL-C by 40%–50%, and the second dose administered three months later sustains the lipid-lowering effect. Long-term treatment enables stable control of LDL-C levels within the target range. In addition, PCSK9 inhibitors can moderately improve other lipid profiles: they slightly decrease total cholesterol and triglyceride levels while mildly elevating high-density lipoprotein cholesterol levels, further optimizing lipid metabolism. Notably, the lipid-lowering effect of PCSK9 inhibitors is not affected by age, gender, or mild to moderate hepatic and renal dysfunction, maintaining stable therapeutic efficacy even in special patient populations. 3.2 Efficacy in the Prevention of Cardiovascular Events PCSK9 inhibitors not only exert potent lipid‑lowering effects but also significantly reduce the risk of cardiovascular events in patients with ischemic stroke complicated by dyslipidemia, with well‑established benefits particularly in secondary prevention. The FOURIER trial demonstrated that evolocumab combined with statin therapy reduced the risk of recurrent stroke by 15% and the risk of major adverse cardiovascular events (including stroke, myocardial infarction, and cardiovascular death) by 20% in extremely high‑risk patients with recent ischemic stroke or transient ischemic attack (TIA). Such benefits began to emerge as early as 6 months after treatment initiation and continued to accumulate during long‑term therapy (median follow‑up of 2.2 years). The ODYSSEY OUTCOMES trial confirmed that alirocumab added to statin therapy lowered the all‑cause mortality risk by 15% and cardiovascular mortality risk by 20% in patients with ischemic stroke. Greater clinical benefits were observed with lower achieved LDL‑C levels, and no relevant safety concerns emerged even when LDL‑C was reduced below 1.0 mmol/L. Clinical studies of small interfering RNA agents have likewise shown that inclisiran can markedly decrease cardiovascular event risk in extremely high‑risk populations, with long‑term benefits comparable to those of monoclonal antibody PCSK9 inhibitors. Furthermore, for statin‑intolerant patients who cannot receive statin therapy, PCSK9 inhibitor monotherapy also significantly reduces the risks of stroke recurrence and cardiovascular events, providing an effective strategy for cardiovascular risk management in this patient subgroup. 4、Clinical Application Strategies of PCSK9 Inhibitors 4.1 Applicable Population The clinical application of PCSK9 inhibitors is prioritized for extremely high-risk patients with ischemic stroke (IS) complicated by dyslipidemia, specifically including the following populations: patients whose LDL-C still fails to reach the target (<1.8 mmol/L) after treatment with moderate-to-high intensity statins combined with ezetimibe; patients with severe statin intolerance (such as severe muscle injury and abnormal liver function) who are unable to receive statin therapy and present with significantly elevated blood lipid levels; and IS patients complicated with familial hypercholesterolemia. Such patients have markedly elevated LDL-C levels and limited response to traditional lipid-lowering drugs, whereas PCSK9 inhibitors can effectively control blood lipids and reduce the risk of recurrence. In addition, for extremely high-risk IS patients complicated with diabetes, coronary heart disease, or stage 3–4 chronic kidney disease with poor lipid control, early initiation of PCSK9 inhibitors may be considered to rapidly achieve lipid targets and lower the risk of cardiovascular events. For elderly extremely high-risk patients aged 75 years and above, PCSK9 inhibitors demonstrate a favorable safety profile. They can be administered after evaluating that the benefits outweigh the risks without dose adjustment, providing a safe and potent lipid-lowering option for the elderly population. 4.2 Medication Regimen and Dose Adjustment The medication regimen of PCSK9 inhibitors should be individualized according to patient classification, blood lipid levels, and drug categories.For patients who fail to achieve lipid targets after statin combined with ezetimibe therapy, PCSK9 inhibitors can be directly added. Monoclonal antibodies are administered at standard doses: evolocumab 140 mg every two weeks or 420 mg monthly, and alirocumab 75 mg or 150 mg every two weeks. The small interfering RNA agent inclisiran is given at a fixed dose of 284 mg once every six months. Blood lipids should be re-examined 4–8 weeks after medication initiation, and doses may be adjusted based on target attainment (e.g., alirocumab can be increased from 75 mg to 150 mg). For statin-intolerant patients, PCSK9 inhibitor monotherapy can be adopted at the same dosage as in combined therapy. If the LDL-C reduction is insufficient, combination with ezetimibe 10 mg daily may be added to further enhance the lipid-lowering effect.For patients with familial hypercholesterolemia, a triple therapy regimen consisting of a PCSK9 inhibitor, a statin at the tolerated dose, and ezetimibe is recommended to maximally lower LDL-C levels and delay the progression of atherosclerosis. During dose adjustment, it should be noted that the lipid-lowering effect of PCSK9 inhibitors is dose-dependent, and blind dose escalation is not recommended. If lipid targets remain unmet after standard-dose treatment, factors such as patient compliance and lifestyle should be evaluated, and additional lipid-lowering agents may be combined when necessary. 