C3G/Primary IC-MPGN

About C3G and primary IC-MPGN

Cause & impact
Disease burden
Symptoms & diagnosis
Key measures

Complement overactivation drives these devastating glomerular diseases1-6

The cause and impact of C3G and primary IC-MPGN

C3G and primary IC-MPGN are rare glomerular diseases that can have devastating physical, mental, emotional, and financial impacts on patients and their caregivers.7-9

~5000

people in the US are affected by C3G or primary IC-MPGN10

C3G and primary IC-MPGN are driven by complement overactivation, in which C3 plays a critical role.2,3,7,11

Without effective intervention, overactivation goes unchecked, leading to inflammation and declining kidney function, which may progress to kidney failure.1-6

Most treatment approaches focus on managing symptoms and few target the driver of disease, complement overactivation.2,12,13

Progression to ESKD and post-transplant disease recurrence are common

Many patients progress to ESKD

Disease recurrence is common even after transplant

In a retrospective analysis of 18 adult patients with C3G who underwent transplantation

“I... was returning to dialysis, and felt like I lost my chance at a normal life. My hope was destroyed.”

Real C3G patient

Individual patient experiences may vary.

Diagnosis requires renal biopsy due to nonspecific symptoms

The clinical signs and symptoms of C3G and primary IC-MPGN are heterogeneous and can appear in other renal diseases. This is why renal biopsy is a necessary part of the diagnostic process.2,6,15

Signs and symptoms

  • Proteinuria2,15 
  • Edema/swelling7
  • Hypertension2
  • Hematuria2,15
  • Fatigue7
  • Hyperlipidemia19
  • Decreased eGFR2
  • Low serum C316-18
  • Drusen20,21

Patients may also experience anxiety and depression due to their disease.7

Making a diagnosis

A renal biopsy is required to make a definitive diagnosis of C3G and primary IC-MPGN.2,15

Among other forms of histopathological analysis, immunofluorescence is the one used to distinguish between the 2 diseases—detecting glomerular deposition of C3 through staining of C3 fragments and/or Ig.2,6,22

C3 deposits (C3G)

C3/Ig deposits (IC-MPGN)
Examples of C3 staining under immunofluorescence, with intensity ranging from 0 to 3+

Microscopic images: Courtesy of Patrick D. Walker, MD, Senior Renal Pathologist at Arkana Laboratories.

3 key measures of disease activity

According to the Kidney Health Initiative, a partnership between the ASN and FDA, 3 key clinical trial endpoints are important to determine an effective therapy12,*:

  • Proteinuria reduction
  • eGFR stabilization
  • Histopathological improvement

*A therapy may be deemed effective even without all 3 prespecified endpoints if there was meaningful lowering of proteinuria and stabilization or improvement in eGFR.

Nester C, Decker DA, Meier M, et al. Developing therapies for C3 glomerulopathy: report of the Kidney Health Initiative C3 Glomerulopathy Trial Endpoints Work Group. Clin J Am Soc Nephrol. 2024;19(9):1201-1208.

Impact of proteinuria reduction on kidney function

RaDaR

Using retrospective and prospective data collection from C3G and IC-MPGN patients (N=371) from RaDaR, a reduction in uPCR to <100 mg/mmol (<0.88 g/g) at 12 months (n=91) was associated with a 90% lower risk of kidney failure23,†

Adjusted HR‡=0.10 (95% CI: 0.03-0.30); P<0.0001 (n=91)

Limitations23:

  • Incomplete data inherent in registry studies
  • Study may not represent the population and clinical practices outside of the UK, and data were from a restricted cohort that was younger at diagnosis
  • Heterogeneous data collection and limited medication data

†Note: 50 mg/mmol=0.44 g/g. Analyses of kidney survival were conducted using Kaplan-Meier and univariable Cox regression.

‡Adjusted for age, sex, and eGFR.

