Navigating the Complement Pathway to Optimize PNH Treatment with Pegcetacoplan and Other Currently Approved Complement Inhibitors
Abstract
:1. Paroxysmal Nocturnal Hemoglobinuria
2. Eculizumab, Ravulizumab, and Crovalimab, Terminal Complement Inhibitors for PNH
3. Pegcetacoplan, the First C3 Complement Inhibitor for PNH
4. Iptacopan and Danicopan, New Proximal Complement Inhibitors for PNH
5. Conclusions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Parameter | Levels in Untreated Patients with PNH | Physiological Cause |
---|---|---|
LDH or LDH ratio (LDH/ULN) (marker of hemolysis) | High often ≥ 1.5 × ULN (up to 10 × ULN) | Increased due to hemolysis of PNH red blood cells (mostly through IVH) |
Hemoglobin (marker of anemia) | Low (≤10 g/dL) | Decreased due to hemolysis of PNH red blood cells (through IVH and EVH) or bone marrow failure |
ARC (marker of bone marrow compensation) a | High often > ULN (up to 1.5 × ULN) | Increased due to bone marrow compensation for hemolyzed PNH red blood cells |
PNH red blood cell clone size | Variable (usually > 5%) | Increased due to PIGA gene somatic mutation and subsequent loss of GPI-linked proteins (e.g., CD59 for red blood cells) |
PNH granulocyte clone size (diagnostic marker of PNH) | Variable (usually ≥ 10%) |
Inhibition Target | Drug Name | Approval Date | Indication | Administration Regimen | Molecule | MOA |
---|---|---|---|---|---|---|
C5 | Eculizumab [34,35] | 03/2007 | Adults (≥18 years) with PNH | IV infusion every 2 weeks | C5 mAB | Inhibits C5 cleavage to C5a and C5b |
C5 | Ravulizumab [36,37] | 12/2018 | Adults and children (≥1 month) with PNH | IV infusions every 4 or 8 weeks based on body weight | C5 hmAB | Inhibits C5 cleavage to C5a and C5b |
C5 | Crovalimab [38] | 06/2024 | Adults and children (≥13 years) with PNH and body weight ≥ 40 kg | SC injection every 4 weeks | C5 hmAB | Inhibits C5 cleavage to C5a and C5b |
C3 and C3b | Pegcetacoplan [39,40] | 03/2021 | Adults with PNH | SC infusion twice weekly | Pegylated compstatin | Regulates C3 cleavage and generation of downstream effectors |
Factor B | Iptacopan [41,42] | 12/2023 | Adults with PNH | Orally twice daily | Small peptide | Regulates AP-dependent C3 cleavage and AP amplification loop |
Factor D | Danicopan [43,44] | 03/2024 | Add-on to ravulizumab or eculizumab for EVH in adults with PNH | Orally 3 times daily | Small peptide | Prevents factor B cleavage to Ba and Bb, regulating C3 cleavage and AP amplification loop |
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Hillmen, P.; Horneff, R.; Yeh, M.; Kolev, M.; Deschatelets, P. Navigating the Complement Pathway to Optimize PNH Treatment with Pegcetacoplan and Other Currently Approved Complement Inhibitors. Int. J. Mol. Sci. 2024, 25, 9477. https://doi.org/10.3390/ijms25179477
Hillmen P, Horneff R, Yeh M, Kolev M, Deschatelets P. Navigating the Complement Pathway to Optimize PNH Treatment with Pegcetacoplan and Other Currently Approved Complement Inhibitors. International Journal of Molecular Sciences. 2024; 25(17):9477. https://doi.org/10.3390/ijms25179477
Chicago/Turabian StyleHillmen, Peter, Regina Horneff, Michael Yeh, Martin Kolev, and Pascal Deschatelets. 2024. "Navigating the Complement Pathway to Optimize PNH Treatment with Pegcetacoplan and Other Currently Approved Complement Inhibitors" International Journal of Molecular Sciences 25, no. 17: 9477. https://doi.org/10.3390/ijms25179477