5、Safety and Adverse Reaction Management of PCSK9 Inhibitors PCSK9 inhibitors demonstrate an overall favorable safety profile with a low incidence of adverse reactions, most of which are mild to moderate. They are better tolerated than high-intensity statins, and their long-term safety has been validated by numerous clinical studies. Adverse reactions are predominantly localized to injection sites, while systemic side effects are rare. Their specific characteristics and management strategies are outlined below. Injection site reaction is the most common adverse event, with an incidence of 5%–10%. Manifestations include local redness, swelling, pain, pruritus and induration, which mostly occur at the initial stage of treatment, last for a short duration (1–3 days), and resolve spontaneously with repeated administration. Management measures: Rotate injection sites (abdomen, lateral thigh) and avoid repeated injections at the same location; apply local compression for 5–10 seconds after injection without rubbing. For marked local reactions, cold compresses can relieve symptoms, and drug discontinuation is generally unnecessary. The incidence of systemic adverse reactions is extremely low. Occasional events such as headache, dizziness, fatigue and nausea occur in less than 3% of patients, and are mostly transient without interfering with continued treatment. Rare hypersensitivity reactions (rash, urticaria, angioedema) have an incidence below 0.1%. Once these occur, the drug should be discontinued immediately with symptomatic treatment, and subsequent reuse of this class of agents should be avoided. Notably, PCSK9 inhibitors have no adverse impact on liver function, muscle function or glucose metabolism. For patients complicated with diabetes or mild to moderate hepatic and renal insufficiency, no additional adjustment of monitoring frequency is required, reflecting a prominent safety advantage. At present, there is no clear evidence of long-term safety risks associated with PCSK9 inhibitors. Long-term follow-up studies (over 5 years) have shown no unfavorable effects on all-cause mortality or malignancy incidence, supporting their safe application in long-term lipid-lowering therapy. Nevertheless, safety data remain limited in patients with severe hepatic insufficiency, severe infection, as well as pregnant and lactating women, for whom PCSK9 inhibitors should be used with caution or avoided altogether. 6、Latest Research Progress and Future Prospects In recent years, research on PCSK9 inhibitors has continued to advance steadily, yielding remarkable progress in expanding mechanisms of action, broadening clinical indications, and developing novel pharmaceutical agents. In terms of mechanism of action, accumulating evidence indicates that beyond regulating lipid metabolism, PCSK9 inhibitors exert lipid-independent cardiovascular protection. They can suppress the release of inflammatory cytokines, alleviate vascular endothelial injury, and inhibit platelet aggregation, thereby further reducing the risk of cardiovascular events. Their beneficial effect on stabilizing atherosclerotic plaques is independent of lipid-lowering efficacy, providing additional theoretical evidence for their clinical benefits. With regard to clinical application, multiple studies have explored the value of PCSK9 inhibitors in the primary prevention of ischemic stroke. Preliminary findings demonstrate that in high-risk individuals with markedly elevated LDL-C but no prior stroke history and multiple cardiovascular risk factors, PCSK9 inhibitors can significantly reduce the risk of first-ever ischemic stroke, offering a new strategy for primary prevention. Meanwhile, studies on combined therapy with other novel lipid-lowering agents are ongoing. Combination with ATP citrate lyase inhibitors is expected to achieve more potent lipid-lowering effects, providing an optimized therapeutic solution for patients with severe dyslipidemia. In novel drug development, oral PCSK9 inhibitors have entered clinical trials. The oral formulation can substantially improve patient adherence and is expected to become a mainstream alternative to injectable preparations in the future. Furthermore, research on PCSK9-targeted gene editing therapy is progressing rapidly. The CRISPR-Cas9 technique can edit the PCSK9 gene to achieve long-term or even permanent reduction of LDL-C, bringing potential curative prospects for refractory dyslipidemia such as familial hypercholesterolemia. Nevertheless, PCSK9 inhibitors still have certain limitations. Their relatively high cost restricts long-term accessibility for some patients. In addition, evidence regarding safety and efficacy remains insufficient in special populations, including patients with severe hepatic or renal insufficiency and children, requiring further clinical investigation. In the future, with advances in pharmaceutical research, reduced drug costs, and the accumulation of more real-world clinical data, PCSK9 inhibitors are expected to play an increasingly vital role in the prevention and management of ischemic stroke combined with dyslipidemia, ushering in a new era of precise, potent, and long-acting lipid-lowering therapy. 