Pegcetacoplan Explained

Width:250
Tradename:Empaveli, Aspaveli, Syfovre
Dailymedid:Pegcetacoplan
Pregnancy Au:B3
Pregnancy Au Comment:[1]
Pregnancy Category:Not recommended
Routes Of Administration:Subcutaneous, intravitreal
Class:Complement inhibitor
Atc Prefix:L04
Atc Suffix:AJ03
Legal Au:S4
Legal Au Comment:[2]
Legal Ca:Rx-only
Legal Ca Comment:[3] [4] [5]
Legal Uk:POM
Legal Uk Comment:[6]
Legal Us:Rx-only
Legal Eu:Rx-only
Cas Number:2019171-69-6
Drugbank:DB16694
Unii:TO3JYR3BOU
Kegg:D11613
Chembl:4298211
Synonyms:APL-2
C:1970
H:3848
N:50
O:947
S:4

Pegcetacoplan, sold under the brand name Empaveli, among others, is a medication used to treat paroxysmal nocturnal hemoglobinuria[7] [8] [9] [10] and geographic atrophy of the retina.[11] [12] Pegcetacoplan is a complement inhibitor.

The most common side effects include injection-site reactions, infections, diarrhea, abdominal pain, respiratory tract infection, viral infection, and fatigue.[13]

Paroxysmal nocturnal hemoglobinuria is characterized by red blood cell destruction, anemia (red blood cells unable to carry enough oxygen to tissues), blood clots, and impaired bone marrow function (not making enough blood cells).[14]

Pegcetacoplan is the first treatment for paroxysmal nocturnal hemoglobinuria that binds to and inhibits complement protein C3. Pegcetacoplan was approved for medical use in the United States in May 2021. The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[15]

Medical uses

Pegcetacoplan is indicated to treat adults with paroxysmal nocturnal hemoglobinuria. In February 2023, the indication was updated to include the treatment of people with geographic atrophy secondary to age-related macular degeneration.[16] The medication is given through a subcutaneous infusion for paroxysmal nocturnal hemoglobinuria and through intravitreal injection for age-related macular degeneration.[17]

Pharmacology

Pegcetacoplan acts as a complement inhibitor, specifically targeting complement protein C3, which plays a crucial role in the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH). In individuals with PNH, there is a heightened and uninhibited complement activity, which may lead to intravascular (inside blood vessels) or extravascular (within the liver or spleen) hemolysis. By binding to and inhibiting C3, pegcetacoplan helps regulate complement activation, thereby reducing red blood cell destruction, anemia, blood clot formation, and improving bone marrow function. This targeted mechanism of action makes pegcetacoplan the first-in-class medication for the treatment of PNH, offering a promising therapeutic approach to address the underlying complement dysregulation in this condition.[18]

Pharmacokinetics

Pegcetacoplan exhibits proportional exposure with increasing doses and reaches peak concentration within 4.5–6 days after a single subcutaneous dose. Steady-state concentrations are achieved in about 4–6 weeks of treatment, with average serum trough concentrations ranging from 655-706 μg/mL. Pegcetacoplan is metabolized into smaller peptides and amino acids and has a median effective elimination half-life of approximately 8.0 days in patients with PNH.[17]

Adverse effects

Meningococcal (a type of bacteria) infections can occur in people taking pegcetacoplan. Pegcetacoplan may also predispose individuals to serious infections, especially infections caused by encapsulated bacteria. These infections include but are not limited to Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. Common adverse effects associated with the medication include stomach pain, vomiting, diarrhea, cold sores, common-cold like symptoms, tiredness as well as any itching, redness, or sensitivity at the injection site. Pegcetacoplan may cause fetal harm. Pegcetacoplan may also interfere with silica reagents in laboratory coagulation panels.

History

The therapeutic efficacy of subcutaneous pegcetacoplan in treating paroxysmal nocturnal hemoglobinuria (PNH) has been established through several clinical trials. Initial phase I and II trials, such as PADDOCK, PALOMINO, and PHAROAH, evaluated pegcetacoplan in PNH patients who had not received a complement inhibitor or had previously received eculizumab. These trials demonstrated that 1–2 years of pegcetacoplan treatment effectively controlled hemolysis and improved quality of life in PNH patients.,[19] [20]

Building upon these findings, the efficacy of pegcetacoplan was further assessed in phase III trials. The PRINCE trial, a 26-week study, focused on complement inhibitor-naïve patients with PNH, while the PEGASUS trial, a 48-week multinational study, included complement inhibitor-treated patients with PNH. In these trials, subcutaneous pegcetacoplan was administered at a dosage of 1080 mg twice weekly, delivered as a 20-mL subcutaneous infusion. Patients had the option to self-administer the medication or have it administered by qualified research personnel.[21]

Society and culture

Legal status

The FDA granted the application for pegcetacoplan orphan drug designation.

