C3 Glomerulonephritis, C3 Glomerulopathy, Dense Deposit Disease, IC-MPGN, Immune Complex Membranoproliferative Glomerulonephritis
Conditions
Keywords
factor D, fD, alternative pathway, complement mediated disease, C3GN, DDD, idiopathic MPGN, MPGN Type I, MPGN Type II, MPGN Type III, Primary MPGN, MCGN, Mesangiocapillary Glomerulonephritis
Brief summary
The primary purpose of this study was to evaluate the efficacy of 12 months of oral ACH-0144471 (also known as danicopan and ALXN2040) in participants with C3G or IC-MPGN based on histologic scoring and proteinuria.
Detailed description
This was an open-label study to evaluate the efficacy of treatment with danicopan in participants 12 years of age or older with biopsy-confirmed C3G or IC-MPGN who had not undergone renal transplantation. All participants were to receive active treatment with danicopan for approximately 40 months. The starting dosage was to be 100 mg TID, and after 2 weeks, the dosage was to be increased to 200 mg TID for participants with body weight ≥ 60 kg or 150 mg TID for participants with body weight \< 60 kg. Planned enrollment was approximately 20 participants.
Interventions
DRUGDanicopan
Danicopan was to be administered as an oral tablet.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. At least 12 years of age 2. Completion of the ACH471-201 clinical study OR diagnosed with biopsy-confirmed primary C3G or IC-MPGN 3. If a pre-treatment biopsy is obtained, or if a historical biopsy is available for review, it must have no more than 50% global fibrosis and no more than 50% of glomeruli with cellular crescents 4. Clinical evidence of ongoing disease based on significant proteinuria (defined as ≥500 mg/day of protein in a 24-hour urine) attributable to C3G disease or IC-MPGN in the opinion of the principal investigator (PI), and present prior to study entry and confirmed during Screening 5. If on corticosteroids, anti-hypertensive medications, anti-proteinuric medications (for example, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), or mycophenolate mofetil, must be on a stable dose for at least 2 weeks prior to screening 6. Female participants must use an acceptable method birth control to prevent pregnancy during the clinical study and for 30 days after the last dose of study medication 7. Male participants must use highly effective birth control with a female partner to prevent pregnancy during the clinical study and for 90 days after the last dose of study medication 8. Must be up-to-date on routine vaccinations, or willing to be brought up-to-date, based on local guidelines 9. Must have access to emergency medical care Key
Exclusion criteria
1. Have a history of a major organ transplant (for example, heart, lung, kidney, or liver) or hematopoietic stem cell/marrow transplant 2. Have a history or presence of any clinically relevant co-morbidities that would make the participant inappropriate for the study (for example, a comorbidity that is likely to result in deterioration of the participant's condition, affect the participant's safety during the study, or confound the results of the study), in the opinion of the PI 3. Have an eGFR \<30 milliliter/minute/1.73 m\^2 at the time of screening or at any time over the preceding 4 weeks 4. Is a renal transplant recipient or receiving renal replacement therapy 5. Have other renal diseases that would interfere with the interpretation of the study 6. Have evidence of monoclonal gammopathy of unclear significance, infections, malignancy, autoimmune diseases, or other conditions to which C3G or IC-MPGN is secondary 7. Have been diagnosed with or show evidence of hepatobiliary cholestasis 8. Females who are pregnant, nursing, or planning to become pregnant during the study or within 90 days of ACH-0144471 administration or participants with a female partner who is pregnant, nursing, or planning to become pregnant during the study or within 90 days of ACH-0144471 administration 9. Have a history of febrile illness, a body temperature \>38°Celsius, or other evidence of a clinically significant active infection, within 14 days prior to danicopan administration 10. Have evidence of human immunodeficiency virus, hepatitis B infection, or active hepatitis C infection at Screening 11. Have a history of meningococcal infection within the prior year 12. Have a history of hypersensitivity reactions to commonly used antibacterial agents, including beta-lactams, penicillin, aminopenicillins, fluoroquinolones, cephalosporins, and carbapenems, which, in the opinion of the investigator and/or an appropriately qualified immunology or infectious disease expert, would make it difficult to properly provide either empiric antibiotic therapy or treat an active infection. 