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

A Phase 2, Proof-of-Concept, Randomized, Double-Blinded, Placebo-Controlled Study of ACH-0144471 Treatment for 6 Months in Patients With C3 Glomerulopathy (C3G), With an Open-label Extension

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03369236

Enrollment

Registered

2017-12-11

Start date

2018-06-12

Completion date

2020-12-18

Last updated

2022-10-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

C3 Glomerulonephritis, C3 Glomerulopathy, Dense Deposit Disease

Keywords

factor D, fD, Alternative pathway, Complement mediated disease, Membranoproliferative Glomerulonephritis, Primary MPGN, MPGN, Mesangiocapillary Glomerulonephritis, Idiopathic MPGN, DDD, C3GN

Brief summary

The primary purpose of this proof-of-concept clinical study was to evaluate the efficacy and safety of the study drug, ACH-0144471 (also known as danicopan and ALXN2040), in participants with C3G who also had significant proteinuria attributable to C3G.

Interventions

DRUGDanicopan

Danicopan was administered as an oral tablet.

DRUGPlacebo

Matching placebo was administered as an oral tablet.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Masking description

Investigator and participant blinded; Sponsor open. Participants were randomized 1:1 to receive either danicopan or placebo for a period of 6 months, followed by an open-label extension.

Eligibility

Sex/Gender

ALL

Age

17 Years to 65 Years

Healthy volunteers

Inclusion criteria

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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 Proteinuria At Week 28	Baseline, Week 28	Proteinuria was assessed based on 24-hour urine collections at baseline and Week 28.
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.
Change From Baseline In eGFR At Week 28	Baseline, Week 28	Change from baseline in eGFR at Week 28 is presented.
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.

Countries

United Kingdom, United States

Participant flow

Recruitment details

To enroll in the study, participants were required to have a biopsy confirmed diagnosis of C3 Glomerulopathy (C3G), with initial diagnosis made at least 3 months prior to dosing and significant proteinuria.

Participants by arm

Arm	Count
Danicopan (Double-blind Treatment Period) Danicopan was administered at a starting dose of 100 mg 3 times daily (TID) for the first 2 weeks, then dosage was to be increased to 200 mg TID for the remainder of the 6-month treatment period.	6
Placebo (Double-blind Treatment Period) Placebo was administered TID during the 6-month treatment period.	7
Total	13

Withdrawals & dropouts

Period	Reason	FG000	FG001
Double-blind Treatment Period	Accidental unblinding	0	1
Open-label Extension Period	Adverse Event	0	1
Open-label Extension Period	Lack of Efficacy	2	1
Open-label Extension Period	Sponsor decision to close study	3	4

Baseline characteristics

Characteristic	Danicopan (Double-blind Treatment Period)	Placebo (Double-blind Treatment Period)	Total
Age, Continuous	25.5 years STANDARD_DEVIATION 10.54	24.9 years STANDARD_DEVIATION 4.85	25.2 years STANDARD_DEVIATION 7.63
Race/Ethnicity, Customized Asian	0 Participants	2 Participants	2 Participants
Race/Ethnicity, Customized Hispanic or Latino	3 Participants	1 Participants	4 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	3 Participants	6 Participants	9 Participants
Race/Ethnicity, Customized Other	1 Participants	1 Participants	2 Participants
Race/Ethnicity, Customized White	5 Participants	4 Participants	9 Participants
Region of Enrollment United Kingdom	0 participants	1 participants	1 participants
Region of Enrollment United States	6 participants	6 participants	12 participants
Sex: Female, Male Female	2 Participants	2 Participants	4 Participants
Sex: Female, Male Male	4 Participants	5 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 6	0 / 7	0 / 12
other Total, other adverse events	5 / 6	5 / 7	8 / 12
serious Total, serious adverse events	0 / 6	0 / 7	1 / 12

Outcome results

Primary

Change From Baseline In Composite Biopsy Score At 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.

Time frame: Baseline, Week 28