Pegcetacoplan

Last updated

Pegcetacoplan
Pegcetacoplan v01.svg
Clinical data
Trade names Empaveli, Aspaveli, Syfovre
Other namesAPL-2
AHFS/Drugs.com Monograph
MedlinePlus a621045
License data
Pregnancy
category
Routes of
administration 		Subcutaneous, intravitreal
Drug class Complement inhibitor
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C1970H3848N50O947S4
Molar mass 43520.10 g·mol−1

Pegcetacoplan, sold under the brand name Empaveli, among others, is a medication used to treat paroxysmal nocturnal hemoglobinuria [7] [10] [11] [12] [13] and geographic atrophy of the retina. [9] [14] Pegcetacoplan is a complement inhibitor. [7] [9]

Contents

The most common side effects include injection-site reactions, infections, diarrhea, abdominal pain, respiratory tract infection, viral infection, and fatigue. [7] [10]

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). [8]

Pegcetacoplan is the first treatment for paroxysmal nocturnal hemoglobinuria that binds to and inhibits complement protein C3. [8] Pegcetacoplan was approved for medical use in the United States in May 2021. [8] 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. [7] [8] [10] In February 2023, the indication was updated to include the treatment of people with geographic atrophy secondary to age-related macular degeneration. [9] [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. [7] 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. [8] Pegcetacoplan may also predispose individuals to serious infections, especially infections caused by encapsulated bacteria. [8] These infections include but are not limited to Streptococcus pneumoniae , Neisseria meningitidis , and Haemophilus influenzae . [7] 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. [7] Pegcetacoplan may cause fetal harm. [7] Pegcetacoplan may also interfere with silica reagents in laboratory coagulation panels. [7]

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

The FDA granted the application for pegcetacoplan orphan drug designation. [15]

On 14 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. [22] 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. [10] [23]

Related Research Articles

<span class="mw-page-title-main">Paroxysmal nocturnal hemoglobinuria</span> Medical condition

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the body's innate immune system. This destructive process occurs due to deficiency of the red blood cell surface protein DAF, which normally inhibits such immune reactions. Since the complement cascade attacks the red blood cells within the blood vessels of the circulatory system, the red blood cell destruction (hemolysis) is considered an intravascular hemolytic anemia. There is ongoing research into other key features of the disease, such as the high incidence of venous blood clot formation. Research suggests that PNH thrombosis is caused by both the absence of GPI-anchored complement regulatory proteins on PNH platelets and the excessive consumption of nitric oxide (NO).

<span class="mw-page-title-main">Macular degeneration</span> Medical condition associated with vision loss

Macular degeneration, also known as age-related macular degeneration, is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, some people experience a gradual worsening of vision that may affect one or both eyes. While it does not result in complete blindness, loss of central vision can make it hard to recognize faces, drive, read, or perform other activities of daily life. Visual hallucinations may also occur.

<span class="mw-page-title-main">Anecortave acetate</span> Chemical compound

Anecortave (rINN) is a novel angiogenesis inhibitor used in the treatment of the exudative (wet) form of age-related macular degeneration. Although similar in chemical structure to the corticosteroid hydrocortisone acetate, it possesses no glucocorticoid activity. If it is approved, it will be marketed by Alcon as anecortave acetate for depot suspension under the trade name Retaane. No development has been reported since 2010.

<span class="mw-page-title-main">Factor D</span> Class of enzymes

Factor D is a protein which in humans is encoded by the CFD gene. Factor D is involved in the alternative complement pathway of the complement system where it cleaves factor B.

Eculizumab, sold under the brand name Soliris among others, is a recombinant humanized monoclonal antibody used to treat paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis, and neuromyelitis optica. In people with PNH, it reduces both the destruction of red blood cells and need for blood transfusion, but does not appear to affect the risk of death. Eculizumab was the first drug approved for each of its uses, and its approval was granted based on small trials. It is given by intravenous infusion.

<span class="mw-page-title-main">Pegaptanib</span> Drug to treat macular degeneration

Pegaptanib sodium injection is an anti-angiogenic medicine for the treatment of neovascular (wet) age-related macular degeneration (AMD). It was discovered by NeXstar Pharmaceuticals and licensed in 2000 to EyeTech Pharmaceuticals, now OSI Pharmaceuticals, for late stage development and marketing in the United States. Gilead Sciences continues to receive royalties from the drugs licensing. Outside the US pegaptanib is marketed by Pfizer. Approval was granted by the U.S. Food and Drug Administration (FDA) in December 2004.

Aflibercept, sold under the brand names Eylea among others, is a medication used to treat wet macular degeneration and metastatic colorectal cancer. It was developed by Regeneron Pharmaceuticals and is approved in the United States and the European Union.

