A Proof-of-Concept Study of Danicopan for 6 Months of Treatment in Participants With C3 Glomerulopathy (C3G)

• Danicopan (Drug), also known as ACH-4471, ACH4471, 4471, ACH-0144471 (formerly), ALXN2040: Danicopan was administered as an oral tablet.
• Placebo (Drug): Matching placebo was administered as an oral tablet.

Primary outcomes

• Change From Baseline In Composite Biopsy Score At Week 28 [Baseline, Week 28]: The composite biopsy score was based on a score incorporating changes in the activity index, glomerular C3c staining, and glomerular macrophage infiltration at the end of 6 months of treatment. The composite renal biopsy index scoring system ranged from 0 to 21, with higher scores indicating worse outcomes.
• Participants With Reduction In Proteinuria At Week 28 [Week 28]: Proteinuria reduction was defined as ≥ 30% decrease from baseline based on 24-hour urine protein (mg/day).

Secondary outcomes

• Change From Baseline In Proteinuria At Week 28 [Baseline, Week 28]: Proteinuria was assessed based on 24-hour urine collections at baseline and Week 28.
• Percent Change From Baseline In Proteinuria At Week 28 [Baseline, Week 28]: Proteinuria was assessed based on 24-hour urine collections at baseline and Week 28.
• Slope Of Estimated Glomerular Filtration Rate (eGFR) From Baseline To 6 Months [6 months]: Slope of eGFR was estimated using a simple linear regression for each participant, including all data values from baseline until the end of the 6-month blinded treatment period, with eGFR as the dependent variable and time as the independent variable.
• Slope Of Estimated Glomerular Filtration Rate (eGFR) After Open-label Danicopan Treatment [12 months]: Slope of eGFR was estimated using a simple linear regression for each participant, including all data values during the open-label extension period with eGFR as the dependent variable and time as the independent variable.
• Change From Baseline In eGFR At Week 28 [Baseline, Week 28]: Change from baseline in eGFR at Week 28 is presented.
• Participants With Significant Improvement In eGFR Relative To Baseline At Week 28 [Baseline, Week 28]: Significant improvement relative to baseline was defined as a ≥ 20% increase from baseline in eGFR.
• Participants With Significant Improvement In eGFR Relative To Baseline At Week 52 [Baseline, Week 52]: Significant improvement relative to baseline was defined as a ≥ 20% increase from baseline in eGFR.

Sex: All, ages: 17 Years to 65 Years

Key Inclusion Criteria:

* Had biopsy-confirmed primary C3G
* Had clinical evidence of ongoing disease based on significant proteinuria, attributable to C3G disease in the opinion of the Principal Investigator (PI), and present prior to study entry and confirmed during Screening
* Was willing to comply with vaccination requirements.

Key Exclusion Criteria:

* Had a history or presence of any clinically relevant co-morbidities that would make the participant inappropriate for the study
* Had ever received danicopan
* Had more than 50% fibrosis or more than 50% of glomeruli with cellular crescents on the pre-treatment renal biopsy
* Had an estimated glomerular filtration rate <30 milliliters/minute/1.73 meters squared at the time of screening or at any time over the preceding 4 weeks
* Was a renal transplant recipient or receiving renal replacement therapy
* Had a history of a major organ transplant or hematopoietic stem cell/marrow transplant
* Had evidence of monoclonal gammopathy of unclear significance, infections, malignancy, autoimmune diseases, or other conditions to which C3G is secondary
* Had other renal diseases that would interfere with interpretation of the study
* Had been diagnosed with or showed evidence of hepatobiliary cholestasis
* Females who were pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration
* Had a history of febrile illness, a body temperature >38°Celsius, or other evidence of a clinically significant active infection, within 14 days prior to study drug administration
* Had evidence of human immunodeficiency virus, hepatitis B infection, or active hepatitis C infection at Screening
* Had laboratory abnormalities at screening that, in the opinion of the PI, would make the participant inappropriate for the study

Participant flow

Outcome results

• Change From Baseline In Composite Biopsy Score At Week 28 (Primary), Mean, score on a scale: Danicopan (Double-blind Treatment Period) 11.7 +/- 4.23; Placebo (Double-blind Treatment Period) 9.3 +/- 3.50
• Participants With Reduction In Proteinuria At Week 28 (Primary), Number, participants: Danicopan (Double-blind Treatment Period) 0; Placebo (Double-blind Treatment Period) 1
• Change From Baseline In Proteinuria At Week 28 (Secondary), Mean, mg/day: Danicopan (Double-blind Treatment Period) 6137.67 +/- 2904.359; Placebo (Double-blind Treatment Period) 4274.47 +/- 2992.819
• Percent Change From Baseline In Proteinuria At Week 28 (Secondary), Mean, percent change: Danicopan (Double-blind Treatment Period) 12.5 +/- 31.11; Placebo (Double-blind Treatment Period) -10.4 +/- 31.35
• Slope Of Estimated Glomerular Filtration Rate (eGFR) From Baseline To 6 Months (Secondary), Mean, mL/min/1.73 m^2 per month: Danicopan (Double-blind Treatment Period) -2.26840 +/- 1.790814; Placebo (Double-blind Treatment Period) -1.45421 +/- 2.228395
• Slope Of Estimated Glomerular Filtration Rate (eGFR) After Open-label Danicopan Treatment (Secondary), Mean, mL/min/1.73 m^2 per month: Danicopan (Double-blind Treatment Period), Followed by Danicopan (Open-label Extension Period -1.02556 +/- 1.389128; Placebo (Double-blind Treatment Period), Followed by Danicopan (Open-label Extension Period) -1.84935 +/- 3.506810; Total -1.39169 +/- 2.401039
• Change From Baseline In eGFR At Week 28 (Secondary), Mean, mL/min/1.73 m^2: Danicopan (Double-blind Treatment Period) 79.890 +/- 44.4571; Placebo (Double-blind Treatment Period) 68.381 +/- 36.7249
• Participants With Significant Improvement In eGFR Relative To Baseline At Week 28 (Secondary), Number, participants: Danicopan (Double-blind Treatment Period) 0; Placebo (Double-blind Treatment Period) 0
• Participants With Significant Improvement In eGFR Relative To Baseline At Week 52 (Secondary), Number, participants: Danicopan (Double-blind Treatment Period), Followed by Danicopan (Open-label Extension Period) 0; Placebo (Double-blind Treatment Period), Followed by Danicopan (Open-label Extension Period) 0

Adverse events

Time frame: Day 1 (after dosing) through Week 28 (treatment period and follow-up) and Week 104 (open-label extension and follow-up). The median study duration was 548.0 days.

Serious adverse events by term

Other adverse events by term

• Results publication: Nester C, Appel GB, Bomback AS, Bouman KP, Cook HT, Daina E, Dixon BP, Rice K, Najafian N, Hui J, Podos SD, Langman CB, Lightstone L, Parikh SV, Pickering MC, Sperati CJ, Trachtman H, Tumlin J, de Vries AP, Wetzels JFM, Remuzzi G. Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan: Final Results from Two Phase 2 Studies. Am J Nephrol. 2022;53(10):687-700. doi: 10.1159/000527167. Epub 2022 Nov 24. PMID 36423588

• Study Protocol (PDF, 2020-05-15)
• Statistical Analysis Plan (PDF, 2020-10-30)

NIH grants: 2017