Is pegcetacoplan (C3 inhibitor) used in C3 glomerulopathy (C3G)?

Pegcetacoplan in C3 Glomerulopathy (C3G)

Yes, pegcetacoplan is used in C3 glomerulopathy (C3G) and is FDA-approved for this indication in patients aged 12 years and older. Pegcetacoplan is a C3 inhibitor that targets the complement cascade at the level of C3, which is central to the pathogenesis of C3G.

Mechanism of Action and Rationale

• Pegcetacoplan binds to complement protein C3 and its activation fragment C3b, thereby regulating C3 cleavage and downstream complement activation 1
• In C3G, complement dysregulation and overactivation causes deposition of C3 fragments in glomeruli, which directly contributes to the pathogenesis of the disease 1
• By inhibiting C3 activation, pegcetacoplan decreases C3 glomerular fragment deposition and reduces C5 convertase activity and subsequent assembly of C5b-9 (membrane attack complex) 1

Treatment Algorithm for C3G

First-Line Therapy

• For patients with moderate-to-severe C3G without monoclonal gammopathy, initial treatment should be mycophenolate mofetil (MMF) plus glucocorticoids 2
• If this fails, eculizumab (terminal complement inhibitor) should be considered 2

Role of Pegcetacoplan

• Pegcetacoplan is indicated for patients who have failed first-line therapy or as part of a clinical trial 2
• FDA has approved pegcetacoplan for the treatment of C3G in patients aged 12 years and older 1
• In clinical studies, pegcetacoplan demonstrated significant efficacy in reducing C3 deposits in glomeruli and improving clinical outcomes 1, 3

Efficacy of Pegcetacoplan in C3G

• In patients with C3G treated with pegcetacoplan, mean serum C3 levels increased from 62 mg/dL at baseline to 371 mg/dL at Week 26 1
• Mean plasma soluble C5b-9 levels decreased from 903 ng/mL at baseline to 290 ng/mL at Week 26 1
• 74% of patients on pegcetacoplan had a decrease in C3 complement staining by at least 2 orders of magnitude from baseline to Week 26 compared to only 12% on placebo 1
• In a Phase 2 study, pegcetacoplan reduced proteinuria by 50.9% in the intent-to-treat population and 65.4% in the per-protocol population over 48 weeks 3
• Mean serum albumin normalized and mean eGFR remained stable over 48 weeks of treatment 3

Special Considerations

• Evaluate for monoclonal proteins in patients over 50 years old with C3G diagnosis, as this may affect treatment approach 2
• Rule out infection-related GN or post-infectious GN prior to diagnosing C3G 2
• For transplant recipients with recurrent C3G, pegcetacoplan has shown efficacy with 50% of patients achieving ≥2 orders of magnitude reduction in C3 staining at week 12 4

Safety Profile

• Most common adverse events include upper respiratory tract infection, injection site erythema, nausea, and headache 3
• Injection site reactions are common but typically mild and tend to decrease over time with continued treatment 5
• No cases of meningitis or sepsis were reported in clinical trials for C3G 3
• Patients should receive appropriate vaccinations against encapsulated bacteria before initiating therapy 6

Monitoring During Treatment

• Monitor serum C3 levels, which typically increase with treatment 1
• Follow plasma soluble C5b-9 levels, which should decrease with effective treatment 1
• Assess proteinuria regularly to evaluate treatment response 3, 4
• Monitor renal function through eGFR measurements 3, 4

Pegcetacoplan represents an important advancement in the treatment of C3G by directly targeting the central component of complement dysregulation in this disease. Its approval for C3G provides a much-needed therapeutic option for patients with this rare but serious kidney disorder.