What is pegcetacopan?

Pegcetacoplan: A Complement Inhibitor for PNH and Other Complement-Mediated Diseases

Pegcetacoplan (Empaveli™) is a complement inhibitor that binds to complement protein C3 and its activation fragment C3b, controlling both C3b-mediated extravascular hemolysis and terminal complement-mediated intravascular hemolysis. It is the first C3-targeted therapy approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

Mechanism of Action and Structure

• Pegcetacoplan is a symmetrical molecule comprised of two identical pentadecapeptides covalently bound to the ends of a linear 40-kiloDalton (kDa) PEG molecule 1
• It binds to complement protein C3 and its activation fragment C3b, regulating the cleavage of C3 and the generation of downstream effectors of complement activation 1
• By acting proximally in the complement cascade, pegcetacoplan controls both C3b-mediated extravascular hemolysis (EVH) and terminal complement-mediated intravascular hemolysis (IVH) 1

FDA Approval and Indications

• Pegcetacoplan received FDA approval in May 2021 as the first C3-targeted therapy for PNH 2
• In the United States, it is indicated for the treatment of adults with PNH, including those switching from C5 inhibitor therapy with eculizumab and ravulizumab 2
• In the European Union, it is approved for adults with PNH who are anemic despite C5-targeted therapy for ≥3 months 3
• In Australia, it is approved for adults with PNH with inadequate response or intolerance to a C5 inhibitor 3

Clinical Efficacy in PNH

• In the PRINCE phase 3 trial with complement inhibitor-naive PNH patients, pegcetacoplan demonstrated superiority over supportive care for:

  • Hemoglobin stabilization (85.7% vs 0%, p<0.0001) 3
  • Reduction in lactate dehydrogenase levels (mean change: -1870.5 U/L vs -400.1 U/L, p<0.0001) 3

• In the PEGASUS trial in patients with PNH who had hemoglobin <10.5 g/dL despite eculizumab therapy, pegcetacoplan was superior to eculizumab in improving hemoglobin levels 4

• Real-world evidence from the UK and France showed:

  • Mean hemoglobin increase of 22.3 g/L after 3 months of treatment 5
  • Significant reduction in reticulocyte count (from 205 × 10^9/L to 107 × 10^9/L) 5
  • Maintained LDH control 5

Dosage and Administration

• The recommended dosage is 1080 mg administered twice weekly as a subcutaneous infusion via an infusion pump with a ≥20 mL reservoir 1, 2
• Steady-state concentrations are achieved approximately 4-6 weeks after the first dose 1

Safety Profile and Adverse Effects

• Pegcetacoplan is generally well tolerated in both complement inhibitor-naive patients and those previously treated with eculizumab 4

• Common adverse reactions include:

  • Injection site reactions
  • Infections
  • Diarrhea
  • Abdominal pain
  • Respiratory tract infections 6

• Breakthrough hemolysis (BTH) can occur but is manageable with prompt intervention, such as daily pegcetacoplan subcutaneously for 3 days or single eculizumab doses 5

Pharmacokinetics

• Mean volume of distribution: approximately 3.98 L 1
• Estimated mean clearance: 0.36 L/day 1
• Median effective half-life: 8 days 1
• Trough serum concentration at steady state: approximately 706-744 mcg/mL 1

Ongoing Research and Future Applications

• Pegcetacoplan is being investigated for other complement-mediated diseases, including:
  • Age-related macular degeneration
  • C3 glomerulopathy
  • Autoimmune hemolytic anemia 2

Clinical Considerations

• Patients should be monitored for breakthrough hemolysis, particularly during complement-activating conditions 5
• For patients with PNH experiencing extravascular hemolysis despite C5 inhibitor therapy, pegcetacoplan offers a valuable treatment option 4
• Long-term safety data is still being collected to further support the safety profile of pegcetacoplan 4

Pegcetacoplan represents a significant advancement in the treatment of complement-mediated diseases, particularly for PNH patients who continue to experience anemia despite treatment with C5 inhibitors.