BioCryst Pharmaceuticals, Inc. is an American pharmaceutical company headquartered in Durham, North Carolina. The company is a late stage biotech company that focuses on oral drugs for rare and serious diseases. BioCryst's antiviral drug peramivir (Rapivab) was approved by FDA in December 2014. It has also been approved in Japan, Korea, and China.

Anti–vascular endothelial growth factor therapy, also known as anti-VEGF therapy or medication, is the use of medications that block vascular endothelial growth factor. This is done in the treatment of certain cancers and in age-related macular degeneration. They can involve monoclonal antibodies such as bevacizumab, antibody derivatives such as ranibizumab (Lucentis), or orally-available small molecules that inhibit the tyrosine kinases stimulated by VEGF: sunitinib, sorafenib, axitinib, and pazopanib.

<span class="mw-page-title-main">CD55 deficiency</span> Medical condition

CD55deficiency, also called DAF deficiency or CHAPLE syndrome, is a rare genetic disorder of the immune system. CHAPLE stands for "CD55 deficiency with hyper-activation of complement, angiopathic thrombosis, and severe protein-losing enteropathy (PLE)." The disorder usually manifests in childhood and can be life-threatening. This condition was described by Özen, et al. in 2017.

Ravulizumab, sold under the brand name Ultomiris, is a humanized monoclonal antibody complement inhibitor medication designed for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome. It is designed to bind to and prevent the activation of Complement component 5 (C5).

Sutimlimab, sold under the brand name Enjaymo, is a monoclonal antibody that is used to treat adults with cold agglutinin disease (CAD). It is given by intravenous infusion. Sutimlimab prevents complement-enhanced activation of autoimmune human B cells in vitro.

<span class="mw-page-title-main">Intravitreal injection</span> Method of administration of drugs into the eye by injection with a fine needle

Intravitreal injection is the method of administration of drugs into the eye by injection with a fine needle. The medication will be directly applied into the vitreous humor. It is used to treat various eye diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and infections inside the eye such as endophthalmitis. As compared to topical administration, this method is beneficial for a more localized delivery of medications to the targeted site, as the needle can directly pass through the anatomical eye barrier and dynamic barrier. It could also minimize adverse drug effects on other body tissues via the systemic circulation, which could be a possible risk for intravenous injection of medications. Although there are risks of infections or other complications, with suitable precautions throughout the injection process, chances for these complications could be lowered.

Ropeginterferon alfa-2b, sold under the brand name Besremi, is a medication used to treat polycythemia vera. It is an interferon. It is given by injection.

Conbercept, sold under the commercial name Lumitin, is a novel vascular endothelial growth factor (VEGF) inhibitor used to treat neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME). The anti-VEGF was approved for the treatment of neovascular AMD by the China State FDA (CFDA) in December 2013. As of December 2020, conbercept is undergoing phase III clinical trials through the U.S. Food and Drug Administration’s PANDA-1 and PANDA-2 development programs.

<span class="mw-page-title-main">Zilucoplan</span> Chemical compound

Zilucoplan, sold under the brand name Zilbrysq, is a medication used for the treatment of generalized myasthenia gravis. It is a complement inhibitor that is injected subcutaneously.

<span class="mw-page-title-main">Iptacopan</span> Chemical compound

Iptacopan, sold under the brand name Fabhalta, is a medication used for the treatment of paroxysmal nocturnal hemoglobinuria. It is a complement factor B inhibitor that was developed by Novartis. It is taken by mouth.

<span class="mw-page-title-main">Sucrose lysis test</span>

The sucrose lysis test is a diagnostic laboratory test used for diagnosing paroxysmal nocturnal hemoglobinuria (PNH), as well as for hypoplastic anemias and any hemolytic anemia with an unclear cause. The test works by using sucrose, which creates a low ionic strength environment that allows complement to bind to red blood cells. In individuals with PNH, some red blood cells are especially vulnerable to lysis caused by complement. The test may also produce suspicious results in other hematologic conditions, including megaloblastic anemia and autoimmune hemolytic anemia. False-negative results can occur when complement activity is absent in the serum. A simpler alternative called the sugar water test also involves mixing blood with sugar and observing for hemolysis, using the same principle as the sucrose lysis test.

Avacincaptad pegol, sold under the brand name Izervay, is a medication used for the treatment of age-related macular degeneration. Avacincaptad pegol is a complement inhibitor.