GLOSEN
  • A retrospective, longitudinal, multicenter, observational cohort study, using data from patients with C3G and primary IC-MPGN (N=149) by GLOSEN, evaluated whether changes in proteinuria could serve as a surrogate marker for kidney failure24,§
  • The main study outcome was kidney failure, defined as eGFR <15 mL/min/1.73 m2, the need for dialysis, or kidney transplantation. The study found that each unit increase in proteinuria was associated with a 3.2-fold increased risk of kidney failure24
  • Complete remission was a secondary outcome and defined as an eGFR >60 mL/min/1.73 m2, proteinuria <0.5 g/24 h, and no microscopic hematuria. The study found achieving proteinuria levels of <0.5 g/day was one of the indicators of partial or complete remission24

Limitations24:

  • Due to the retrospective nature of this study, no causal relationships were established
  • Demographic imbalances between the C3G and IC-MPGN groups due to the underrepresentation of pediatric patients with IC-MPGN
  • Heterogeneity in the initial clinical presentation and the wide range of therapeutic strategies may have introduced variability in eGFR values and influenced the trend in proteinuria at certain time points
  • Residual confounding factors related to the unmeasured variables or differences in patient management over time

§A joint modeling approach was applied to simultaneously analyze the longitudinal evolution of proteinuria and the risk of progression to kidney failure. The model comprised 2 components: a linear mixed-effects model for the longitudinal outcome (proteinuria) and a Cox proportional hazards model for the time-to-event outcome (kidney failure).

EMPAVELI makes a strong move on complement overactivationSEE IT IN ACTION

ASN=American Society of Nephrology; C3G=C3 glomerulopathy; eGFR=estimated glomerular filtration rate; ESKD=end-stage kidney disease; FDA=US Food and Drug Administration; GLOSEN=Glomerular Diseases Working Group of the Spanish Society of Nephrology; HR=hazard ratio; IC-MPGN=immune-complex membranoproliferative glomerulonephritis; Ig=immunoglobulin; RaDaR=UK National Registry of Rare Kidney Diseases; uPCR=urine protein-to-creatinine ratio.

