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Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan: Final Results from
Carla Nester1, Gerald B Appel2, Andrew S Bomback2
1Divisions of Nephrology, Stead Family Children's Hospital, University of Iowa, Iowa City, Iowa, USA.
Insights
Danicopan showed a good safety profile but did not effectively inhibit complement alternative pathway (AP) in C3G patients. Achieving sustained AP inhibition is crucial for C3G treatment efficacy.
Area of Science:
- Nephrology
- Complement System Biology
- Pharmacology
Background:
- C3 glomerulopathy (C3G) is a rare kidney disease driven by complement alternative pathway (AP) dysregulation.
- Limited treatment options exist for C3G, necessitating novel therapeutic strategies.
- Factor D (FD) inhibition is a targeted approach to control AP activity in C3G.
Purpose of the Study:
- To evaluate the proof-of-concept for danicopan, an oral FD inhibitor, in C3G and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN).
- To assess the pharmacokinetic/pharmacodynamic (PK/PD), efficacy, and safety of danicopan in clinical studies.
- To determine if danicopan can achieve adequate AP inhibition for clinical benefit in C3G patients.
Main Methods:
- Two Phase 2 clinical studies (NCT03369236, NCT03459443) were conducted.
- A double-blind, placebo-controlled study and a single-arm, open-label study evaluated danicopan.
- Co-primary endpoints included changes in biopsy scores and proteinuria reduction.
Main Results:
- Danicopan demonstrated a favorable safety profile.
- Optimal systemic concentrations for sustained AP inhibition were not achieved.
- Limited and inconsistent clinical responses were observed in efficacy endpoints.
Conclusions:
- Danicopan showed incomplete and inadequately sustained AP inhibition due to PK/PD limitations.
- The drug's efficacy in C3G was limited, likely because complete and sustained AP inhibition was not met.
- Future C3G therapies require robust and sustained AP inhibition for clinical success.
Introduction:
C3 glomerulopathy (C3G) is an ultrarare, chronic and progressive nephropathy mediated by dysregulation of the alternative pathway of complement (AP), with poor prognosis and limited treatment options. Targeted inhibition of proximal AP through factor D (FD) blockade represents a rational treatment approach. We present two phase 2 proof-of-concept clinical studies of the orally active FD inhibitor danicopan in patients with C3G and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) (NCT03369236 and NCT03459443).
Methods:
A double-blind, placebo-controlled study in patients with C3G and a single-arm, open-label study in patients with C3G or IC-MPGN treated with danicopan are reported. The studies evaluated pharmacokinetic/pharmacodynamic (PK/PD), efficacy, and safety outcomes. The co-primary endpoints were change from baseline in composite biopsy score and the proportion of patients with a 30% reduction in proteinuria relative to baseline at 6 or 12 months.
Results:
Optimal systemic concentrations of danicopan were not achieved for complete and sustained inhibition of AP, although there was evidence that blockade of FD reduced AP activity shortly after drug administration. Consequently, limited clinical response was observed in key efficacy endpoints. While stable disease or improvement from baseline was seen in some patients, response was not consistent. The data confirmed the favorable safety profile of danicopan.
Conclusion:
While demonstrating a favorable safety profile, danicopan resulted in incomplete and inadequately sustained inhibition of AP, probably due to limitations in its PK/PD profile in C3G, leading to lack of efficacy. Complete and sustained AP inhibition is required for a clinical response in patients with C3G.
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