Primary Hyperoxaluria Type 1 (PH1)
Conditions
Keywords
PH1, Primary Hyperoxaluria, RNAi therapeutic, siRNA, AGT
Brief summary
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single-ascending doses (SAD) and multiple-ascending doses (MAD) of lumasiran in healthy adult volunteers and subjects with primary hyperoxaluria type 1 (PH1). In Part A, single ascending dose (SAD) part, healthy adults were dosed with lumasiran or placebo once. In Part B, multiple ascending doses (MAD) part, patients with primary hyperoxaluria type 1 (PH1) were dosed with lumasiran or placebo. All patients that initially received placebo received lumasiran after completing placebo dosing.
Interventions
DRUGLumasiran
Lumasiran will be administered SC once in Part A. In Part B lumasiran will be administered SC qM (Days 1, 29 and 57) or q3M (Days 1 and 85).
DRUGPlacebo
Matching placebo (sterile saline: 0.9% sodium chloride \[NaCl\]) will be administered SC once in Part A. In Part B matching placebo will be administered SC qM (Days 1, 29 and 57) or q3M (Days 1 and 85).
Sponsors
Alnylam Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
6 Years to 64 Years
Healthy volunteers
Yes
Inclusion criteria
for Parts A and B: * Women of child bearing potential must have a negative pregnancy test, cannot be breastfeeding, and must be willing to use contraception. * Willing to provide written informed consent and to comply with study requirements. Additional Inclusion Criteria for Part B: * Confirmation of PH1 disease * Meet 24 hour urine oxalate excretion requirements * Estimated glomerular filtration rate (GFR) of \>45 mL/min/1.73m\^2 * If taking Vitamin B6 (pyridoxine), must have been on stable regimen for at least 90 days
Exclusion criteria
for Parts A and B: * Clinically significant health concerns (with the exception of PH1 for patients in Part B) * Clinically significant electrocardiogram (ECG) abnormalities * Abnormal for aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and any other clinical safety laboratory result considered clinically significant * Received an investigational agent within 3 months before the first dose of study drug or are in follow-up of another clinical study * Known history of allergic reaction to an oligonucleotide or N-acetylgalactosamine (GalNAc) * History of intolerance to subcutaneous injection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | Part A (SAD): Up to 405 days; Part B (MAD): Up to 546 days | An AE is any untoward medical occurrence in a clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Cmax (Tmax) of Lumasiran in Plasma | Part A (SAD): Day 1: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h; Part B (MAD): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h | Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups. |
| Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma | Part A (SAD): Day 1: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h; Part B (MAD): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h | Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups. |
| Terminal Half-life (t1/2) of Lumasiran in Plasma | Part A (SAD): Day 1: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h; Part B (MAD): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h | Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups. |
| Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran | Part A (SAD): Day 1: pooled urine 0-4 h, 4-8 h and 8-24 h; Part B (MAD): Part B (MAD phase): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: pooled urine 0-4 h, 4-8 h, 8-12 h and 12-24 h | Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups. |
| Renal Clearance (CLR) of Lumasiran | Part A (SAD): Day 1: pooled urine 0-4 h, 4-8 h and 8-24 h; Part B (MAD): Part B (MAD phase): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: pooled urine 0-4 h, 4-8 h, 8-12 h and 12-24 h | Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups. |
| Baseline Plasma Glycolate Concentration | Part A (SAD): Baseline, Part B (MAD): Baseline | The pharmacodynamic (PD) outcome measure of plasma glycolate concentration could only be calculated for Part A. Due to an issue with the plasma glycolate assay at the testing laboratory the data for Part B could not be calculated. |