13. Have participated in a clinical study in which an investigational drug was given within 30 days, or within 5 half-lives of the investigational drug, whichever is longer, prior to the first dose of ACH-0144471 14. Have received eculizumab at any dose or interval within the past 50 days prior to the first dose of ACH-0144471 15. Have received tacrolimus or cyclosporine within 2 weeks of the first dose of ACH-0144471 16. Have a 12-lead electrocardiogram (ECG) with a QT interval Fridericia correction formula \>450 millisecond (msec) for males or \>470 msec for females, or have ECG findings which, in the opinion of the PI, could put the participant at undue risk 17. Have received any drug known to prolong the corrected QT interval within 2 weeks of the first dose of ACH-0144471 and which, in the opinion of the PI, could put the participant at undue risk 18. Have any of the following laboratory abnormalities at screening: * Alanine transaminase \> upper limit of normal (ULN) * Aspartate aminotransferase \> ULN * Absolute neutrophil counts \<1,000/microliter * Total bilirubin \>1.5\* ULN * Indirect bilirubin \> ULN * Any laboratory abnormality that, in the opinion of the PI, would make the participant inappropriate for the study 19. Unwilling or unable to comply with the study protocol for any reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In Composite Biopsy Score At End Of Initial 12-Month Treatment Period | Baseline, end of initial 12-Month Treatment Period | 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 the initial 12 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 End Of Initial 12-Month Treatment Period | Baseline, end of initial 12-Month Treatment Period | 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 End Of Initial 12-Month Treatment Period | End of initial 12-Month Treatment Period | Slope of eGFR was estimated using a simple linear regression for each participant, including all data values from baseline until the end of the Initial 12-Month Treatment Period, with eGFR as the dependent variable and time as the independent variable. |
| Change From Baseline In eGFR At End Of Initial 12-Month Treatment Period | Baseline, end of initial 12-Month Treatment Period | Change from baseline in eGFR at end of initial 12-Month Treatment Period is presented. |
| Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period | Baseline, end of initial 12-Month Treatment Period | Proteinuria was assessed based on 24-hour urine collections at baseline and end of the initial 12-month Treatment Period. |
| Change From Baseline in eGFR Over 12 Months of Treatment For Participants Meeting eGFR Inclusion Criteria | End of initial 12-Month Treatment Period | Participants were eligible for enrollment if inclusion criteria were met including having an eGFR \>=30 milliliters (mL)/minute (min)/1.73 square meter (m\^2) at the time of screening or at any time over the preceding 4 weeks. This Outcome Measure was registered in case there were participants who were enrolled and ended up not meeting the Eligibility Criteria and was intended to report data for change from baseline in eGFR for only the participants who met the eligibility criteria (that is, participants who did not meet the eligibility criteria would have been excluded from analysis for this Outcome Measure). Since all enrolled participants met the Eligibility Criteria, none of the participants were excluded from this analysis. Therefore, this data is the same data that is presented in Outcome Measure #6 Change From Baseline In eGFR At End Of Initial 12-Month Treatment Period. Change from baseline in eGFR at end of initial 12-Month Treatment Period is presented. |
| Change From Baseline In Measured GFR At The End Of The Initial 12-Month Treatment Period | End of initial 12-Month Treatment Period | Data for this Outcome Measure was to be collected where available. None of the sites collected data for this Outcome Measure. |
| Participants With Significant Improvement In eGFR Relative To Baseline At End Of Initial 12-Month Treatment Period | Baseline, end of initial 12-Month Treatment Period | Significant improvement relative to baseline was defined as a ≥ 25% increase from baseline in eGFR. |
| Percent Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period | Baseline, end of initial 12-Month Treatment Period | Proteinuria was assessed based on 24-hour urine collections at baseline and end of initial 12-month Treatment Period. |
Countries
Australia, Belgium, Italy, Netherlands, United States
Participant flow
Pre-assignment details
To enroll in the study, participants were required to have a biopsy-confirmed diagnosis of C3 glomerulopathy (C3G) or immune-complex membranoproliferative glomerulonephritis (IC-MPGN).
