New frontiers in the treatment of hypercholesterolaemia: oral inhibition of PCSK9

Abstract

PCSK9 inhibitors represent a cornerstone of lipid-lowering therapy; however, the need for cost containment and simplified routes of administration has stimulated the development of oral small molecules and peptidomimetics capable of modulating or blocking the PCSK9–LDL receptor (LDL-R) interaction, inhibiting PCSK9 mRNA transcription, or preventing lysosomal degradation of the LDL-R. Agents in advanced development include enlicitide (MK-0616) and laroprovstat (AZD0780), while DC371739, NNC0385-0434 (development currently suspended), and CVI-LM001 should also be considered. Enlicitide decanoate, owing to improved intestinal permeability, significantly reduces free PCSK9 (>90%) and LDL-cholesterol (C) (≈60%) in Phase I–II studies, with excellent tolerability. Phase III trials (CORALreef–Lipids and CORALreef–HeFH) have confirmed LDL-C reductions of 55–60%, along with favourable effects on non-HDL-C, apolipoprotein B (apoB), and Lipoprotein(a) Lp(a), comparable to those achieved with monoclonal antibodies. AZD0780 demonstrates dose-dependent reductions in LDL-C (up to 50%) and potential synergism with rosuvastatin, whereas NNC0385-0434—despite documenting significant decreases in LDL-C and Lp(a)—has been discontinued. DC371739 (a dual PCSK9/ANGPTL3 inhibitor) and CVI-LM001 (a transcriptional modulator) may represent additional therapeutic perspectives. Overall, oral PCSK9 inhibitors show consistent efficacy and favourable safety profiles, positioning them as next-generation lipid-lowering therapies, pending cardiovascular outcome data from ongoing studies.

Lipid-lowering therapy with monoclonal antibodies (evolocumab, alirocumab) or siRNA (inclisiran) targeting PCSK9 has enabled patients at high or very high cardiovascular (CV) risk to achieve plasma C concentrations previously unattainable, with a consequent reduction in CV risk.¹ However, the need for cost containment and simpler routes of administration has stimulated research into orally administered small molecules and peptidomimetics targeting PCSK9, with the aim of improving accessibility to therapy.¹ Several targets may be exploited to inhibit the effects of PCSK9, including disruption of the PCSK9–LDL-R interaction, inhibition of lysosomal degradation of the LDL-R, and induction of allosteric conformational changes in PCSK9.¹

Below, we discuss the most promising oral agents, noting that none has yet reached the commercial stage.

Enlicitide (MK-0616)

Crystallographic studies show that the macrocyclic peptide enlicitide interacts with high affinity with the flat surface of the catalytic domain of PCSK9, thereby inhibiting its interaction with the EGF-A domain of the LDL-R.² With regard to pharmacokinetics, fasting doses ranging from 10 to 300 mg are associated with increases in AUC_₀−∞ (259–2260 h nmol/L), C_max (5.21–149 nmol/L), T_max (1.5–2 h), and half-life (T_1/2: 35.14–129.95 h).²

Because its structure and polarity confer limited intestinal absorption, enhancement of bioavailability (up to 2%) was achieved by replacing the chloride salt with the decanoate form, which acts as a permeation enhancer by transiently loosening tight junctions between intestinal epithelial cells.² As food intake may reduce bioavailability and absorption, the drug should be administered after an 8-h fast, which should be maintained for at least 30 min after dosing.² Selected pharmacokinetic parameters of enlicitide are reported in Table 1.

Table 1.

Pharmacokinetic parameters of enlicitide decanoate

After conversion to the decanoate formulation, oral bioavailability under fasting conditions increased to approximately 2%.

Weak plasma protein binding (≈30%).

Limited clearance, with excretion predominantly as the unchanged parent peptide, mainly via the renal route.

No metabolic turnover observed after incubation in human hepatocytes; this likely reflects limited cellular uptake due to low membrane permeability and/or minimal transport mediated by OATP.

No reversible or clinically relevant inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. No time-dependent inhibition of CYP3A4.

No induction of CYP1A2, CYP2B6, or CYP3A4 expression in human hepatocytes.

No inhibition of hepatic uptake mediated by human OATP1B1, OATP1B3, BSEP, or P-glycoprotein (P-gp) in vitro. Consequently, a low risk of P-gp–related interactions and of interactions mediated by hepatic OATP transporters is anticipated.

BSEP, Bile salt export pump; CYP, Cytochrome P450; OATP, Organic anion–transporting polypeptides; P-gp, P-glycoprotein.

