Glomerulonephritis
Conditions
Brief summary
The study is an open-label, two cohort non-randomized study evaluating the efficacy, safety, and pharmacokinetics of LNP023 in patients with C3G (Cohort A) and patients who have undergone kidney transplant and have C3G recurrence (Cohort B).
Interventions
DRUGLNP023
Increasing doses of LNP023 up to 200 mg.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open label study
Intervention model description
The study is an open-label, two cohort non-randomized study evaluating the efficacy, safety, and pharmacokinetics of LNP023 in patients with C3G (Cohort A) and patients who have undergone kidney transplant and have C3G recurrence (Cohort B).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for Cohort A and B: * Written informed consent must be obtained before any assessment is performed * Male and female patients between the ages of 18 to 65 (inclusive) at screening * C3G patients wit proteinuria * Able to communicate well with the investigator, to understand and comply with the requirements of the study * At screening and baseline visits, patients must weigh at least 35 kg * Supine vital signs should be within the following ranges : oral body temperature between 35.0-37.5 °C systolic blood pressure, 80-170 mm Hg diastolic blood pressure, 50-105 mm Hg pulse rate, 45 - 100 bpm . Inclusion Criteria for Cohort A: * Estimated GFR (using the CKD-EPI formula) or measured GFR ≥30 mL/min per 1.73 m2 for patients on a maximum recommended or maximum tolerated dose of an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) * UPCR ≥ 100 mg/mmol (equivalent to ≥ 1 g/24h total urinary protein excretion) * Prior to entry, all patients must have been on supportive care including a maximally tolerated dose of ACEi or ARB for at least 30 days. Inclusion Criteria for Cohort B: * No histological/laboratory/clinical signs of allorejection * If applicable, induction treatment after allotransplantation needs to be completed \>30 days before inclusion. * Transplantation of a kidney allograft \>90 days before inclusion * Patients need to be on a stable dose of immunosuppressive regimen prior to inclusion. Any approved treatments are allowed for this purpose.
Exclusion criteria
for Cohort A and B: * Use of other investigational drugs at the time of enrollment, or within 5 half-lives of randomization, or within 30 days, whichever is longer; or longer if required by local regulations * A history of clinically significant ECG abnormalities, * Known family history or known presence of long QT syndrome or Torsades de Pointes * Use of agents known to prolong the QT interval unless they can be permanently discontinued for the duration of the study * Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. * Women of child bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after stopping of investigational drug. * History of immunodeficiency diseases, or a positive HIV test result. * Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). * Patients who cannot receive vaccinations against N. meningitidis, S. pneumoniae, or H. influenzae
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort A: Change From Baseline in Urine Protein to Creatinine Concentration Ratio (UPCR) | Week 12 | Change in proteinuria assessed by ratio to baseline of UPCR derived from 24h urine collection |
| Cohort B: Change From Baseline in C3 Deposit | Week 12 | Histopathological changes in kidney biopsies as assessed by change from baseline in C3 Deposit Score (based on immunofluorescence microscopy) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Urine Albumin Creatinine Concentration Ratio (UACR) Excretion | Week 12: Day 84 | Ratio to baseline UACR excretion derived from 24 hour urine collection |
| Change From Baseline Change in Urinary Albumin (UA) Excretion | Week 12: Day 84 | Ratio to baseline UA excretion derived from 24 hour urine collection |
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 84 | Effect of LNP023 on estimated glomerular filtration rate (eGFR) |
| Change From Baseline in Serum Creatinine | Week 12: Day 84 | The effect of LNP023 on renal function - serum creatinine |
