A Proof-of-Mechanism Study to Determine the Effect of Danicopan on C3 Levels in Participants With C3G or IC-MPGN

• Danicopan (Drug), also known as ACH-4471, ACH4471, 4471, ACH-0144471, ALXN2040: Participants received study drug for 14 days (Treatment Period), followed by a taper over the next 7 days (Taper Period).

Primary outcomes

• Change From Baseline In Serum C3 Complement Protein (C3) Levels On Day 15 [Baseline, Day 15]: Serum C3 levels were measured by conventional Roche immunoturbidimetric assay method. Change from Baseline = Serum C3 levels on Day 15 - Baseline Serum C3 levels
• Change From Baseline In Plasma Intact C3 Level On Day 15 [Baseline, Day 15]: Plasma Intact C3 level were measured by a novel multiplex assay method. Change from Baseline = Plasma Intact C3 levels on Day 15 - Baseline Plasma Intact C3 levels

Secondary outcomes

• Change From Baseline In Total Complement Classical Pathway (CP) Activity On Day 14 [Baseline, Day 14]: CP activity was measured in serum by the DiaSorin Complement Activation Enzyme (CAE) functional immunoassay method, which measures terminal complement complex formation following activation. Results are expressed in CAE units which are calculated relative to previously established CAE activity of a positive control serum. Change from Baseline = Total Complement CP Activity on Day 14 - Baseline Total Complement CP Activity
• Change From Baseline In Total Complement Alternative Pathway (AP) Functional Activity (AP Wieslab) On Day 15 [Baseline, Day 15]: AP functional activity was measured in serum by the Wieslab functional immunoassay method, which measures terminal complement complex (TCC) formation following AP-specific activation. Results are expressed as percent TCC production relative to a positive control serum. Change from Baseline = Total Complement AP Functional Activity on Day 15 - Baseline Total Complement AP Functional Activity
• Time To Achieving Peak Serum C3 Levels [From The First Day Of Dosing through Day 14]: Serial serum samples were collected on Days 1, 7, and 14.
• Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Treatment-emergent Adverse Events (TEAEs), And Adverse Events (AEs) Leading To Discontinuation [Up to Day 49]: An AE was as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE was an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization for the AE, persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug), important medical event or reaction. The intensity of an AE was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Adverse Event Severity Grading Table. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
• Pharmacokinetics (PK): Area Under The Plasma Concentration-time Curve From Time Of Administration To 8 Hours Postdose (AUC0-8) [Days 1 and 7]: Serial blood samples were collected at 0, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours post-dose on Days 1 and 7.
• PK: Maximum Plasma Concentration (Cmax) [Days 1 and 7]: Serial blood samples were collected at 0, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours post-dose on Days 1 and 7.
• PK: Time To Maximum Concentration (Tmax) [Days 1 and 7]: Serial blood samples were collected at 0, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours post-dose on Days 1 and 7.
• Change From Baseline In Bb Fragment Of Complement Factor B (Bb) At Day 15 [Baseline, Day 15]: Plasma Bb was measured by enzyme-linked immunosorbent assay (ELISA). Change from Baseline = Complement Bb on Day 15 - Baseline
• Change From Baseline In Soluble Terminal Complement Complex (sC5b-9) At Day 15 [Baseline, Day 15]: Plasma sC5b-9 was measured by ELISA. Change from Baseline = sC5b-9 on Day 15 - Baseline sC5b-9

Sex: All, ages: 16 Years to 65 Years

Key Inclusion Criteria:

* Must have had clinical diagnosis of C3G (C3 glomerulonephritis or dense deposit disease, the 2 types of C3G) or idiopathic IC-MPGN by renal biopsy for at least 3 months prior to dosing, with the pathologic diagnosis verified by a review of the renal biopsy by the study central pathologist
* C3 must have been <50% of the lower limit of normal
* C4 complement protein (C4) must have been >90% of the lower limit of normal
* Must have been willing to comply with study-specific vaccination requirements for Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis strains A, C, W, and Y
* Negative pregnancy test for females prior to dosing and throughout the study

Key Exclusion Criteria:

* History of a major organ transplant (for example, heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant. Individuals receiving renal replacement therapy were also excluded
* Evidence of monoclonal gammopathy of unclear significance, infections, malignancy, autoimmune diseases, or other conditions to which C3G or IC-MPGN may have been secondary
* Estimated glomerular filtration rate (using Modification of Diet in Renal Disease equation) <45 milliliters/minute/1.73 square meters at the time of Screening or at any time over the preceding 4 weeks
* Receipt of eculizumab at any dose or interval within the past 75 days prior to dosing
* Use of tacrolimus or cyclosporine within 2 weeks of the first dose of danicopan
* 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
* History of meningococcal infection, or a first-degree relative or household contact with a history of meningococcal infection
* Females who were pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration or participants with a female partner who was pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration

Participant flow

Outcome results

• Change From Baseline In Serum C3 Complement Protein (C3) Levels On Day 15 (Primary), Mean, g/L: Group 1: Danicopan 100 mg TID (Sentinel) 0.32 +/- 0.060; Group 2: Danicopan up to 200 mg TID 0.56 +/- 0.230; Total 0.48 +/- 0.220
• Change From Baseline In Plasma Intact C3 Level On Day 15 (Primary), Mean, μg/mL: Group 1: Danicopan 100 mg TID (Sentinel) 39.50 +/- 0.710; Group 2: Danicopan up to 200 mg TID 58.25 +/- 47.910; Total 52.00 +/- 38.360
• Change From Baseline In Total Complement Classical Pathway (CP) Activity On Day 14 (Secondary), Mean, CAE unit: Group 1: Danicopan 100 mg TID (Sentinel) 31.00 +/- 21.210; Group 2: Danicopan up to 200 mg TID 91.00 +/- 41.370; Total 71.00 +/- 45.570
• Change From Baseline In Total Complement Alternative Pathway (AP) Functional Activity (AP Wieslab) On Day 15 (Secondary), Mean, percentage of activity: Group 1: Danicopan 100 mg TID (Sentinel) 8.350 +/- 10.508; Group 2: Danicopan up to 200 mg TID 31.073 +/- 19.779; Total 23.498 +/- 19.862
• Time To Achieving Peak Serum C3 Levels (Secondary), Mean, days: Group 1: Danicopan 100 mg TID (Sentinel) 2.5 +/- 2.12; Group 2: Danicopan up to 200 mg TID 10.5 +/- 4.43; Total 7.8 +/- 5.46
• Number Of Participants With Serious Adverse Events (SAEs), Grade 3 And Grade 4 Treatment-emergent Adverse Events (TEAEs), And Adverse Events (AEs) Leading To Discontinuation (Secondary), Count of participants, Participants: Group 1: Danicopan 100 mg TID (Sentinel) 2; Group 2: Danicopan up to 200 mg TID 3; Total 5
• Pharmacokinetics (PK): Area Under The Plasma Concentration-time Curve From Time Of Administration To 8 Hours Postdose (AUC0-8) (Secondary), Geometric mean, h*ng/mL: Group 1: Danicopan 100 mg TID 871 +/- 38.1; Group 2: Danicopan 150 mg TID 2060; Group 2: Danicopan 200 mg TID 1640 +/- 42.8
• PK: Maximum Plasma Concentration (Cmax) (Secondary), Geometric mean, ng/mL: Group 1: Danicopan 100 mg TID 199 +/- 6.75; Group 2: Danicopan 150 mg TID 563; Group 2: Danicopan 200 mg TID 427 +/- 46.3
• PK: Time To Maximum Concentration (Tmax) (Secondary), Median, hours: Group 1: Danicopan 100 mg TID 1.00 (1.00 to 1.00); Group 2: Danicopan 150 mg TID 2.50 (2.50 to 2.50); Group 2: Danicopan 200 mg TID 2.00 (1.50 to 2.00)
• Change From Baseline In Bb Fragment Of Complement Factor B (Bb) At Day 15 (Secondary), Mean, µg/mL: Group 1: Danicopan 100 mg TID (Sentinel) 1.789 +/- 1.2116; Group 2: Danicopan up to 200 mg TID 1.229 +/- 0.4729; Total 1.416 +/- 0.7152
• Change From Baseline In Soluble Terminal Complement Complex (sC5b-9) At Day 15 (Secondary), Mean, ng/mL: Group 1: Danicopan 100 mg TID (Sentinel) 1002.0 +/- 684.4794; Group 2: Danicopan up to 200 mg TID 613.750 +/- 225.2397; Total 743.167 +/- 405.3874

Adverse events

Time frame: After the first dose of study medication (following Day 0) through the follow-up visit at Day 49.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The sample size of the study was based on very limited clinical cases of C3G and IC-MPGN and the exploratory nature of this study to evaluate the effectiveness of danicopan. Plasma intact C3 values should be regarded with caution. Plasma intact C3 values were generated using a new multiplex assay method with limited historical experience, and internal studies have suggested this new assay is subject to unexplained experimental variation arising during sample preparation and handling.

• Study Protocol (PDF, 2017-06-09)
• Statistical Analysis Plan (PDF, 2019-01-02)

NIH grants: 2016