| Percentage Change From Baseline in Plasma Glycolate Concentration | Part A (SAD): Days 15, 29, 57 and 85; Part B (MAD): Days 15, 29, 57, 85 | The PD outcome measure of plasma glycolate concentration could only be calculated for Part A. Due to an issue with the plasma glycolate assay at the testing laboratory the data for Part B could not be calculated. |
| Maximum Concentration (Cmax) of Lumasiran in Plasma | Part A (SAD): Day 1: predose, 30 minutes (min), 1 hour (h), 2 h, 4 h, 6 h, 8 h and 24 h; Part B (MAD): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h | Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups. |
| Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A | Part A (SAD): Days 29 and 57 | The endpoint was only measured in Part A. |
| Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Part B (MAD): Baseline | The endpoint was only measured in Part B. |
| Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Part B (MAD): 24 hour urine collections on Days 29, 57, 85, 113, 141, 169, 197 | The endpoint was only measured in Part B. |
| Baseline 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | Part B (MAD): Baseline | The endpoint was only measured during the initial 85 days in Part B. |
| Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | Part B (MAD): 24 hour urine collections on Days 29, 57 and 85 | The endpoint was only measured during the initial 85 days in Part B. |
| Baseline Creatinine Clearance Corrected for BSA in Part B | Part B (MAD): Baseline | — |
| Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Part B (MAD): Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365, 393, 421, 449 | — |
| Baseline Spot Urine Glycolate:Creatinine Ratio in Part A | Part A (SAD): Baseline | The endpoint was only measured in Part A. |
Countries
France, Germany, Israel, Netherlands, United Kingdom
Participant flow
Recruitment details
Participants were enrolled at ten sites in Germany, France, the United Kingdom, Israel, and the Netherlands.
Pre-assignment details
In Part A, single ascending dose (SAD) part, healthy adults were dosed with lumasiran or placebo once. In Part B, multiple ascending doses (MAD) part, patients with primary hyperoxaluria type 1 (PH1) were dosed with lumasiran or placebo. All patients, who initially received placebo, received lumasiran after completing placebo dosing.
Participants by arm
| Arm | Count |
|---|---|
| Part A: SAD: Placebo A single dose of matching placebo was administered SC. | 8 |
| Part A: SAD: Lumasiran 0.3 mg/kg A single dose of 0.3 mg/kg lumasiran was administered SC. | 6 |
| Part A: SAD: Lumasiran 1.0 mg/kg A single dose of 1.0 mg/kg lumasiran was administered SC. | 6 |
| Part A: SAD: Lumasiran 3.0 mg/kg A single dose of 3.0 mg/kg lumasiran was administered SC. | 6 |
| Part A: SAD: Lumasiran 6.0 mg/kg A single dose of 6.0 mg/kg lumasiran was administered SC. | 6 |
| Part B: MAD: Placebo Participants with primary hyperoxaluria type 1 (PH1) were treated with placebo matching one of the lumasiran dosages in the lumasiran arms (one placebo participant for each lumasiran arm). At Day 85 these placebo-treated participants crossed over to their respective Part B lumasiran arms in Part B: MAD Study Day 85-End of Study and were then treated with lumasiran. The estimated total time on study was up to 546 days. | 3 |
| Part B: MAD: Lumasiran 1.0 mg/kg qM Participants with PH1 were treated with 1.0 mg/kg lumasiran SC once monthly (qM) on Days 1, 29 and 57. The estimated total time on study was up to 546 days. One participant from the Part B: MAD: Placebo arm crossed over to this lumasiran arm at Day 85. For this participant treatment with lumasiran started at Day 85. | 7 |
| Part B: MAD: Lumasiran 3.0 mg/kg qM Participants with PH1 were treated with 3.0 mg/kg lumasiran SC qM on Days 1, 29 and 57. The estimated total time on study was up to 546 days. One participant from the Part B: MAD: Placebo arm crossed over to this lumasiran arm at Day 85. For this participant treatment with lumasiran started at Day 85. | 7 |