7、Conclusion As a novel class of potent lipid-lowering agents, PCSK9 inhibitors markedly reduce LDL-C levels through a unique mechanism of action, while significantly lowering the risks of stroke recurrence and major adverse cardiovascular events in extremely high-risk patients with ischemic stroke complicated by dyslipidemia. With a favorable safety profile, they provide an effective solution to the clinical limitations of conventional lipid-lowering therapies. PCSK9 inhibitors have well-established clinical value in extremely high-risk patients failing to achieve lipid targets, statin-intolerant individuals, and patients with familial hypercholesterolemia. They also feature convenient administration and high patient adherence. In clinical practice, it is essential to strictly define the applicable population for PCSK9 inhibitors, select appropriate drug types and administration regimens based on individual patient conditions, and combine pharmacological treatment with lifestyle intervention to achieve precise lipid control. In the future, with the development of new formulations, further advancement of clinical research, and improved drug accessibility, PCSK9 inhibitors are expected to become a cornerstone therapy for lipid management in extremely high-risk patients with ischemic stroke and dyslipidemia, offering strong support for reducing disease burden and improving long-term patient prognosis. Disclaimer： Reposted from: https://www.miaoshou.com/ Copyright of images and texts belongs to the original authors. The purpose of reproduction is to convey more information and does not represent the views of this platform. If there are issues related to content, copyright, or other matters, please leave a message on this platform, and we will remove them promptly.
2026.06.08
Merck Strikes New Partnership, Betting on AI for the Next Drug Discovery Wave
Guide: Merck has described macrocyclic peptides as "the next wave of drug discovery". On January 23, Merck signed a $220 million Biobucks agreement with UnnaturalProducts (UNP for short) to further expand its footprint in the macrocyclic peptide sector.UNP was founded in 2017 and focuses on macrocyclic compounds, a class of molecules capable of addressing complex targets that are intractable to traditional small molecules and biologics. Small molecules can penetrate cells and be delivered orally, yet they struggle to bind to complex targets. Biologics only act on extracellular targets and are generally administered via injection. Naturally occurring macrocycles have evolved to transcend the boundaries of cell permeability and oral bioavailability, engaging complex targets with high specificity. UNP’s AI-empowered discovery platform enables the engineering and synthesis of synthetic macrocycles that mimic natural macrocyclic compounds. The company has established technologies for the intelligent design, rapid synthesis and screening of cyclic peptide macrocycles. Merck has described macrocyclic peptides as “the next wave of drug discovery”. Now, Merck will leverage UNP’s technology to develop macrocyclic drug candidates against an undisclosed challenging oncology target. MK-0616, an investigational therapy from Merck & Co., is a macrocyclic peptide that binds to PCSK9 and is currently in Phase 3 trials for its ability to lower low-density lipoprotein cholesterol. The press release did not disclose any financial details, only revealing that UNP will receive an undisclosed upfront payment plus potential development and commercial milestone payments of up to $220 million. Rob Garbaccio, Head of Discovery Chemistry at Merck Research Laboratories, stated in the press release: “Merck continues to harness our strong medicinal chemistry capabilities to advance our oncology pipeline. We look forward to collaborating with the Unnatural Products team to develop candidate drugs aimed at this challenging oncology target.” Macrocyclic drugs have a long history of clinical use, with examples including the immunosuppressant cyclosporine and the antibiotic erythromycin. However, systematic efforts to develop macrocyclic compounds have faced a series of challenges related to pharmacokinetics, cell permeability and oral bioavailability. Notably, UNP closed a $32 million Series A financing round last December. The financing was led by the Merck Global Health Innovation Fund (MGHIF) and TechBio-focused venture capital firm ARTIS Ventures. New institutional investors also included First Spark Ventures, The Venture Collective, Humain Ventures, Longe VC and Not Boring Capital, alongside participation from existing investors. Disclaimer： Reprinted from: https://news.yaozh.com/. Copyright of images and texts belongs to the original author. This reprint is for the purpose of disseminating more information only and does not represent the views of this platform. If there are any issues regarding content, copyright or other matters, please leave a message on this platform, and we will remove the content promptly.
2026.06.08