The pharmacokinetics of enlicitide are being evaluated in two Phase I studies in patients with varying degrees of renal impairment. The NCT05934292 trial (open-label, single 20 mg dose) compares patients receiving statins with controls, whereas study NCT05070390 assesses safety, tolerability, and pharmacokinetics in 10 patients with moderate renal impairment compared with healthy controls. A Phase I single-dose study is also ongoing to characterize pharmacokinetics in patients with hepatic dysfunction (NCT06575959). With regard to pharmacodynamics, enlicitide decanoate (10–300 mg vs. placebo) has been shown to reduce free plasma PCSK9 by more than 93% in a randomized, double-blind clinical study.²

Enlicitide decanoate (10–20 mg once daily for 14 days) reduced free plasma PCSK9 by more than 90%, with a concomitant increase in total PCSK9 (122 ± 45% vs. baseline 24 h after the 14th dose of 20 mg).² LDL-C reduction was gradual and continuous over the 14-day period (−58.2% and −60.5% vs. baseline, respectively), and was attenuated by 11.6% when administration occurred within 30 min of a meal, with maximal effects observed between days 7 and 14.²

In the randomized, double-blind Phase IIb study NCT05261126, conducted using enlicitide chloride (6, 12, 18, or 30 mg/day vs. placebo for 8 weeks) in 380 patients with hypercholesterolaemia, a dose-dependent reduction in LDL-C was observed (−41.2%, −55.7%, −59.1%, and −60.9%, respectively), along with reductions in Lp(a) (−12.2%, −21.3%, −21.7%, and −23.7%, respectively) compared with placebo. Reductions of up to 52% and 56% in apolipoprotein B (apoB) and non-HDL.C, respectively, were also reported. Safety and tolerability were excellent, with adverse events comparable to placebo and not dose-dependent.³

These results paved the way for evaluation of the efficacy, safety, and tolerability of enlicitide decanoate (20 mg/day for 52 weeks vs. placebo) in the Phase III CORALreef–Lipids trial, conducted in 2912 patients with hypercholesterolaemia: (i) with a previous major atherosclerotic cardiovascular disease (ASCVD) event and LDL-C ≥ 55 mg/dL; (ii) at intermediate risk of a first ASCVD event with LDL-C ≥ 70 mg/dL, either receiving statins or intolerant to them.

After 24 weeks, enlicitide reduced LDL-C by 55.8% compared with placebo (primary end-point), and two-thirds of patients achieved LDL-C reductions >50%, reaching the recommended target of LDL-C < 55 mg/dL (vs. 1.2% with placebo). Notably, reductions in non-HDL-C, apoB, and Lp(a) (−53.7%, −49.6%, and −29.0%, respectively) were essentially identical to those obtained with monoclonal antibodies, with no safety or tolerability concerns.⁴

The reduction in LDL-C, as well as the safety and tolerability of enlicitide decanoate 20 mg administered for 24 weeks in 303 adults with heterozygous familial hypercholesterolaemia (HeFH) already receiving lipid-lowering therapy, were evaluated in the randomized, double-blind, placebo-controlled Phase III CORALreef–HeFH study (NCT05952869). Results were highly promising for LDL-C, apoB, non-HDL-C, and Lp(a) (−58.2%, −48.2%, −52.3%, and −29.0%, respectively).⁵

Safety and efficacy vs. placebo are also the objectives of the Phase III randomized CORALreef-Outcomes trial, enrolling 14 550 patients with a history of major ASCVD events and LDL-C ≥ 70 mg/dL (or non-HDL-C ≥100 mg/dL) despite lipid-lowering therapy. The primary end-point—time to first major adverse cardiovascular event (MACE)—is expected in November 2029.

The Phase III CORALreef Add-on study (NCT06450366), with results expected shortly, was designed to assess the safety, tolerability, and efficacy of 8 weeks of treatment with enlicitide decanoate vs. ezetimibe and bempedoic acid (alone or in combination) in reducing LDL-C in adults with hypercholesterolaemia.

In addition, the Phase III CORALreef Extension study (NCT06492291) is ongoing to evaluate the long-term safety and efficacy of enlicitide decanoate in patients with hypercholesterolaemia who have completed studies NCT05952856, NCT05952869, or NCT06450366 (expected results: October 2028).

Finally, in November 2025 (completion expected March 2027), the Phase III randomized CORALreef Combination trial was initiated. This double-blind, placebo-controlled study will assess the safety and LDL-C-lowering effect of enlicitide, alone or in combination with rosuvastatin, over 8 weeks in adults with hyperlipidaemia. In study NCT07058077, the same parameters will be evaluated in paediatric and adolescent patients with HeFH.