References: 1. Donadelli R, Pulieri P, Piras R, et al. Unraveling the molecular mechanisms underlying complement dysregulation by nephritic factors in C3G and IC-MPGN. Front Immunol. 2018;9:2329. 2. Smith RJH, Appel GB, Blom AM, et al. C3 glomerulopathy — understanding a rare complement-driven renal disease. Nat Rev Nephrol. 2019;15(3):129-143. 3. Caravaca-Fontán F, Lucientes L, Cavero T, Praga M. Update on C3 glomerulopathy: a complement-mediated disease. Nephron. 2020;144(6):272-280. 4. Mastrangelo A, Serafinelli J, Giani M, Montini G. Clinical and pathophysiological insights into immunological mediated glomerular diseases in childhood. Front Pediatr. 2020;8:205. 5. Fakhouri F, Le Quintrec M, Frémeaux-Bacchi V. Practical management of C3 glomerulopathy and Ig-mediated MPGN: facts and uncertainties. Kidney Int. 2020;98(5):1135-1148. 6. Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis — a new look at an old entity. N Engl J Med. 2012;366(12):1119-1131. 7. National Kidney Foundation. Voice of the patient. Accessed May 15, 2025. https://www.kidney.org/sites/default/files/C3G_EL-PFDD_VoP-Report_3-29-18.pdf 8. American Kidney Fund. Mental health and kidney disease. Accessed May 15, 2025. https://www.kidneyfund.org/living-kidney-disease/mental-health-and-kidney-disease 
9. Golestaneh L, Alvarez PJ, Reaven NL, et al. All-cause costs increase exponentially with increased chronic kidney disease stage. Am J Manag Care. 2017;23(10 Suppl):S163-S172. 10. Data on file. Apellis Pharmaceuticals, Inc., Waltham, MA. 11. Noris M, Daina E, Remuzzi G. Membranoproliferative glomerulonephritis: no longer the same disease and may need very different treatment. Nephrol Dial Transplant. 2023;38(2):283-290. 12. Nester C, Decker DA, Meier M, et al. Developing therapies for C3 glomerulopathy: report of the Kidney Health Initiative C3 Glomerulopathy Trial Endpoints Work Group. Clin J Am Soc Nephrol. 2024;19(9):1201-1208. 13. National Kidney Foundation. Complement 3 glomerulopathy (C3G). Accessed May 15, 2025. https://www.kidney.org/kidney-topics/complement-3-glomerulopathy-c3g 14. Tarragón B, Peleg Y, Jagannathan G, et al. C3 glomerulopathy recurs early after kidney transplantation in serial biopsies performed within the first 2 years after transplantation. Clin J Am Soc Nephrol. 2024;19(8):1005-1015. 15. Schena FP, Esposito P, Rossini M. A narrative review on C3 glomerulopathy: a rare renal disease. Int J Mol Sci. 2020;21(2):525. 16. Medjeral-Thomas NR, O’Shaughnessy MM, O’Regan JA, et al. C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol. 2014;9(1):46-53. 17. Pickering MC, D’Agati VD, Nester CM, et al. C3 Glomerulopathy: consensus report. Kidney Int. 2013;84(6):1079-1089. 18. Zhang Y, Nester CM, Martin B, et al. Defining the complement biomarker profile of C3 glomerulopathy. Clin J Am Soc Nephrol. 2014;9(11):1876-1882. 19. Rosenstein K, Tannock LR. Dyslipidemia in chronic kidney disease. In: Feingold KR, Anawalt B, Blackman MR, et al, eds. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2022. 20. American Academy of Ophthalmology. What are drusen? Accessed May 15, 2025. https://www.aao.org/eye-health/diseases/what-are-drusen 21. Heiderscheit AK, Hauer JJ, Smith RJH. C3 glomerulopathy: understanding an ultra-rare complement-mediated renal disease. Am J Med Genet C Semin Med Genet. 2022;190(3):344-357. 22. Kidney disease: improving global outcomes (KDIGO) glomerular diseases work group. KDIGO 2021 Clinical practice guideline for the management of glomerular diseases. Kidney Int. 2021;100(4S):S1-S276. 23. Masoud S, Wong K, Pitcher D, et al. Quantifying association of early proteinuria and estimated glomerular filtration rate changes with long-term kidney failure in C3 glomerulopathy and immune-complex membranous proliferative glomerulonephritis using the United Kingdom RaDaR Registry. Kidney Int. Published online June 27, 2025. doi:10.1016/j.kint.2025.06.003 24. Caravaca-Fontán F, Toledo-Rojas R, Huerta A, et al. Comparative analysis of proteinuria and longitudinal outcomes in immune complex membranoproliferative glomerulonephritis and C3 glomerulopathy. Kidney Int Rep. 2025;10(4):1223-1236.

IMPORTANT SAFETY INFORMATION

WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA

EMPAVELI, a complement inhibitor, increases the risk of serious infections, especially those caused by encapsulated bacteria, such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B. Life-threatening and fatal infections with encapsulated bacteria have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early.

  • Complete or update vaccination for encapsulated bacteria at least 2 weeks prior to the first dose of EMPAVELI, unless the risks of delaying therapy with EMPAVELI outweigh the risks of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria in patients receiving a complement inhibitor.
  • Patients receiving EMPAVELI are at increased risk for invasive disease caused by encapsulated bacteria, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious infections and evaluate immediately if infection is suspected.

Because of the risk of serious infections caused by encapsulated bacteria, EMPAVELI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the EMPAVELI REMS.

CONTRAINDICATIONS

  • Hypersensitivity to pegcetacoplan or to any of the excipients
  • For initiation in patients with unresolved serious infection caused by encapsulated bacteria including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B

WARNINGS AND PRECAUTIONS

Serious Infections Caused by Encapsulated Bacteria

EMPAVELI, a complement inhibitor, increases a patient’s susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria including Streptococcus pneumoniae, Neisseria meningitidis (caused by any serogroup, including non-groupable strains), and Haemophilus influenzae type B. Life-threatening and fatal infections with encapsulated bacteria have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of EMPAVELI treatment is contraindicated in patients with unresolved serious infection caused by encapsulated bacteria.