| Part B: MAD: Lumasiran 3.0 mg/kg q3M Participants with PH1 were treated with 3.0 mg/kg lumasiran SC once every three months (q3M) on Days 1 and 85. The estimated total time on study was up to 546 days. One participant from the Part B: MAD: Placebo arm crossed over to this lumasiran arm at Day 85. For this participant treatment with lumasiran started at Day 85. | 3 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Part A: SAD Period | Withdrawal by Subject | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part A: SAD: Placebo | Part A: SAD: Lumasiran 0.3 mg/kg | Part A: SAD: Lumasiran 1.0 mg/kg | Part A: SAD: Lumasiran 3.0 mg/kg | Part A: SAD: Lumasiran 6.0 mg/kg | Part B: MAD: Placebo | Part B: MAD: Lumasiran 1.0 mg/kg qM | Part B: MAD: Lumasiran 3.0 mg/kg qM | Part B: MAD: Lumasiran 3.0 mg/kg q3M | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 29.8 years STANDARD_DEVIATION 6.25 | 28.8 years STANDARD_DEVIATION 7.36 | 30.2 years STANDARD_DEVIATION 7.81 | 27.3 years STANDARD_DEVIATION 3.44 | 28.8 years STANDARD_DEVIATION 5.46 | 20.7 years STANDARD_DEVIATION 19.4 | 14.0 years STANDARD_DEVIATION 9.93 | 15.4 years STANDARD_DEVIATION 7.89 | 9.7 years STANDARD_DEVIATION 5.51 | 23.6 years STANDARD_DEVIATION 10.41 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 5 Participants | 6 Participants | 6 Participants | 5 Participants | 3 Participants | 7 Participants | 7 Participants | 3 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 7 Participants | 6 Participants | 5 Participants | 3 Participants | 4 Participants | 2 Participants | 5 Participants | 5 Participants | 3 Participants | 40 Participants |
| Sex: Female, Male Female | 5 Participants | 0 Participants | 3 Participants | 3 Participants | 5 Participants | 1 Participants | 6 Participants | 4 Participants | 2 Participants | 29 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 3 Participants | 3 Participants | 1 Participants | 2 Participants | 1 Participants | 3 Participants | 1 Participants | 23 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 3 | 0 / 8 | 0 / 8 | 0 / 4 |
| other Total, other adverse events | 5 / 8 | 6 / 6 | 3 / 6 | 6 / 6 | 6 / 6 | 2 / 3 | 7 / 8 | 7 / 8 | 4 / 4 |
| serious Total, serious adverse events | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 1 / 3 | 1 / 8 | 3 / 8 | 0 / 4 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs)
An AE is any untoward medical occurrence in a clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.
Time frame: Part A (SAD): Up to 405 days; Part B (MAD): Up to 546 days
Population: Safety Analysis Set consisted of all healthy participants and patients, who received at least 1 dose of study drug (lumasiran, placebo), grouped according to actual treatment received. Part B participants who crossed over from placebo to the lumasiran arms are included in the placebo arm as well as lumasiran arms.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: SAD: Placebo | Number of Participants With Adverse Events (AEs) | 5 Participants |
| Part A: SAD: Lumasiran 0.3 mg/kg | Number of Participants With Adverse Events (AEs) | 6 Participants |
| Part A: SAD: Lumasiran 1.0 mg/kg | Number of Participants With Adverse Events (AEs) | 2 Participants |
| Part A: SAD: Lumasiran 3.0 mg/kg | Number of Participants With Adverse Events (AEs) | 6 Participants |
| Part A: SAD: Lumasiran 6.0 mg/kg | Number of Participants With Adverse Events (AEs) | 6 Participants |
| Part B: MAD: Placebo | Number of Participants With Adverse Events (AEs) | 2 Participants |
| Part B: MAD: Lumasiran 1.0 mg/kg qM | Number of Participants With Adverse Events (AEs) | 8 Participants |
| Part B: MAD: Lumasiran 3.0 mg/kg qM | Number of Participants With Adverse Events (AEs) | 7 Participants |
| Part B: MAD: Lumasiran 3.0 mg/kg q3M | Number of Participants With Adverse Events (AEs) | 4 Participants |
Secondary
Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma
Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups.