In October 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Aspaveli, intended for the treatment of adults with paroxysmal nocturnal hemoglobinuria. The applicant for this medicinal product is Swedish Orphan Biovitrum AB (publ).[22] Pegcetacoplan was approved for the treatment of paroxysmal nocturnal haemoglobinuria in the European Union in December 2021.[23]

In June 2024, the CHMP recommended the refusal of a marketing authorization for Syfovre, a medicine intended for the treatment of geographic atrophy caused by age-related macular degeneration.[24] The manufacturer requested a re-examination in July 2024.[25]

Notes and References

  1. Web site: Updates to the Prescribing Medicines in Pregnancy database . Therapeutic Goods Administration (TGA) . 21 December 2022 . 2 January 2023 . 3 April 2022 . https://web.archive.org/web/20220403064059/https://www.tga.gov.au/updates-prescribing-medicines-pregnancy-database . live .
  2. Web site: Empaveli APMDS . Therapeutic Goods Administration (TGA) . 17 February 2022 . 20 February 2022.
  3. Web site: Details for: Empaveli . . 15 February 2023 . 3 March 2024 . 3 March 2024 . https://web.archive.org/web/20240303051911/https://dhpp.hpfb-dgpsa.ca/dhpp/resource/102229 . live .
  4. Web site: Notice: Multiple Additions to the Prescription Drug List (PDL) [2023-03-08] ]. . 8 March 2023 . 21 March 2023 . 22 March 2023 . https://web.archive.org/web/20230322024545/https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/notices-changes/mutliple-additions-2023-03-08.html . live .
  5. Web site: Summary Basis of Decision for Empaveli . . 13 April 2023 . 5 June 2023.
  6. Web site: Aspaveli Summary of Product Characteristics (SmPC) . (emc) . 21 September 2022 . 20 December 2023 . 20 December 2023 . https://web.archive.org/web/20231220061107/https://www.medicines.org.uk/emc/product/13369/smpc . live .
  7. Web site: 6 September 2022 . Aspaveli EPAR . live . https://web.archive.org/web/20230218190811/https://www.ema.europa.eu/en/medicines/human/EPAR/aspaveli . 18 February 2023 . 18 February 2023 . European Medicines Agency (EMA) .
  8. Heo YA . Pegcetacoplan: A Review in Paroxysmal Nocturnal Haemoglobinuria . Drugs . 82 . 18 . 1727–1735 . December 2022 . 36459381 . 10234880 . 10.1007/s40265-022-01809-w . 254149706 . free .
  9. Wong RS . Safety and efficacy of pegcetacoplan in paroxysmal nocturnal hemoglobinuria . Therapeutic Advances in Hematology . 13 . 20406207221114673 . 28 July 2022 . 35923770 . 9340389 . 10.1177/20406207221114673 . . 2040-6215 . Review .
  10. Xu B . Novel targeted C3 inhibitor pegcetacoplan for paroxysmal nocturnal hemoglobinuria . Clinical and Experimental Medicine . 23 . 3 . 717–726 . July 2023 . 35441351 . 10.1007/s10238-022-00830-3 . 248245151 .
  11. Web site: Syfovre- pegcetacoplan injection, solution . DailyMed . 23 February 2023 . 6 June 2023.
  12. Liao DS, Metlapally R, Joshi P . Pegcetacoplan treatment for geographic atrophy due to age-related macular degeneration: a plain language summary of the FILLY study . Immunotherapy . 14 . 13 . 995–1006 . September 2022 . 35860926 . 10.2217/imt-2022-0078 . 250731980 . free .
  13. Web site: 13 April 2023 . Empaveli- pegcetacoplan injection, solution . 5 June 2023 . . 13 July 2021 . https://web.archive.org/web/20210713140929/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c23d89e9-b00b-4520-e053-2995a90a95af . live .
  14. Web site: 18 May 2021 . FDA approves new treatment for adults with serious rare blood disease . live . https://web.archive.org/web/20211017091350/https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-new-treatment-adults-serious-rare-blood-disease . 17 October 2021 . 18 February 2023 . U.S. Food & Drug Administration (FDA).