| Change From Baseline in Creatinine Clearance | Week 12: Day 84 | The effect of LNP023 on renal function - creatinine clearance |
| Number of Patients With Hematuria | Week 12: Day 84 | The effect of LNP023 on renal function - hematuria |
| Change From Baseline in Urine Protein to Creatinine Concentration Ratio (UPCR) First Morning Void | Week 9: Day 64 | Ratio to baseline of UPCR reduction derived from total cumulative urinary excretion first morning void |
| Change From Baseline in Urine Protein Creatinine Concentration Ratio (UPCR) | Week 12: Day 84 | Ratio to baseline UPCR derived from 24 hour urine collection |
| Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUClast (AUC) | Day 7, Day 14, Day 21, Day 28 (pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h post dose) and Day 36, Day 64 and Day 84 (pre-dose) | The area under the plasma concentration-time curve calculated from time zero to the last quantifiable concentration point (hr\*ng/mL) |
| Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUCtau (AUC) | Day 7, Day 14, Day 21, Day 28 (pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h post dose) and Day 36, Day 64 and Day 84 (pre-dose) | The area under the plasma concentration-time curve calculated to the end of the dosing interval (hr\*ng/mL) |
| Observed Maximum Concentration After Drug Administration (Cmax) | Day 7, Day 14, Day 21, Day 28 (pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h post dose) and Day 36, Day 64 and Day 84 (pre-dose) | The observed maximum plasma concentration (ng/mL) |
| Observed Minimum Concentration After Drug Administration (Ctrough) | Day 7, Day 14, Day 21, Day 28 (pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h post dose) and Day 36, Day 64 and Day 84 (pre-dose) | The concentration that is just prior to the beginning of, or at the end, of a dosing interval (ng/mL) |
| Time to Reach the Maximum Plasma Concentration (Tmax) | Day 7, Day 14, Day 21, Day 28 (pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h post dose) and Day 36, Day 64 and Day 84 (pre-dose) | The time to reach peak or maximum concentration (hr) |
| Summary of Change From Baseline Complement C3 Biomarker in Serum | Baseline, Day 1, Day 7, Day 14, Day 21, Day 28, Day 36, Day 64, Day 84 | To assess the effect of LNP023 on alternative complement pathway hyperactivity. |
| Ratio to Baseline Summary of Plasma Bb | Baseline, Day 1, Day 7, Day 14, Day 21, Day 28, Day 36, Day 64, Day 84 | To assess the relationship between LNP023 dose and pharmacodynamic biomarker levels of blood Bb |
| Change From Baseline in Urine Albumin to Creatinine Concentration Ratio (UACR) First Morning Void | Week 9: Day 64 | UACR reduction derived from total cumulative urinary excretion first morning void |
| Change From Baseline in Urine Protein (UP) Excretion | Week 12: Day 84 | Ratio to baseline UP excretion derived from 24 hour urine collection |
Countries
France, Germany, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 27 patients (16 patients in Cohort A and 11 patients in Cohort B) were enrolled and treated in the treatment period 1. All 27 patients completed the study and there were no patients who discontinued the study.
Pre-assignment details
A total of 27 patients (16 patients in Cohort A and 11 patients in Cohort B) were enrolled and treated in the treatment period 1. All 27 patients completed the study and there were no patients who discontinued the study.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A - no Kidney Transplant C3G patients who have not received a kidney transplant and have reduced C3 blood levels. | 16 |
| Cohort B - Kidney Transplant C3G patients who have received a kidney transplant and have C3G recurrence. | 11 |
| Total | 27 |
Baseline characteristics
| Characteristic | Cohort B - Kidney Transplant | Total | Cohort A - no Kidney Transplant |
|---|---|---|---|
| Age, Customized | 31.0 Years | 24.0 Years | 22.0 Years |
| Race/Ethnicity, Customized American Indian or Alaska | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 8 Participants | 24 Participants | 16 Participants |