Time frame: Part A (SAD): Day 1: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h; Part B (MAD): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h
Population: PK Analysis Set consisted of all healthy participants and patients who received at least 1 dose of lumasiran and had at least 1 postdose sample for PK parameters and who had evaluable PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: SAD: Placebo | Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma | Day 1 | 293.5232 h*ng/mL | Standard Deviation 96.86989 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma | Day 1 | 1899.8119 h*ng/mL | Standard Deviation 558.25326 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma | Day 1 | 7211.5890 h*ng/mL | Standard Deviation 1125.64173 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma | Day 1 | 16778.0579 h*ng/mL | Standard Deviation 4380.15325 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma | Day 57 | 1608.1457 h*ng/mL | Standard Deviation 708.95156 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma | Day 1 | 1428.0412 h*ng/mL | Standard Deviation 697.85233 |
| Part B: MAD: Placebo | Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma | Day 1 | 7400.2181 h*ng/mL | Standard Deviation 2331.89843 |
| Part B: MAD: Placebo | Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma | Day 57 | 7959.7873 h*ng/mL | Standard Deviation 1726.57675 |
| Part B: MAD: Lumasiran 1.0 mg/kg qM | Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma | Day 85 | 5136.3462 h*ng/mL | Standard Deviation 2757.90139 |
| Part B: MAD: Lumasiran 1.0 mg/kg qM | Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma | Day 1 | 6337.9082 h*ng/mL | Standard Deviation 3840.0334 |
Secondary
Baseline 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days
The endpoint was only measured during the initial 85 days in Part B.
Time frame: Part B (MAD): Baseline
Population: PD Analysis Set in Part B consisted of all patients with PH1 who received at least 1 dose of study drug (lumasiran, placebo) and had at least 1 postdose blood and/or urine sample available that was evaluable for PD assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: SAD: Placebo | Baseline 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | 193 mg/g | Standard Deviation 117.2 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Baseline 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | 241 mg/g | Standard Deviation 85.6 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Baseline 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | 289 mg/g | Standard Deviation 146 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Baseline 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | 281 mg/g | Standard Deviation 139 |
Secondary
Baseline Creatinine Clearance Corrected for BSA in Part B
Time frame: Part B (MAD): Baseline
Population: PD Analysis Set in Part B consisted of all patients with PH1 who received at least 1 dose of study drug (lumasiran, placebo) and had at least 1 postdose blood and/or urine sample available that was evaluable for PD assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: SAD: Placebo | Baseline Creatinine Clearance Corrected for BSA in Part B | 64.389 mL/min/1.73 m^2 | Standard Deviation 19.8024 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Baseline Creatinine Clearance Corrected for BSA in Part B | 108.149 mL/min/1.73 m^2 | Standard Deviation 44.1783 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Baseline Creatinine Clearance Corrected for BSA in Part B | 86.268 mL/min/1.73 m^2 | Standard Deviation 22.1226 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Baseline Creatinine Clearance Corrected for BSA in Part B | 88.251 mL/min/1.73 m^2 | Standard Deviation 30.0118 |
Secondary
Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B
The endpoint was only measured in Part B.
Time frame: Part B (MAD): Baseline
Population: PD Analysis Set in Part B consisted of all patients with PH1 who received at least 1 dose of study drug (lumasiran, placebo) and had at least 1 postdose blood and/or urine sample available that was evaluable for PD assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: SAD: Placebo | Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | 1.96 mmol/24h/1.73m^2 | Standard Deviation 0.321 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | 1.73 mmol/24h/1.73m^2 | Standard Deviation 0.696 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | 1.84 mmol/24h/1.73m^2 | Standard Deviation 0.621 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | 1.30 mmol/24h/1.73m^2 | Standard Deviation 0.35 |
Secondary
Baseline Plasma Glycolate Concentration
The pharmacodynamic (PD) outcome measure of plasma glycolate concentration could only be calculated for Part A. Due to an issue with the plasma glycolate assay at the testing laboratory the data for Part B could not be calculated.