Laroprovstat (AZD0780)

Laroprovstat is an orally administered PCSK9 inhibitor at an advanced stage of clinical development. It binds directly to a site within the C-terminal domain of PCSK9, thereby blocking trafficking of the PCSK9–LDL-R complex to the lysosome and promoting LDL-R recycling. Owing to its long half-life (∼40 h), AZD0780 can be administered once daily.⁶ It has demonstrated a favourable safety and tolerability profile, with minimal adverse effects and food-independent absorption.⁷

A Phase I study conducted by Vega et al.⁷ evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD0780, both as monotherapy and in combination with rosuvastatin. Administration of AZD0780 at doses of 30 or 60 mg (vs. placebo) for 28 days in patients with LDL-C of 70–190 mg/dL resulted in LDL-C reductions of 30% and 38%, respectively. In another cohort of 35 patients with LDL-C of 100–190 mg/dL, after 3 weeks of treatment with rosuvastatin 20 mg, the addition of AZD0780 30 mg led to a 78% reduction in LDL-C from baseline, suggesting a synergistic effect that may facilitate achievement of LDL-C targets recommended by clinical guidelines.⁷

Studies assessing the pharmacokinetics, safety, and tolerability of AZD0780 in patients with hepatic and/or renal impairment are currently ongoing (NCT06576765, NCT06592482). In addition, the Phase I trial NCT06742853 is evaluating the same parameters in adults with hypercholesterolaemia treated with AZD0780 in combination with ezetimibe, ezetimibe/rosuvastatin, or ezetimibe/bempedoic acid.

The Phase 2b PURSUIT trial, a randomized, double-blind, placebo-controlled study, evaluated the efficacy, safety, and tolerability of AZD0780 (1, 2, 10, or 30 mg/day) in 426 patients with hypercholesterolaemia (LDL-C 70–190 mg/dL) already receiving statins or ezetimibe. After 12 weeks, LDL-C concentrations decreased in a dose-dependent manner (−35.3% to −50.7%), with no safety or tolerability concerns. Notably, 84% of patients treated with AZD0780 achieved the LDL-C target of <70 mg/dL, compared with 13% of those treated with statin/ezetimibe alone.⁸

Results regarding the efficacy, safety, tolerability, pharmacodynamics, and pharmacokinetics of AZD0780 are expected shortly from the sequential Phases II–III AZURE China study, initiated in December 2024. This randomized, double-blind, placebo-controlled trial (52-week duration) is being conducted in 380 patients with hypercholesterolaemia, either treatment-naïve or receiving statin therapy.

Finally, patient enrollment is beginning for the Phase II, randomized, double-blind LAZURE trial, designed to evaluate the safety, tolerability, and efficacy of AZD0780 (once daily for 12 weeks), administered alone or in combination with rosuvastatin, in 76 adults with dyslipidaemia and a history of ASCVD with LDL-C ≥ 55 mg/dL, or LDL-C ≥ 70 mg/dL in individuals at risk of a first ASCVD event.

NNC0385-0434

NNC0385-0434 is a small peptide that mimics the EGF-A domain of the human LDL-R and competitively binds free PCSK9, thereby preventing its interaction with the LDL-R. To enhance oral absorption, the compound is co-administered with sodium N-[8-(2-hydroxybenzoyl)amino] caprylate (SNAC).¹

A randomized, double-blind, placebo-controlled, parallel-group Phase II clinical trial conducted by Koren et al. was designed to evaluate the efficacy and safety of NNC0385-0434⁹ in patients with hypercholesterolaemia aged >40 years with established ASCVD, or >50 years with moderate chronic kidney disease, type 2 diabetes mellitus, or both, and LDL-C ≥ 70 mg/dL. Patients received NNC0385-0434, placebo, or evolocumab (140 mg subcutaneously every 2 weeks). After 12 weeks, LDL-C was reduced by 32.0%, 44.9%, and 61.8% with NNC0385-0434 at doses of 15, 40, and 100 mg once daily, respectively. A significant effect was observed in all treatment groups as early as 2 weeks, with maximal reductions between weeks 6 and 12, followed by a return to baseline 53 days after the last dose. NNC0385-0434 was well tolerated, with mild-to-moderate gastrointestinal adverse effects that were not dose dependent.

Notably:

• LDL-C reduction was comparable between NNC0385-0434 100 mg (−61.8%) and evolocumab (−59.6%);

• a significant reduction in Lp(a) concentrations was also observed (−36% with the 100 mg dose).