| Race/Ethnicity, Customized Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 9 Participants | 25 Participants | 16 Participants |
| Sex: Female, Male Female | 3 Participants | 9 Participants | 6 Participants |
| Sex: Female, Male Male | 8 Participants | 18 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 11 | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 0 / 16 | 6 / 16 | 8 / 16 | 0 / 11 | 5 / 11 | 6 / 11 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 11 | 0 / 11 | 2 / 11 |
Outcome results
Primary
Cohort A: Change From Baseline in Urine Protein to Creatinine Concentration Ratio (UPCR)
Change in proteinuria assessed by ratio to baseline of UPCR derived from 24h urine collection
Time frame: Week 12
Population: Pharmacodynamics (PD) Analysis Set 1: number of patients included in the analysis with at least one post-baseline value of the outcome variable
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cohort A - no Kidney Transplant | Cohort A: Change From Baseline in Urine Protein to Creatinine Concentration Ratio (UPCR) | 0.55 ratio |
p-value: 0.000380% CI: [0.46, 0.65]Mixed Model Repeated Measures (MMRM)
Primary
Cohort B: Change From Baseline in C3 Deposit
Histopathological changes in kidney biopsies as assessed by change from baseline in C3 Deposit Score (based on immunofluorescence microscopy)
Time frame: Week 12
Population: Pharmacodynamics (PD) Analysis Set 1: number of patients included in the analysis with at least one post-baseline value of the outcome variable
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A - no Kidney Transplant | Cohort B: Change From Baseline in C3 Deposit | -2.50 Percentage change |
p-value: 0.031380% CI: [-3.75, -0.75]Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline Change in Urinary Albumin (UA) Excretion
Ratio to baseline UA excretion derived from 24 hour urine collection
Time frame: Week 12: Day 84
Population: Pharmacodynamics (PD) Analysis Set 1: number of patients included in the analysis with at least one post-baseline value of the outcome variable
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cohort A - no Kidney Transplant | Change From Baseline Change in Urinary Albumin (UA) Excretion | 0.57 ratio |
| Cohort B - Kidney Transplant | Change From Baseline Change in Urinary Albumin (UA) Excretion | 0.81 ratio |
Comparison: Day 84p-value: 0.001880% CI: [0.47, 0.7]Mixed Model Repeated Measures (MMRM)
Comparison: Day 84p-value: 0.163280% CI: [0.67, 0.98]Mixed Model Repeated Measures (MMRM)
Comparison: Overall- Day 84p-value: 0.00480% CI: [0.57, 0.79]Mixed Model Repeated Measure (MMRM)
Secondary
Change From Baseline in Creatinine Clearance
The effect of LNP023 on renal function - creatinine clearance
Time frame: Week 12: Day 84
Population: Pharmacodynamics (PD) Analysis Set 1: number of patients included in the analysis with at least one post-baseline value of the outcome variable
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cohort A - no Kidney Transplant | Change From Baseline in Creatinine Clearance | 1.07 mL/min |
| Cohort B - Kidney Transplant | Change From Baseline in Creatinine Clearance | 1.20 mL/min |
Comparison: Day 84p-value: 0.275280% CI: [0.99, 1.17]Mixed Model Repeated Measures (MMRM)
Comparison: Day 84p-value: 0.47680% CI: [0.83, 1.72]Mixed Model Repeated Measures (MMRM)
Comparison: Overall- Day 84p-value: 0.196380% CI: [1, 1.2]Mixed Model Repeated Measures (MMRM)
Secondary
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)
Effect of LNP023 on estimated glomerular filtration rate (eGFR)
Time frame: Day 84
Population: Pharmacodynamics (PD) Analysis Set 1: number of patients included in the analysis with at least one post-baseline value of the outcome variable
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort A - no Kidney Transplant | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | 2.59 ml/min |
| Cohort B - Kidney Transplant | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | -0.61 ml/min |
Comparison: Day 84p-value: 0.179580% CI: [0.12, 5.06]Mixed Model of Repeated Measures (MMRM)
Comparison: Day 84p-value: 0.77630.7763% CI: [-3.36, 2.15]Mixed Model Repeated Measures (MMRM)