Complete or update vaccination against encapsulated bacteria at least 2 weeks prior to administration of the first dose of EMPAVELI, according to the most current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with EMPAVELI. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent EMPAVELI therapy is indicated in a patient who is not up to date with vaccines against encapsulated bacteria according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. The benefits and risks of treatment with EMPAVELI, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by encapsulated bacteria.

Vaccination does not eliminate the risk of serious encapsulated bacterial infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of EMPAVELI in patients who are undergoing treatment for serious infections.

EMPAVELI is available only through a restricted program under a REMS.

EMPAVELI REMS

EMPAVELI is available only through a restricted program under a REMS called EMPAVELI REMS, because of the risk of serious infections caused by encapsulated bacteria. Notable requirements of the EMPAVELI REMS include the following:

Under the EMPAVELI REMS, prescribers must enroll in the program. Prescribers must counsel patients about the risks, signs, and symptoms of serious infections caused by encapsulated bacteria, provide patients with the REMS educational materials, ensure patients are vaccinated against encapsulated bacteria at least 2 weeks prior to the first dose of EMPAVELI, prescribe antibacterial drug prophylaxis if patients’ vaccine status is not up to date and treatment must be started urgently, and provide instructions to always carry the Patient Safety Card both during treatment, as well as for 2 months following last dose of EMPAVELI. Pharmacies that dispense EMPAVELI must be certified in the EMPAVELI REMS and must verify prescribers are certified.

Further information is available at www.empavelirems.com or 1-888-343-7073.

Infusion-Related Reactions

Systemic hypersensitivity reactions (eg, facial swelling, rash, urticaria, pyrexia) have occurred in patients treated with EMPAVELI, which may resolve after treatment with antihistamines. Cases of anaphylaxis leading to treatment discontinuation have been reported. If a severe hypersensitivity reaction (including anaphylaxis) occurs, discontinue EMPAVELI infusion immediately, institute appropriate treatment, per standard of care, and monitor until signs and symptoms are resolved.

Interference with Laboratory Tests

There may be interference between silica reagents in coagulation panels and EMPAVELI that results in artificially prolonged activated partial thromboplastin time (aPTT); therefore, avoid the use of silica reagents in coagulation panels.

ADVERSE REACTIONS

Most common adverse reactions in adult and pediatric patients 12 years of age and older with C3G or primary IC-MPGN (incidence ≥10%) were infusion-site reactions, pyrexia, nasopharyngitis, influenza, cough, and nausea.

USE IN SPECIFIC POPULATIONS

Females of Reproductive Potential

EMPAVELI may cause embryo-fetal harm when administered to pregnant women. Pregnancy testing is recommended for females of reproductive potential prior to treatment with EMPAVELI. Advise female patients of reproductive potential to use effective contraception during treatment with EMPAVELI and for 40 days after the last dose.

INDICATION

EMPAVELI® (pegcetacoplan) is indicated for the treatment of adult and pediatric patients aged 12 years and older with C3 glomerulopathy (C3G) or primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN), to reduce proteinuria.

Please see full Prescribing Information, including Boxed WARNING regarding serious infections caused by encapsulated bacteria, and Medication Guide.

C3G/Primary IC-MPGN
  • EXPAND
  • COLLAPSE

IMPORTANT SAFETY INFORMATION

WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA

EMPAVELI, a complement inhibitor, increases the risk of serious infections, especially those caused by encapsulated bacteria, such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B. Life-threatening and fatal infections with encapsulated bacteria have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early.

  • Complete or update vaccination for encapsulated bacteria at least 2 weeks prior to the first dose of EMPAVELI, unless the risks of delaying therapy with EMPAVELI outweigh the risks of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria in patients receiving a complement inhibitor.
  • Patients receiving EMPAVELI are at increased risk for invasive disease caused by encapsulated bacteria, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious infections and evaluate immediately if infection is suspected.