  15. Advancing Health Through Innovation: New Drug Therapy Approvals 2021 . U.S. Food and Drug Administration (FDA) . 13 May 2022 . PDF . 22 January 2023 . 6 December 2022 . https://web.archive.org/web/20221206210020/https://www.fda.gov/media/155227/download . live .
  16. FDA Approves Syfovre (pegcetacoplan injection) as the First and Only Treatment for Geographic Atrophy (GA), a Leading Cause of Blindness . Apellis Pharmaceuticals . GlobeNewswire . 17 February 2023 . 18 February 2023 . 17 February 2023 . https://web.archive.org/web/20230217233556/https://www.globenewswire.com/news-release/2023/02/17/2610967/0/en/FDA-Approves-SYFOVRE-pegcetacoplan-injection-as-the-First-and-Only-Treatment-for-Geographic-Atrophy-GA-a-Leading-Cause-of-Blindness.html . live.
  17. Hoy SM . Pegcetacoplan: First Approval . Drugs . 81 . 12 . 1423–1430 . August 2021 . 34342834 . 10.1007/s40265-021-01560-8 . 236884115 .
  18. Bhak RH, Mody-Patel N, Baver SB, Kunzweiler C, Yee CW, Sundaresan S, Swartz N, Duh MS, Krishnan S, Sarda SP . Comparative effectiveness of pegcetacoplan versus ravulizumab in patients with paroxysmal nocturnal hemoglobinuria previously treated with eculizumab: a matching-adjusted indirect comparison . Current Medical Research and Opinion . 37 . 11 . 1913–1923 . November 2021 . 34445916 . 10.1080/03007995.2021.1971182 . 228915088 . free .
  19. Wong RS, Pullon HW, Amine I, Bogdanovic A, Deschatelets P, Francois CG, Ignatova K, Issaragrisil S, Niparuck P, Numbenjapon T, Roman E, Sathar J, Xu R, Al-Adhami M, Tan L, Tse E, Grossi FV . Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria . Annals of Hematology . 101 . 9 . 1971–1986 . September 2022 . 35869170 . 9375762 . 10.1007/s00277-022-04903-x .
  20. de Castro C, Grossi F, Weitz IC, Maciejewski J, Sharma V, Roman E, Brodsky RA, Tan L, Di Casoli C, El Mehdi D, Deschatelets P, Francois C . C3 inhibition with pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria treated with eculizumab . American Journal of Hematology . 95 . 11 . 1334–1343 . November 2020 . 33464651 . 7693064 . 10.1002/ajh.25960 .
  21. Hillmen P, Szer J, Weitz I, Röth A, Höchsmann B, Panse J, Usuki K, Griffin M, Kiladjian JJ, de Castro C, Nishimori H, Tan L, Hamdani M, Deschatelets P, Francois C, Grossi F, Ajayi T, Risitano A, Peffault de la Tour R . Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria . The New England Journal of Medicine . 384 . 11 . 1028–1037 . March 2021 . 33730455 . 10.1056/NEJMoa2029073 . 232296249 . free .
  22. Web site: Aspaveli: Pending EC decision . European Medicines Agency (EMA) . 14 October 2021 . 15 October 2021 . 18 October 2021 . https://web.archive.org/web/20211018120615/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/aspaveli . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  23. Web site: Aspaveli Product information . Union Register of medicinal products . 3 March 2023 . 4 March 2023 . https://web.archive.org/web/20230304103439/https://ec.europa.eu/health/documents/community-register/html/h1595.htm . live .
  24. Web site: Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 24-27 June 2024 . European Medicines Agency . 28 June 2024 . 12 July 2024 . 12 July 2024 . https://web.archive.org/web/20240712152232/https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-24-27-june-2024 . live .
  25. Web site: Syfovre EPAR . European Medicines Agency . 11 July 2024 . 12 July 2024 . 5 July 2024 . https://web.archive.org/web/20240705192955/https://www.ema.europa.eu/en/medicines/human/EPAR/syfovre . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

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