Crovalimab is an C5 inhibiting monoclonal antibody under investigation by Roche/Genentech for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

References

  1. 1 2 "Empaveli APMDS". Therapeutic Goods Administration (TGA). 17 February 2022. Retrieved 20 February 2022.
  2. ↑ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 21 December 2022. Archived from the original on 3 April 2022. Retrieved 2 January 2023.
  3. ↑ "Notice: Multiple Additions to the Prescription Drug List (PDL) [2023-03-08]". Health Canada . 8 March 2023. Archived from the original on 22 March 2023. Retrieved 21 March 2023.
  4. ↑ "Summary Basis of Decision for Empaveli". Health Canada . 13 April 2023. Retrieved 5 June 2023.
  5. ↑ "Aspaveli Summary of Product Characteristics (SmPC)". (emc). 21 September 2022. Retrieved 20 December 2023.
  6. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  7. 1 2 3 4 5 6 7 8 9 10 "Empaveli- pegcetacoplan injection, solution". DailyMed . 13 April 2023. Archived from the original on 13 July 2021. Retrieved 5 June 2023.
  8. 1 2 3 4 5 6 7 "FDA approves new treatment for adults with serious rare blood disease". U.S. Food & Drug Administration (FDA). 18 May 2021. Archived from the original on 17 October 2021. Retrieved 18 February 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  9. 1 2 3 4 "Syfovre- pegcetacoplan injection, solution". DailyMed. 23 February 2023. Retrieved 6 June 2023.
  10. 1 2 3 4 5 "Aspaveli EPAR". European Medicines Agency (EMA). 6 September 2022. Archived from the original on 18 February 2023. Retrieved 18 February 2023.
  11. ↑ Heo YA (December 2022). "Pegcetacoplan: A Review in Paroxysmal Nocturnal Haemoglobinuria". Drugs. 82 (18): 1727–1735. doi: 10.1007/s40265-022-01809-w . PMC   10234880 . PMID   36459381. S2CID   254149706.
  12. ↑ Wong RS (28 July 2022). "Safety and efficacy of pegcetacoplan in paroxysmal nocturnal hemoglobinuria". Therapeutic Advances in Hematology (Review). SAGE Publishing. 13: 20406207221114673. doi:10.1177/20406207221114673. eISSN   2040-6215. PMC   9340389 . PMID   35923770.
  13. ↑ Xu B (July 2023). "Novel targeted C3 inhibitor pegcetacoplan for paroxysmal nocturnal hemoglobinuria". Clinical and Experimental Medicine. 23 (3): 717–726. doi:10.1007/s10238-022-00830-3. PMID   35441351. S2CID   248245151.
  14. ↑ Liao DS, Metlapally R, Joshi P (September 2022). "Pegcetacoplan treatment for geographic atrophy due to age-related macular degeneration: a plain language summary of the FILLY study". Immunotherapy. 14 (13): 995–1006. doi: 10.2217/imt-2022-0078 . PMID   35860926. S2CID   250731980.
  15. 1 2 Advancing Health Through Innovation: New Drug Therapy Approvals 2021 (PDF). U.S. Food and Drug Administration (FDA) (Report). 13 May 2022. Archived from the original on 6 December 2022. Retrieved 22 January 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  16. ↑ "FDA Approves Syfovre (pegcetacoplan injection) as the First and Only Treatment for Geographic Atrophy (GA), a Leading Cause of Blindness" (Press release). Apellis Pharmaceuticals. 17 February 2023. Archived from the original on 17 February 2023. Retrieved 18 February 2023– via GlobeNewswire.
  17. 1 2 Hoy SM (August 2021). "Pegcetacoplan: First Approval". Drugs. 81 (12): 1423–1430. doi:10.1007/s40265-021-01560-8. PMID   34342834. S2CID   236884115.
  18. ↑ Bhak RH, Mody-Patel N, Baver SB, Kunzweiler C, Yee CW, Sundaresan S, et al. (November 2021). "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. doi: 10.1080/03007995.2021.1971182 . PMID   34445916. S2CID   228915088.
  19. ↑ Wong RS, Pullon HW, Amine I, Bogdanovic A, Deschatelets P, Francois CG, et al. (September 2022). "Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria". Annals of Hematology. 101 (9): 1971–1986. doi:10.1007/s00277-022-04903-x. PMC   9375762 . PMID   35869170.
  20. ↑ de Castro C, Grossi F, Weitz IC, Maciejewski J, Sharma V, Roman E, et al. (November 2020). "C3 inhibition with pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria treated with eculizumab". American Journal of Hematology. 95 (11): 1334–1343. doi:10.1002/ajh.25960. PMC   7693064 . PMID   33464651.
  21. ↑ Hillmen P, Szer J, Weitz I, Röth A, Höchsmann B, Panse J, et al. (March 2021). "Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria". The New England Journal of Medicine. 384 (11): 1028–1037. doi: 10.1056/NEJMoa2029073 . PMID   33730455. S2CID   232296249.
  22. 1 2 "Aspaveli: Pending EC decision". European Medicines Agency (EMA). 14 October 2021. Archived from the original on 18 October 2021. Retrieved 15 October 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  23. ↑ "Aspaveli Product information". Union Register of medicinal products. Archived from the original on 4 March 2023. Retrieved 3 March 2023.

PD-icon.svg This article incorporates public domain material from the United States Department of Health and Human Services

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.