Pegcetacoplan dropped proteinuria by 81% in complement-mediated glomerulonephritis

Design

Real-world observational cohort study, no control group

Population

25 paediatric and adult patients with C3 glomerulopathy or primary immune-complex MPGN, largely resistant to conventional immunosuppression; median age 14.9 years

Primary outcome

Change in urine protein-to-creatinine ratio, eGFR and serum C3 to 12 months

Effect

uPCR fell 81% by six months (68% under 1 g/g); eGFR +9.4 mL/min/1.73 m² at three months and +12 at six; C3 normalised in 24 of 25

C3 glomerulopathy and primary immune-complex membranoproliferative glomerulonephritis are driven by complement dysregulation and have had little to offer patients who fail conventional immunosuppression. This real-world cohort, published in June, followed 25 such patients — 18 with C3 glomerulonephritis, three with dense deposit disease, four with immune-complex MPGN — identified through the CompCure registry and an international survey, and treated outside trials.

Median age at initiation was 14.9 years, a median 2.7 years after diagnosis, with baseline urine protein-to-creatinine ratio of 3.5 g/g, mean eGFR 74 mL/min/1.73 m² and low serum C3 in 19 of 25. By six months, urine protein-to-creatinine ratio had fallen 81%, with 68% under 1 g/g, 12% in complete remission and 64% in partial remission. eGFR rose by 9.4 mL/min/1.73 m² at three months and 12 at six, holding at twelve. Serum C3 normalised in all but one patient, in whom non-adherence was suspected. No serious adverse events occurred across 222 months of cumulative exposure.

Twenty-five patients with no control group is a weak design carrying a strong signal. The eGFR rise is the part that argues against pure regression to the mean, and the C3 normalisation shows the drug hit its target. Sequential biopsies in four patients were mixed — C3 deposits disappeared in some and persisted in others.

• Consider referral to a complement-focused centre for patients with C3 glomerulopathy resistant to conventional immunosuppression.
• Measure serum C3 before and during treatment; normalisation is the pharmacodynamic check that the drug is working.
• Vaccinate against encapsulated organisms before starting any complement inhibitor, and keep the patient's vaccination record visible in the notes.
• Track urine protein-to-creatinine ratio monthly for the first six months — the response here was rapid.
• Access and cost put this well out of reach for most Indian patients; the clinical point is the mechanism, not immediate availability.

Why it matters

C3 glomerulopathy has had no targeted therapy, and this is the mechanism finally being tested in real patients.

Don't overread it

An uncontrolled cohort of 25 patients cannot separate drug effect from regression to the mean.

The statistics, in plain English

An 81% fall in proteinuria with no control arm cannot be attributed entirely to the drug: proteinuria fluctuates, and patients are started on new treatments when they are doing badly, which guarantees some apparent improvement. The eGFR increase and the C3 normalisation are harder to explain that way. With 25 patients there are no confidence intervals worth quoting, and "no serious adverse events" across a cohort this small does not establish safety.

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