Participants by arm
| Arm | Count |
|---|---|
| Danicopan Danicopan was to be administered to participants with C3G or IC-MPGN at a starting dose of 100 milligrams (mg) 3 times daily (TID) for the first 2 weeks, then the dosage was to be increased to 200 mg TID for the remainder of the study. | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Lack of Efficacy | 3 |
| Overall Study | Sponsor's decision to close the study | 18 |
Baseline characteristics
| Characteristic | Danicopan |
|---|---|
| Age, Continuous | 24.3 years STANDARD_DEVIATION 9.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 22 |
| other Total, other adverse events | 22 / 22 |
| serious Total, serious adverse events | 3 / 22 |
Outcome results
Primary
Change From Baseline In Composite Biopsy Score At End Of Initial 12-Month Treatment Period
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 the initial 12 months of treatment. The composite renal biopsy index scoring system ranged from 0 to 21, with higher scores indicating worse outcomes.
Time frame: Baseline, end of initial 12-Month Treatment Period
Population: All participants who received at least 1 dose of study drug and had analyzable data at the specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan | Change From Baseline In Composite Biopsy Score At End Of Initial 12-Month Treatment Period | Baseline | 10.6 score on a scale | Standard Deviation 3.59 |
| Danicopan | Change From Baseline In Composite Biopsy Score At End Of Initial 12-Month Treatment Period | End of 12-Month Initial Treatment Period | 8.0 score on a scale | Standard Deviation 4.53 |
| Danicopan | Change From Baseline In Composite Biopsy Score At End Of Initial 12-Month Treatment Period | Change from Baseline | -0.9 score on a scale | Standard Deviation 1.89 |
Primary
Participants With Reduction In Proteinuria At End Of Initial 12-Month Treatment Period
Proteinuria reduction was defined as ≥30% decrease from baseline based on 24-hour urine protein (mg/day).
Time frame: Baseline, end of initial 12-Month Treatment Period
Population: All participants who received at least 1 dose of study drug and had analyzable data at the specified timepoints.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Danicopan | Participants With Reduction In Proteinuria At End Of Initial 12-Month Treatment Period | 8 participants |
Secondary
Change From Baseline In eGFR At End Of Initial 12-Month Treatment Period
Change from baseline in eGFR at end of initial 12-Month Treatment Period is presented.
Time frame: Baseline, end of initial 12-Month Treatment Period
Population: All participants who received at least 1 dose of study drug and had analyzable data at the specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan | Change From Baseline In eGFR At End Of Initial 12-Month Treatment Period | Baseline | 90.692 mL/min/1.73 m^2 | Standard Deviation 35.4939 |
| Danicopan | Change From Baseline In eGFR At End Of Initial 12-Month Treatment Period | End of Initial 12-Month Treatment Period | 81.412 mL/min/1.73 m^2 | Standard Deviation 38.332 |
| Danicopan | Change From Baseline In eGFR At End Of Initial 12-Month Treatment Period | Change from Baseline | -9.795 mL/min/1.73 m^2 | Standard Deviation 14.3806 |
Secondary
Change From Baseline in eGFR Over 12 Months of Treatment For Participants Meeting eGFR Inclusion Criteria
Participants were eligible for enrollment if inclusion criteria were met including having an eGFR \>=30 milliliters (mL)/minute (min)/1.73 square meter (m\^2) at the time of screening or at any time over the preceding 4 weeks. This Outcome Measure was registered in case there were participants who were enrolled and ended up not meeting the Eligibility Criteria and was intended to report data for change from baseline in eGFR for only the participants who met the eligibility criteria (that is, participants who did not meet the eligibility criteria would have been excluded from analysis for this Outcome Measure). Since all enrolled participants met the Eligibility Criteria, none of the participants were excluded from this analysis. Therefore, this data is the same data that is presented in Outcome Measure #6 Change From Baseline In eGFR At End Of Initial 12-Month Treatment Period. Change from baseline in eGFR at end of initial 12-Month Treatment Period is presented.