Despite these encouraging results, in November 2022 the sponsor decided not to continue development of the compound, citing research prioritization considerations.⁹

DC371739

DC371739 is a potent PCSK9 inhibitor, an indole derivative isolated from the herb Corydalis ambigua.¹⁰ By binding to hepatocyte nuclear factor 1α (HNF-1α) in hepatocytes, it inhibits gene transcription of both PCSK9 and ANGPTL3, thereby increasing LDL-R expression and lipoprotein lipase activity.

Based on in vitro experiments, it is not surprising that the combination of DC371739 with atorvastatin increases LDL-R expression by approximately 90% and reduces PCSK9 by about 50% in HepG2 cells compared with atorvastatin alone, given that statins are known to increase circulating PCSK9. In addition, in vitro assays have shown that DC371739 does not inhibit cytochrome P450 isoenzymes and is neither a substrate nor an inhibitor of OATP1B1/OATP1B3,¹⁰ suggesting a low potential for drug–drug interactions and no interference with hepatic uptake of statins.

DC371739 exhibits good oral bioavailability in rats and dogs and is metabolically stable, with metabolites that are poorly detectable or undetectable in hepatocytes from humans, non-human primates, dogs, rats, and mice.¹⁰

In hamster liver, DC371739 reduced transcription of pcsk9 (−41.3%) and angptl3 (−15.7%).⁹ In hamsters fed a high-fat diet, DC371739 administered at doses of 10, 30, or 100 mg/kg/day for 21 days reduced total C (−29%, −35%, and −39%), LDL-C (−23%, −31%, and −35%), and TG (−50%, −58%, and −78%).¹⁰ In the same model, 1 month of treatment (10–30 mg/kg/day) reduced hepatic C and TG content in a dose-dependent manner (−42.9% and −31.2%, respectively, at the highest dose).¹⁰

In hyperlipidaemic rhesus macaques treated for 28 days with DC371739 at 3 or 10 mg/kg/day, reductions in total C and LDL-C were 16% and 28%, and 14% and 31%, respectively.¹⁰

With regard to clinical development, a Phase Ib/IIa study (NCT04927221) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of DC371739 after multiple dosing (20, 40, 60, 80, or 120 mg/day for 28 days; n = 10 per group, including two placebo recipients) in patients with hypercholesterolaemia. Pharmacokinetic analysis in 16 study participants showed dose-dependent increases in DC371739 exposure (AUC), with half-lives of 26.2 and 22.6 h and T_max values of 6.5 and 5.5 h at doses of 20 and 40 mg, respectively. Although the study was completed in December 2021, only partial results have been disclosed.¹⁰ In the Phase I portion, DC371739 at 40 mg/day for 28 days demonstrated good safety, tolerability, and a favourable pharmacokinetic profile, significantly reducing total C (−18.8%), LDL-C (−19.2%), TG (−27.1%), and apoB (−25.3%) compared with placebo, without significant changes in HDL-C, in 20 patients with hypercholesterolaemia.¹⁰

Despite some concerns regarding specificity of action, DC371739 appears to be a well-tolerated dual PCSK9/ANGPTL3 inhibitor. Considering the efficacy of the anti-ANGPTL3 monoclonal antibody evinacumab in patients with homozygous familial hypercholesterolaemia, this compound may prove useful in the future also in patients with LDL-R mutations who are refractory to anti-PCSK9 therapies.¹⁰

CVI-LM001

CVI-LM001 is a derivative of the isoquinoline alkaloid corydaline that inhibits transcription of the pcsk9 gene while stabilizing LDL-R mRNA, thereby increasing LDL-R expression on hepatocytes in a dose-dependent manner. This effect has been demonstrated in hyperlipidaemic hamsters, with a 350% increase in hepatic LDL-R expression at a dose of 160 mg/kg for 4 weeks,¹¹ accompanied by marked reductions in circulating PCSK9 (>90%) and LDL-C (−42.6%) compared with controls. In the same model, CVI-LM001 induced hepatic AMP-activated protein kinase (AMPK) phosphorylation, reduced TG synthesis, and increased fatty acid oxidation, suggesting potential utility in metabolic dysfunction–associated fatty liver disease (MAFLD).¹¹

Double-blind, randomized studies using single doses (up to 800 mg/day) or multiple ascending doses have evaluated the pharmacokinetics of CVI-LM001 in healthy Chinese volunteers aged 18–45 years who received 100, 200, or 300 mg once daily, or placebo, for 10 days. After hepatic metabolism, the compound forms two bioactive metabolites, is rapidly absorbed (T_max 1.5 h; T_1/2 39 h), and reduces plasma PCSK9 levels by approximately 35%.¹¹

