Table 1.
Current pharmaceutical strategies to target PCSK9
| Mechanism of action | Advantages | Disadvantages | Administration | Candidates | Development status | Sponsor/Reference | |
|---|---|---|---|---|---|---|---|
| mAbs | To block the PCSK9-LDLR interaction or neutralize PCSK9 activity | High specificity, low toxicity, efficient and safe | Frequent and parental administration, relatively short shelf life, high cost | Subcutaneous injection | Evolocumab | Approved (EMA and US FDA, 2015) | Amgen |
| Alirocumab | Approved (EMA and US FDA, 2015) | Sanofi/Regeneron | |||||
| Tafolecimab (IBI306) | Approved (China’s NMPA, 2023) | Innovent Biologics (Suzhou) | |||||
| Bococizumab | NCT02458287, Phase 3, completed | Pfizer | |||||
| Recaticimab (SHR-1209) | NCT04849000, Phase 3, completed | Jiangsu HengRui Medicine | |||||
| Ongericimab (JS002) | NCT05325203, Phase 3, recruiting | Shanghai Junshi Bioscience | |||||
| Ebronucimab (AK102) | NCT04358432, Phase 2, completed | Akeso/AD Pharmaceuticals | |||||
| LY3015014 | NCT01890967, Phase 2, completed | Lilly | |||||
| RG7652 (MPSK3169A) | NCT01609140, Phase 2, completed | Genentech/Roche | |||||
| Lodelcizumab (LGT209) | NCT01859455, Phase 1, completed | Novartis | |||||
| MEDI4166 | NCT02524782, Phase 1, completed | MedImmune | |||||
| Ralpancizumab (PF-05335810) | NCT01720537, Phase 1, completed | Pfizer | |||||
| SAL003 | ChiCTR2000031373, Phase 1, ongoing | Shenzhen Salubris Pharmaceuticals | |||||
| siRNA | To target PCSK9 mRNA and inhibit translation | High specificity, infrequent dosing, long-term effect, and safe | Parental injection | Subcutaneous injection | Inclisiran | Approved (EMA, 2020; US FDA, 2021) | Novartis |
| ASOs | To silence PCSK9 mRNA, leading to its degradation | High specificity | High cost, parental administration | Subcutaneous injection (AZD8233 may be orally available; BMS-844421 can also be intravenously injected.) | AZD8233 | NCT04641299, Phase 2, completed | AstraZeneca |
| Civi-007 | NCT04164888, Phase 2, completed | Civi Biopharma, Inc. | |||||
| BMS-844421 | NCT01082562, Phase 1, Terminated | BMS | |||||
| SPC5001 | NCT01350960, Phase 1, Terminated | Santaris Pharma A/S | |||||
| Small molecules | To block the synthesis and interaction of PCSK9 and enzyme or receptor | Oral administration, easy synthesis, low cost | Low selectivity, non-tissue specific effect, narrow therapeutic window | Orally | CVI-LM001 | NCT04438096, Phase 2, Unkonwn status | CVI Pharmaceuticals |
| DC371739 | NCT04927221, Phase 1, completed | Guangzhou JOYO Pharma | |||||
| K-312 | NCT02676596, Phase 1, completed | Kowa Research Institute | |||||
| SAL092 | Phase 1 trial pending in China | Shenzhen Salubris Pharmaceuticals | |||||
| DRP | Preclinical | 380 | |||||
| NYX-330 | Preclinical | 380 | |||||
| PF-06446846 | Preclinical | 391 | |||||
| Mimetic peptides | To block PCSK9-LDLR interaction | High specificity, easy synthesis, low cost | Instable in plasma, parental administration | Orally (MK-0616, NNC0385-0434), Subcutaneous injection (Pep2-8) | MK-0616 | NCT05261126, Phase 2, completed | Merck Sharp & Dohme |
| NNC0385-0434 (NN-6434) | NCT04992065, Phase 2, completed | Novo Nordisk A/S | |||||
| Pep2-8 | Preclinical | 392,501 | |||||
| Adnectins | To block PCSK9-LDLR interaction | High specificity, easy synthesis, low cost | short plasma half-life | Subcutaneous injection (Lerodalcibep); Subcutaneous or intravenous injection (BMS-962476) | Lerodalcibep (LIB003) | NCT04790513, Phase 3, completed | LIB Therapeutics/Medpace |
| BMS-962476 | NCT01587365, Phase 1, completed | BMS | |||||
| Anticalin | To block PCSK9-LDLR interaction | Ab mimetic but smaller, low cost | Hard to design and screen | Subcutaneous or intravenous injection | DS-9001a | Preclinical | Daiichi Sankyo/Pieris Pharmaceuticals502 |
| Vaccines | To induce anti-PCSK9 autoantibodies | Long-term effect, infrequent dosing, easy synthesis, low cost | Autoimmune disorder risk | Subcutaneous injection (AT04A and AT06A); Intramuscular injection (VXX-401) | AT04A | NCT02508896, Phase 1, completed | AFFiRis |
| AT06A | NCT02508896, Phase 1, completed | AFFiRis | |||||
| VXX-401 | NCT05762276, Phase 1, recruiting | Vaxxinity/Novotech | |||||
| Meganuclease based gene editing technology | To disrupt PCSK9 gene | Infrequent dosing, long-term durable effect | Off-target potential, liver injury, integration of viral vector into the genome | Intravenous injection | AAV-mediated | Preclinical (NHP) | 389,390 |
| CRISPR based gene editing technology | To disrupt PCSK9 gene | Infrequent dosing, long-term durable effect | Off target potential, liver injury, integration of viral vector into the genome (only for virus mediated editing) | Intravenous injection | Adenovirus based | Preclinical (mouse) | 393 |
| AAV-mediated | Preclinical (mouse) | 394 | |||||
| LLN-mediated | Preclinical (mouse) | 395 | |||||
| LNP-mediated (ABE8.8) | Preclinical (NHP) | 396 | |||||
| LNP-mediated (ABEmax) | Preclinical (NHP) | 388 | |||||
| Natural products | To block the interaction and function of PCSK9 and enzyme or receptor | Oral administration, easy synthesis, low cost | Low selectivity, non-tissue specific effect | Orally | Berberine and monacolin K | NCT03470376, Phase 4, completed | University Of Perugia |
| Curcumin, Moracin C, Polydatin, etc. | Preclinical | 397 |
AAV adeno-associated virus, EMA European Medicines Agency, LLN lipid-like nanoparticle, LNP lipid nanoparticle, NHP nonhuman primate, NMPA National Medical Products Administration, US FDA Food and Drug Administration of the United States