Comparison: Overall- Day 84p-value: 0.375480% CI: [-0.59, 3.22]Mixed Model Repeated Measures (MMRM)
Secondary
Change From Baseline in Serum Creatinine
The effect of LNP023 on renal function - serum creatinine
Time frame: Week 12: Day 84
Population: Pharmacodynamics (PD) Analysis Set 1: number of patients included in the analysis with at least one post-baseline value of the outcome variable
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort A - no Kidney Transplant | Change From Baseline in Serum Creatinine | -5.04 mmol/L |
| Cohort B - Kidney Transplant | Change From Baseline in Serum Creatinine | 7.17 mmol/L |
Comparison: Day 84p-value: 0.136480% CI: [-9.36, -0.72]Mixed Model Repeated Measuers (MMRM)
Comparison: Day 84p-value: 0.303880% CI: [-1.79, 16.13]Mixed Model Repeated Measures (MMRM)
Comparison: Overall- Day 84p-value: 0.835280% CI: [-5.56, 4.01]Mixed Model Repeated Measures (MMRM)
Secondary
Change From Baseline in Urine Albumin Creatinine Concentration Ratio (UACR) Excretion
Ratio to baseline UACR excretion derived from 24 hour urine collection
Time frame: Week 12: Day 84
Population: Pharmacodynamics (PD) Analysis Set 1: number of patients included in the analysis with at least one post-baseline value of the outcome variable
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cohort A - no Kidney Transplant | Change From Baseline in Urine Albumin Creatinine Concentration Ratio (UACR) Excretion | 0.55 ratio |
| Cohort B - Kidney Transplant | Change From Baseline in Urine Albumin Creatinine Concentration Ratio (UACR) Excretion | 0.61 ratio |
Comparison: Day 84p-value: <0.000180% CI: [0.47, 0.64]Mixed Model Repeated Measures (MRM)
Comparison: Day 84p-value: 0.370780% CI: [0.3, 1.27]Mixed Model Repeated Measures (MMRM)
Comparison: Overall- Day 84p-value: 0.000280% CI: [0.51, 0.71]Mixed Model Repeated Measures (MMRM)
Secondary
Change From Baseline in Urine Albumin to Creatinine Concentration Ratio (UACR) First Morning Void
UACR reduction derived from total cumulative urinary excretion first morning void
Time frame: Week 9: Day 64
Population: Pharmacodynamics (PD) Analysis Set 1: number of patients included in the analysis with at least one post-baseline value of the outcome variable
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cohort A - no Kidney Transplant | Change From Baseline in Urine Albumin to Creatinine Concentration Ratio (UACR) First Morning Void | 0.59 g/mol |
| Cohort B - Kidney Transplant | Change From Baseline in Urine Albumin to Creatinine Concentration Ratio (UACR) First Morning Void | 0.87 g/mol |
Comparison: Day 64p-value: <0.000180% CI: [0.5, 0.69]Mixed Model Repeated Measures (MMRM)
Comparison: Day 64p-value: 0.620980% CI: [0.6, 1.26]Mixed Model Repeated Measures (MMRM)
Comparison: Overall- Day 64p-value: 0.000280% CI: [0.54, 0.73]Mixed Model Repeated Measures (MMRM)
Secondary
Change From Baseline in Urine Protein Creatinine Concentration Ratio (UPCR)
Ratio to baseline UPCR derived from 24 hour urine collection
Time frame: Week 12: Day 84
Population: Pharmacodynamics (PD) Analysis Set 1: number of patients included in the analysis with at least one post-baseline value of the outcome variable
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cohort A - no Kidney Transplant | Change From Baseline in Urine Protein Creatinine Concentration Ratio (UPCR) | 0.55 ratio |
| Cohort B - Kidney Transplant | Change From Baseline in Urine Protein Creatinine Concentration Ratio (UPCR) | 0.79 ratio |
Comparison: Day 84p-value: 0.000380% CI: [0.46, 0.65]Mixed Model Repeated Measures (MMRM)
Comparison: Day 84p-value: 0.476680% CI: [0.49, 1.28]Mixed Model Repeated Measures (MMRM)
Comparison: Overall- Day 84p-value: 0.000280% CI: [0.51, 0.69]Mixed Model of Repeated Measures (MMRM)
Secondary
Change From Baseline in Urine Protein to Creatinine Concentration Ratio (UPCR) First Morning Void
Ratio to baseline of UPCR reduction derived from total cumulative urinary excretion first morning void
Time frame: Week 9: Day 64
Population: Pharmacodynamics (PD) Analysis Set 1: number of patients included in the analysis with at least one post-baseline value of the outcome variable