Time frame: End of initial 12-Month Treatment Period
Population: All participants who received at least 1 dose of study drug and had analyzable data at the specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan | Change From Baseline in eGFR Over 12 Months of Treatment For Participants Meeting eGFR Inclusion Criteria | Baseline | 90.692 mL/min/1.73 m^2 | Standard Deviation 35.4939 |
| Danicopan | Change From Baseline in eGFR Over 12 Months of Treatment For Participants Meeting eGFR Inclusion Criteria | End of Initial 12-Month Treatment Period | 81.412 mL/min/1.73 m^2 | Standard Deviation 38.332 |
| Danicopan | Change From Baseline in eGFR Over 12 Months of Treatment For Participants Meeting eGFR Inclusion Criteria | Change from Baseline | -9.795 mL/min/1.73 m^2 | Standard Deviation 14.3806 |
Secondary
Change From Baseline In Measured GFR At The End Of The Initial 12-Month Treatment Period
Data for this Outcome Measure was to be collected where available. None of the sites collected data for this Outcome Measure.
Time frame: End of initial 12-Month Treatment Period
Population: Analysis was not performed, as data were not collected for this Outcome Measure.
| Arm | Measure | Group | Value |
|---|---|---|---|
| Unknown | Change From Baseline In Measured GFR At The End Of The Initial 12-Month Treatment Period | Baseline | — |
| Unknown | Change From Baseline In Measured GFR At The End Of The Initial 12-Month Treatment Period | End of initial 12-Month Treatment Period | — |
| Unknown | Change From Baseline In Measured GFR At The End Of The Initial 12-Month Treatment Period | Change from Baseline | — |
Secondary
Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period
Proteinuria was assessed based on 24-hour urine collections at baseline and end of the initial 12-month Treatment Period.
Time frame: Baseline, end of initial 12-Month Treatment Period
Population: All participants who received at least 1 dose of study drug and had analyzable data at the specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Danicopan | Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period | Baseline | 4252.28 mg/day | Standard Deviation 2684.959 |
| Danicopan | Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period | End of Initial 12-Month Treatment Period | 3512.63 mg/day | Standard Deviation 3335.765 |
| Danicopan | Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period | Mean Change from Baseline | -671.11 mg/day | Standard Deviation 2695.592 |
Secondary
Participants With Significant Improvement In eGFR Relative To Baseline At End Of Initial 12-Month Treatment Period
Significant improvement relative to baseline was defined as a ≥ 25% increase from baseline in eGFR.
Time frame: Baseline, end of initial 12-Month Treatment Period
Population: All participants who received at least 1 dose of study drug and had analyzable data at the specified timepoints.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Danicopan | Participants With Significant Improvement In eGFR Relative To Baseline At End Of Initial 12-Month Treatment Period | 0 participants |
Secondary
Percent Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period
Proteinuria was assessed based on 24-hour urine collections at baseline and end of initial 12-month Treatment Period.
Time frame: Baseline, end of initial 12-Month Treatment Period
Population: All participants who received at least 1 dose of study drug and had analyzable data at the specified timepoints.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Danicopan | Percent Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period | -17.1 percent change | Standard Deviation 53.17 |
Secondary
Slope Of Estimated Glomerular Filtration Rate (eGFR) From Baseline To End Of Initial 12-Month Treatment Period
Slope of eGFR was estimated using a simple linear regression for each participant, including all data values from baseline until the end of the Initial 12-Month Treatment Period, with eGFR as the dependent variable and time as the independent variable.
Time frame: End of initial 12-Month Treatment Period
Population: All participants who received at least 1 dose of study drug and had analyzable data at the specified timepoints.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Danicopan | Slope Of Estimated Glomerular Filtration Rate (eGFR) From Baseline To End Of Initial 12-Month Treatment Period | -1.24917 mL/min/1.73 m^2 per month | Standard Deviation 1.811457 |