What is the new oral pcsk 9 inhibitors
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oral PCSK9 inhibitor small molecule
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oral PCSK9 inhibitor 2025 2026 MK-0616 clinical trial approval
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PMID: 40167413
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https://www.pharmacytimes.com/view/fda-approves-enlicitide-t…
This is excellent, very current data. Here is a full summary:
Oral PCSK9 Inhibitors - 2026 Update
What Makes Them Different from Injectable PCSK9 Inhibitors?
Traditional PCSK9 inhibitors (evolocumab/Repatha, alirocumab/Praluent) are monoclonal antibodies requiring subcutaneous injection every 2-4 weeks. Inclisiran (Leqvio) is a small-interfering RNA also given by injection. Oral delivery has been a long-sought goal to improve adherence and access.
1. Enlicitide Decanoate (MK-0616) - Brand name: Lipfendra - MERCK
FDA APPROVED: July 16, 2026 - This is breaking news (approved just yesterday).
- Mechanism: Macrocyclic peptide - a ring-shaped peptide structure that directly blocks PCSK9 from binding to the LDL receptor. Macrocyclization increases metabolic stability and oral bioavailability compared to standard linear peptides.
- Dose: 20 mg once daily tablet
- Indication: Adjunct to diet and exercise to reduce LDL-C in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH)
- Pivotal trial results (CORALreef program):
- CORALreef Lipids: 56% placebo-adjusted LDL-C reduction at 24 weeks
- CORALreef HeFH: 59% placebo-adjusted LDL-C reduction at 24 weeks
- Safety: Generally similar to placebo; in HeFH patients, diarrhea (7%) and dizziness (9%) were reported
- Note: A cardiovascular outcomes trial (MACE reduction) is ongoing - lipid lowering is proven, but MACE benefit is still under investigation
- Historic significance: First and only oral PCSK9 inhibitor ever approved by the FDA
The PURSUIT Phase II trial (JACC, 2025) also reported strong Phase 2 data for AZD0780 (see below), confirming the oral PCSK9 concept is now fully validated. [PMID: 40167413]
2. AZD0780 - ASTRAZENECA
- Mechanism: True small molecule oral PCSK9 inhibitor (not a peptide - a conventional small molecule)
- Status: Phase III clinical trials as of 2025 - not yet approved
- Phase II (PURSUIT trial, JACC 2025) - [PMID: 40167413]:
- Dose-dependent LDL-C reductions at 12 weeks:
- 1 mg: -35.3% vs placebo
- 3 mg: -37.9% vs placebo
- 10 mg: -45.2% vs placebo
- 30 mg: -50.7% vs placebo
- Safety comparable to placebo
- Dose-dependent LDL-C reductions at 12 weeks:
- Once-daily oral dosing on background statin therapy
- Phase III program is underway; an NDA has not yet been filed
Comparison Table
| Feature | Enlicitide (Lipfendra) | AZD0780 |
|---|---|---|
| Developer | Merck | AstraZeneca |
| Chemical class | Macrocyclic peptide | Small molecule |
| Regulatory status | FDA Approved (July 2026) | Phase III |
| Dosing | 20 mg once daily | Once daily (dose TBD) |
| LDL-C reduction | ~56-59% | ~35-51% (Phase II) |
| MACE data | Ongoing trial | Not yet |
Pipeline Context
Beyond these two, a review in Current Atherosclerosis Reports (Tokgözoğlu et al., [PMID: 40304930], April 2025) summarizes the broader question of whether oral PCSK9 inhibitors can replicate injectable antibody efficacy - the answer now appears to be yes for lipid lowering, with cardiovascular outcomes data pending.
Key takeaway: As of July 17, 2026, enlicitide decanoate (Lipfendra) - formerly known as MK-0616 - is the world's first FDA-approved oral PCSK9 inhibitor, approved literally yesterday. AstraZeneca's AZD0780 is the second major candidate, currently in Phase III with no approval yet.
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