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cohort A - no Kidney Transplant | Change From Baseline in Urine Protein to Creatinine Concentration Ratio (UPCR) First Morning Void | 0.56 ratio |
| Cohort B - Kidney Transplant | Change From Baseline in Urine Protein to Creatinine Concentration Ratio (UPCR) First Morning Void | 0.99 ratio |
Comparison: Day 64p-value: <0.000180% CI: [0.48, 0.65]Mixed Model Repeated Measures (MMRM)
Comparison: Day 64p-value: 0.954480% CI: [0.76, 1.28]Mixed Model Repeated Measures (MMRM)
Comparison: Overall- Day 64p-value: <0.000180% CI: [0.56, 0.72]Mixed Model Repeated Measures (MMRM)
Secondary
Change From Baseline in Urine Protein (UP) Excretion
Ratio to baseline UP excretion derived from 24 hour urine collection
Time frame: Week 12: Day 84
Population: Pharmacodynamics (PD) Analysis Set 1: number of patients included in the analysis with at least one post-baseline value of the outcome variable
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cohort A - no Kidney Transplant | Change From Baseline in Urine Protein (UP) Excretion | 0.57 ratio |
| Cohort B - Kidney Transplant | Change From Baseline in Urine Protein (UP) Excretion | 1.00 ratio |
Comparison: Day 84p-value: 0.001180% CI: [0.47, 0.68]Mixed Model Repeated Measures (MMRM
Comparison: Day 84p-value: 0.999880% CI: [0.75, 1.33]Mixed Model Repeated Measures (MMRM)
Comparison: Overall- Day 84p-value: 0.001680% CI: [0.56, 0.77]Mixed Model Repeated Measures (MMRM)
Secondary
Number of Patients With Hematuria
The effect of LNP023 on renal function - hematuria
Time frame: Week 12: Day 84
Population: Pharmacodynamics (PD) Analysis Set 1: number of patients included in the analysis with at least one post-baseline value of the outcome variable. n: number of patients in the respective baseline category and post-baseline time point.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A - no Kidney Transplant | Number of Patients With Hematuria | Week 12: Day 84: <9 rbc/hpf n (%) | 10 Participants |
| Cohort A - no Kidney Transplant | Number of Patients With Hematuria | Week 12: Day 84: >= 9 to =<50 rbc/hpf n (%) | 0 Participants |
| Cohort A - no Kidney Transplant | Number of Patients With Hematuria | Week 12: Day 84: >50 rbc/hpf n (%) | 0 Participants |
| Cohort B - Kidney Transplant | Number of Patients With Hematuria | Week 12: Day 84: <9 rbc/hpf n (%) | 3 Participants |
| Cohort B - Kidney Transplant | Number of Patients With Hematuria | Week 12: Day 84: >= 9 to =<50 rbc/hpf n (%) | 0 Participants |
| Cohort B - Kidney Transplant | Number of Patients With Hematuria | Week 12: Day 84: >50 rbc/hpf n (%) | 0 Participants |
Secondary
Observed Maximum Concentration After Drug Administration (Cmax)
The observed maximum plasma concentration (ng/mL)
Time frame: Day 7, Day 14, Day 21, Day 28 (pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h post dose) and Day 36, Day 64 and Day 84 (pre-dose)
Population: PK Analysis Set: all patients with available PK data and no protocol deviations with relevant impact on PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A - no Kidney Transplant | Observed Maximum Concentration After Drug Administration (Cmax) | 637 ng/mL | Standard Deviation 97.1 |
| Cohort B - Kidney Transplant | Observed Maximum Concentration After Drug Administration (Cmax) | 941 ng/mL | Standard Deviation 278 |
| Cohort A -no Kidney Transplant - LNP023 100 mg b.i.d. | Observed Maximum Concentration After Drug Administration (Cmax) | 2270 ng/mL | Standard Deviation 805 |
| Cohort A -no Kidney Transplant - LNP023 200 mg b.i.d. | Observed Maximum Concentration After Drug Administration (Cmax) | 3600 ng/mL | Standard Deviation 1230 |
| Cohort B - Kidney Transplant - LNP023 10mg b.i.d. | Observed Maximum Concentration After Drug Administration (Cmax) | 713 ng/mL | Standard Deviation 292 |
| Cohort B - Kidney Transplant - LNP023 25 mg b.i.d. | Observed Maximum Concentration After Drug Administration (Cmax) | 1280 ng/mL | Standard Deviation 552 |
| Cohort B - Kidney Transplant - LNP023 100 mg b.i.d. | Observed Maximum Concentration After Drug Administration (Cmax) | 3250 ng/mL | Standard Deviation 1790 |