Because of the risk of serious infections caused by encapsulated bacteria, EMPAVELI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the EMPAVELI REMS.

CONTRAINDICATIONS

  • Hypersensitivity to pegcetacoplan or to any of the excipients
  • For initiation in patients with unresolved serious infection caused by encapsulated bacteria including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B

WARNINGS AND PRECAUTIONS

Serious Infections Caused by Encapsulated Bacteria

EMPAVELI, a complement inhibitor, increases a patient’s susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria including Streptococcus pneumoniae, Neisseria meningitidis (caused by any serogroup, including non-groupable strains), and Haemophilus influenzae type B. Life-threatening and fatal infections with encapsulated bacteria have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of EMPAVELI treatment is contraindicated in patients with unresolved serious infection caused by encapsulated bacteria.

Complete or update vaccination against encapsulated bacteria at least 2 weeks prior to administration of the first dose of EMPAVELI, according to the most current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with EMPAVELI. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent EMPAVELI therapy is indicated in a patient who is not up to date with vaccines against encapsulated bacteria according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. The benefits and risks of treatment with EMPAVELI, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by encapsulated bacteria.

Vaccination does not eliminate the risk of serious encapsulated bacterial infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of EMPAVELI in patients who are undergoing treatment for serious infections.

EMPAVELI is available only through a restricted program under a REMS.

EMPAVELI REMS

EMPAVELI is available only through a restricted program under a REMS called EMPAVELI REMS, because of the risk of serious infections caused by encapsulated bacteria. Notable requirements of the EMPAVELI REMS include the following:

Under the EMPAVELI REMS, prescribers must enroll in the program. Prescribers must counsel patients about the risks, signs, and symptoms of serious infections caused by encapsulated bacteria, provide patients with the REMS educational materials, ensure patients are vaccinated against encapsulated bacteria at least 2 weeks prior to the first dose of EMPAVELI, prescribe antibacterial drug prophylaxis if patients’ vaccine status is not up to date and treatment must be started urgently, and provide instructions to always carry the Patient Safety Card both during treatment, as well as for 2 months following last dose of EMPAVELI. Pharmacies that dispense EMPAVELI must be certified in the EMPAVELI REMS and must verify prescribers are certified.

Further information is available at www.empavelirems.com or 1-888-343-7073.

Infusion-Related Reactions

Systemic hypersensitivity reactions (eg, facial swelling, rash, urticaria, pyrexia) have occurred in patients treated with EMPAVELI, which may resolve after treatment with antihistamines. Cases of anaphylaxis leading to treatment discontinuation have been reported. If a severe hypersensitivity reaction (including anaphylaxis) occurs, discontinue EMPAVELI infusion immediately, institute appropriate treatment, per standard of care, and monitor until signs and symptoms are resolved.

Interference with Laboratory Tests

There may be interference between silica reagents in coagulation panels and EMPAVELI that results in artificially prolonged activated partial thromboplastin time (aPTT); therefore, avoid the use of silica reagents in coagulation panels.

ADVERSE REACTIONS

Most common adverse reactions in adult and pediatric patients 12 years of age and older with C3G or primary IC-MPGN (incidence ≥10%) were infusion-site reactions, pyrexia, nasopharyngitis, influenza, cough, and nausea.

USE IN SPECIFIC POPULATIONS

Females of Reproductive Potential

EMPAVELI may cause embryo-fetal harm when administered to pregnant women. Pregnancy testing is recommended for females of reproductive potential prior to treatment with EMPAVELI. Advise female patients of reproductive potential to use effective contraception during treatment with EMPAVELI and for 40 days after the last dose.

INDICATION

EMPAVELI® (pegcetacoplan) is indicated for the treatment of adult and pediatric patients aged 12 years and older with C3 glomerulopathy (C3G) or primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN), to reduce proteinuria.

Please see full Prescribing Information, including Boxed WARNING regarding serious infections caused by encapsulated bacteria, and Medication Guide.