In a Phase Ia randomized, double-blind study conducted in normolipidaemic subjects, CVI-LM001 at 300 mg once daily for 10 days reduced serum PCSK9 by 36.4% compared with baseline. In a separate Phase Ib study, the same dose administered for 28 days significantly reduced LDL-C (−26.3%), total C (−20.1%), apoB (−17.4%), and PCSK9 (−39.2%) compared with placebo in patients with hypercholesterolaemia. In both studies, safety profiles were favourable.¹¹

Finally, an ongoing Phase II trial is evaluating the efficacy and safety of CVI-LM001 at doses of 100, 200, and 300 mg once daily for 12 weeks vs. placebo in patients with hypercholesterolaemia (NCT04438096).

CiVi008

If its development is confirmed, CiVi008 would represent the first oral formulation of an antisense oligonucleotide (ASO) targeting PCSK9 mRNA (cepadacursen sodium).

Conclusions

• The development of small-molecule PCSK9 inhibitors has proven chemically and structurally challenging because of the nature of the PCSK9/EGF-A domain interface of the LDL-R and the need to optimize hepatic tropism. Nevertheless, several orally administered compounds—although not yet commercially available—have shown encouraging results, owing to favourable pharmacokinetic and pharmacodynamic profiles, and appear suitable for combination therapy with statins, bempedoic acid, and ezetimibe.

• A very recent meta-analysis by Masson et al.¹² provides a comprehensive overview of the safety and efficacy of the most advanced oral PCSK9 inhibitors, including enlicitide, laroprovstat, and NNC0385-0434, demonstrating significant reductions in LDL-C (−55.7%), apoB (−46.9%), non-HDL-C (−49.4%), TG (−13.2%), and Lp(a) (−24.9%). A synopsis of the pharmacological properties and clinical development status of the most promising oral PCSK9 inhibitors is presented in Table 2.

• Additional compound-specific effects have also been documented, such as ANGPTL3 inhibition with DC371739 and significant reductions in Lp(a) with enlicitide.^3,10 The latter effect, already observed with monoclonal antibodies, further supports a link between Lp(a) and PCSK9.

• Finally, no significant effects on high-sensitivity C-reactive protein (hs-CRP) are expected with oral PCSK9 inhibitors, as evolocumab and alirocumab have likewise shown no meaningful impact on chronic inflammation.¹³

• In conclusion, based on current evidence, oral PCSK9 inhibitors appear poised to represent the future of lipid-lowering therapy, provided that their safety and efficacy profiles, as well as CV outcome data, are confirmed in ongoing clinical studies.

Table 2.

Pharmacological properties and clinical development stage of novel oral anti-PCSK9 agents

PCSK9 inhibitors	Mechanism of action	Dose	LDL-C reduction	Clinical study
Enlicitide decanoate (MK-0616)	Inhibits PCSK9–LDL-R interaction	20 mg once daily	55.8% vs. placebo	CORALreef–Lipids, Phase III
		20 mg once daily	59.4% vs. placebo	CORALreef–HeFH, Phase III
Laroprovstat (AZD0780)	Binds PCSK9, preventing LDL-R degradation	1, 3, 10, or 30 mg once daily	50.7% (30 mg vs. placebo)	PURSUIT, Phase II
NNC0385-0434	Inhibits PCSK9–LDL-R interaction	15, 40, or 100 mg once daily	61.8% (100 mg vs. baseline)	Development discontinued
DC371739	Reduces transcription of PCSK9 and ANGPTL3	20, 40, 60, 80, or 120 mg once daily	18.8% (40 mg vs. placebo)	Phase IIa/IIb
CVI-LM001	Reduces PCSK9 transcription; activates AMPK	300 mg once daily	26.3% (300 mg vs. baseline)	Phase Ib

Funding

Funded by the European Union – Next Generation EU, Mission 4, Component 1 CUP: C53D23006260006.

Data availability

No new data were generated or analysed in support of this research.

Disclaimer

This paper was originally published in the Italian language as ‘Nuove frontiere nel trattamento della colesterolemia: l'inibizione orale del PCSK9’, in the Volume degli Atti del Congresso “Conoscere e Cuare il Cuore 2026”, published by Centro per la Lotta contro l'Infarto for distribution at the CCC Conference. This paper was translated by Dr. Mario Albertucci, representative of the CLI Foundation, and republished with permission.