| Cohort B - Kidney Transplant - LNP023 200 mg b.i.d. | Observed Maximum Concentration After Drug Administration (Cmax) | 4700 ng/mL | Standard Deviation 2200 |
Secondary
Observed Minimum Concentration After Drug Administration (Ctrough)
The concentration that is just prior to the beginning of, or at the end, of a dosing interval (ng/mL)
Time frame: Day 7, Day 14, Day 21, Day 28 (pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h post dose) and Day 36, Day 64 and Day 84 (pre-dose)
Population: PK Analysis Set: all patients with available PK data and no protocol deviations with relevant impact on PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A - no Kidney Transplant | Observed Minimum Concentration After Drug Administration (Ctrough) | 314 ng/mL | Standard Deviation 133 |
| Cohort B - Kidney Transplant | Observed Minimum Concentration After Drug Administration (Ctrough) | 519 ng/mL | Standard Deviation 133 |
| Cohort A -no Kidney Transplant - LNP023 100 mg b.i.d. | Observed Minimum Concentration After Drug Administration (Ctrough) | 1090 ng/mL | Standard Deviation 408 |
| Cohort A -no Kidney Transplant - LNP023 200 mg b.i.d. | Observed Minimum Concentration After Drug Administration (Ctrough) | 1480 ng/mL | Standard Deviation 653 |
| Cohort B - Kidney Transplant - LNP023 10mg b.i.d. | Observed Minimum Concentration After Drug Administration (Ctrough) | 417 ng/mL | Standard Deviation 237 |
| Cohort B - Kidney Transplant - LNP023 25 mg b.i.d. | Observed Minimum Concentration After Drug Administration (Ctrough) | 644 ng/mL | Standard Deviation 325 |
| Cohort B - Kidney Transplant - LNP023 100 mg b.i.d. | Observed Minimum Concentration After Drug Administration (Ctrough) | 1650 ng/mL | Standard Deviation 1010 |
| Cohort B - Kidney Transplant - LNP023 200 mg b.i.d. | Observed Minimum Concentration After Drug Administration (Ctrough) | 2180 ng/mL | Standard Deviation 1610 |
Secondary
Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUClast (AUC)
The area under the plasma concentration-time curve calculated from time zero to the last quantifiable concentration point (hr\*ng/mL)
Time frame: Day 7, Day 14, Day 21, Day 28 (pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h post dose) and Day 36, Day 64 and Day 84 (pre-dose)
Population: PK Analysis Set: all patients with available PK data and no protocol deviations with relevant impact on PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A - no Kidney Transplant | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUClast (AUC) | 3690 hr*ng/mL | Standard Deviation 693 |
| Cohort B - Kidney Transplant | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUClast (AUC) | 5790 hr*ng/mL | Standard Deviation 1630 |
| Cohort A -no Kidney Transplant - LNP023 100 mg b.i.d. | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUClast (AUC) | 13200 hr*ng/mL | Standard Deviation 4410 |
| Cohort A -no Kidney Transplant - LNP023 200 mg b.i.d. | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUClast (AUC) | 20300 hr*ng/mL | Standard Deviation 8180 |
| Cohort B - Kidney Transplant - LNP023 10mg b.i.d. | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUClast (AUC) | 4560 hr*ng/mL | Standard Deviation 2060 |
| Cohort B - Kidney Transplant - LNP023 25 mg b.i.d. | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUClast (AUC) | 7880 hr*ng/mL | Standard Deviation 3830 |
| Cohort B - Kidney Transplant - LNP023 100 mg b.i.d. | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUClast (AUC) | 19600 hr*ng/mL | Standard Deviation 12100 |
| Cohort B - Kidney Transplant - LNP023 200 mg b.i.d. | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUClast (AUC) | 28100 hr*ng/mL | Standard Deviation 15900 |
Secondary
Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUCtau (AUC)
The area under the plasma concentration-time curve calculated to the end of the dosing interval (hr\*ng/mL)
Time frame: Day 7, Day 14, Day 21, Day 28 (pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h post dose) and Day 36, Day 64 and Day 84 (pre-dose)
Population: PK Analysis Set: all patients with available PK data and no protocol deviations with relevant impact on PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A - no Kidney Transplant | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUCtau (AUC) | 5020 hr*ng/mL | Standard Deviation 1110 |
| Cohort B - Kidney Transplant | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUCtau (AUC) | 7970 hr*ng/mL | Standard Deviation 2250 |
| Cohort A -no Kidney Transplant - LNP023 100 mg b.i.d. | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUCtau (AUC) | 17800 hr*ng/mL | Standard Deviation 5800 |
| Cohort A -no Kidney Transplant - LNP023 200 mg b.i.d. | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUCtau (AUC) | 26900 hr*ng/mL | Standard Deviation 10900 |
| Cohort B - Kidney Transplant - LNP023 10mg b.i.d. | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUCtau (AUC) | 6300 hr*ng/mL | Standard Deviation 3000 |
| Cohort B - Kidney Transplant - LNP023 25 mg b.i.d. | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUCtau (AUC) | 10700 hr*ng/mL | Standard Deviation 5310 |
| Cohort B - Kidney Transplant - LNP023 100 mg b.i.d. | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUCtau (AUC) | 26600 hr*ng/mL | Standard Deviation 16500 |
| Cohort B - Kidney Transplant - LNP023 200 mg b.i.d. | Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUCtau (AUC) | 37700 hr*ng/mL | Standard Deviation 22000 |
Secondary
Ratio to Baseline Summary of Plasma Bb
To assess the relationship between LNP023 dose and pharmacodynamic biomarker levels of blood Bb
Time frame: Baseline, Day 1, Day 7, Day 14, Day 21, Day 28, Day 36, Day 64, Day 84
Population: PD Analysis Set 2: included all patients with available Pharmacodynamics (PD) data and no protocol deviations with relevant impact on PD data. At each timepoint only subjects with a value at both baseline and that timepoint were included
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A - no Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 36 pre-dose | 102.5 Ratio of plasma Bb | Standard Deviation 54.06 |
| Cohort A - no Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 1 pre-dose | 101.8 Ratio of plasma Bb | Standard Deviation 45.18 |
| Cohort A - no Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 7 pre-dose | 102.4 Ratio of plasma Bb | Standard Deviation 40.47 |
| Cohort A - no Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 14 pre-dose | 104.4 Ratio of plasma Bb | Standard Deviation 43.35 |
| Cohort A - no Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 21 pre-dose | 97.0 Ratio of plasma Bb | Standard Deviation 58.06 |
| Cohort A - no Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 28 pre-dose | 90.2 Ratio of plasma Bb | Standard Deviation 46.24 |
| Cohort A - no Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 64 pre-dose | 116.8 Ratio of plasma Bb | Standard Deviation 59.76 |
| Cohort A - no Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 84 pre-dose | 116.6 Ratio of plasma Bb | Standard Deviation 57.85 |
| Cohort B - Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 84 pre-dose | 76.3 Ratio of plasma Bb | Standard Deviation 35.84 |
| Cohort B - Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 36 pre-dose | 65.9 Ratio of plasma Bb | Standard Deviation 31.2 |
| Cohort B - Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 21 pre-dose | 66.4 Ratio of plasma Bb | Standard Deviation 22.95 |
| Cohort B - Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 1 pre-dose | 109.7 Ratio of plasma Bb | Standard Deviation 34.08 |
| Cohort B - Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 64 pre-dose | 73.2 Ratio of plasma Bb | Standard Deviation 29.62 |
| Cohort B - Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 7 pre-dose | 83.6 Ratio of plasma Bb | Standard Deviation 27.73 |
| Cohort B - Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 28 pre-dose | 71.5 Ratio of plasma Bb | Standard Deviation 29.52 |
| Cohort B - Kidney Transplant | Ratio to Baseline Summary of Plasma Bb | Day 14 pre-dose | 81.8 Ratio of plasma Bb | Standard Deviation 39.34 |
Secondary
Summary of Change From Baseline Complement C3 Biomarker in Serum
To assess the effect of LNP023 on alternative complement pathway hyperactivity.
Time frame: Baseline, Day 1, Day 7, Day 14, Day 21, Day 28, Day 36, Day 64, Day 84
Population: PD Analysis Set 2: included all patients with available Pharmacodynamics (PD) data and no protocol deviations with relevant impact on PD data. At each timepoint only subjects with a value at both baseline and that timepoint were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A - no Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 1 pre-dose | 0.0 g/L | Standard Deviation 0.06 |
| Cohort A - no Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 7 - pre-dose | 0.1 g/L | Standard Deviation 0.1 |
| Cohort A - no Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 14 - pre-dose | 0.3 g/L | Standard Deviation 0.17 |
| Cohort A - no Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 21 - pre-dose | 0.5 g/L | Standard Deviation 0.25 |
| Cohort A - no Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 28 - pre-dose | 0.5 g/L | Standard Deviation 0.29 |
| Cohort A - no Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 36 - pre-dose | 0.6 g/L | Standard Deviation 0.28 |
| Cohort A - no Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 64 - pre-dose | 0.6 g/L | Standard Deviation 0.27 |
| Cohort A - no Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 84 - pre-dose | 0.6 g/L | Standard Deviation 0.3 |
| Cohort B - Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 84 - pre-dose | 0.5 g/L | Standard Deviation 0.26 |
| Cohort B - Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 1 pre-dose | 0.0 g/L | Standard Deviation 0.12 |
| Cohort B - Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 28 - pre-dose | 0.4 g/L | Standard Deviation 0.27 |
| Cohort B - Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 7 - pre-dose | 0.2 g/L | Standard Deviation 0.22 |
| Cohort B - Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 64 - pre-dose | 0.4 g/L | Standard Deviation 0.26 |
| Cohort B - Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 14 - pre-dose | 0.4 g/L | Standard Deviation 0.29 |
| Cohort B - Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 36 - pre-dose | 0.4 g/L | Standard Deviation 0.32 |
| Cohort B - Kidney Transplant | Summary of Change From Baseline Complement C3 Biomarker in Serum | Day 21 - pre-dose | 0.4 g/L | Standard Deviation 0.33 |
Secondary
Time to Reach the Maximum Plasma Concentration (Tmax)
The time to reach peak or maximum concentration (hr)
Time frame: Day 7, Day 14, Day 21, Day 28 (pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h post dose) and Day 36, Day 64 and Day 84 (pre-dose)
Population: PK Analysis Set: all patients with available PK data and no protocol deviations with relevant impact on PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A - no Kidney Transplant | Time to Reach the Maximum Plasma Concentration (Tmax) | 2.00 hr |
| Cohort B - Kidney Transplant | Time to Reach the Maximum Plasma Concentration (Tmax) | 2.00 hr |
| Cohort A -no Kidney Transplant - LNP023 100 mg b.i.d. | Time to Reach the Maximum Plasma Concentration (Tmax) | 2.00 hr |
| Cohort A -no Kidney Transplant - LNP023 200 mg b.i.d. | Time to Reach the Maximum Plasma Concentration (Tmax) | 2.00 hr |
| Cohort B - Kidney Transplant - LNP023 10mg b.i.d. | Time to Reach the Maximum Plasma Concentration (Tmax) | 2.00 hr |
| Cohort B - Kidney Transplant - LNP023 25 mg b.i.d. | Time to Reach the Maximum Plasma Concentration (Tmax) | 2.00 hr |
| Cohort B - Kidney Transplant - LNP023 100 mg b.i.d. | Time to Reach the Maximum Plasma Concentration (Tmax) | 2.00 hr |
| Cohort B - Kidney Transplant - LNP023 200 mg b.i.d. | Time to Reach the Maximum Plasma Concentration (Tmax) | 2.00 hr |