Time frame: Part A (SAD): Baseline, Part B (MAD): Baseline
Population: PD Analysis Set consisted of all participants who received at least 1 dose of study drug (lumasiran, placebo) and had at least 1 postdose blood sample available that was evaluable for PD assessments. Due to an issue with plasma glycolate assay at the testing laboratory the data for Part B could not be calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: SAD: Placebo | Baseline Plasma Glycolate Concentration | 5.1 umol/L | Standard Deviation 1.73 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Baseline Plasma Glycolate Concentration | 5.3 umol/L | Standard Deviation 1.51 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Baseline Plasma Glycolate Concentration | 5.7 umol/L | Standard Deviation 1.97 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Baseline Plasma Glycolate Concentration | 6.2 umol/L | Standard Deviation 2.56 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Baseline Plasma Glycolate Concentration | 4.8 umol/L | Standard Deviation 1.72 |
Secondary
Baseline Spot Urine Glycolate:Creatinine Ratio in Part A
The endpoint was only measured in Part A.
Time frame: Part A (SAD): Baseline
Population: PD Analysis Set for Part A consisted of all healthy participants who received at least 1 dose of study drug (lumasiran, placebo) and had at least 1 postdose blood and/or urine sample available that was evaluable for PD assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: SAD: Placebo | Baseline Spot Urine Glycolate:Creatinine Ratio in Part A | 12.4 mg/g | Standard Deviation 4.63 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Baseline Spot Urine Glycolate:Creatinine Ratio in Part A | 15.7 mg/g | Standard Deviation 4.27 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Baseline Spot Urine Glycolate:Creatinine Ratio in Part A | 15.7 mg/g | Standard Deviation 3.14 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Baseline Spot Urine Glycolate:Creatinine Ratio in Part A | 13.0 mg/g | Standard Deviation 3.52 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Baseline Spot Urine Glycolate:Creatinine Ratio in Part A | 14.8 mg/g | Standard Deviation 4.31 |
Secondary
Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran
Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups.
Time frame: Part A (SAD): Day 1: pooled urine 0-4 h, 4-8 h and 8-24 h; Part B (MAD): Part B (MAD phase): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: pooled urine 0-4 h, 4-8 h, 8-12 h and 12-24 h
Population: PK Analysis Set consisted of all healthy participants and patients who received at least 1 dose of lumasiran and had at least 1 postdose sample for PK parameters and who had evaluable PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: SAD: Placebo | Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran | Day 1 | 17.4219 percentage fractional excretion | Standard Deviation 2.44129 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran | Day 1 | 19.0713 percentage fractional excretion | Standard Deviation 3.88914 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran | Day 1 | 21.0472 percentage fractional excretion | Standard Deviation 5.36667 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran | Day 1 | 25.7931 percentage fractional excretion | Standard Deviation 3.25937 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran | Day 57 | 9.4698 percentage fractional excretion | Standard Deviation 4.21949 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran | Day 1 | 11.0895 percentage fractional excretion | Standard Deviation 3.74207 |
| Part B: MAD: Placebo | Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran | Day 1 | 11.1877 percentage fractional excretion | Standard Deviation 6.07719 |
| Part B: MAD: Placebo | Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran | Day 57 | 12.4604 percentage fractional excretion | Standard Deviation 4.02897 |
| Part B: MAD: Lumasiran 1.0 mg/kg qM | Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran | Day 85 | 13.6938 percentage fractional excretion | Standard Deviation 3.60004 |
| Part B: MAD: Lumasiran 1.0 mg/kg qM | Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran | Day 1 | 7.1691 percentage fractional excretion | Standard Deviation 2.37465 |
Secondary
Maximum Concentration (Cmax) of Lumasiran in Plasma
Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups.
Time frame: Part A (SAD): Day 1: predose, 30 minutes (min), 1 hour (h), 2 h, 4 h, 6 h, 8 h and 24 h; Part B (MAD): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h
Population: Pharmacokinetic (PK) Analysis Set consisted of all healthy participants and patients who received at least 1 dose of lumasiran and had at least 1 postdose sample for PK parameters and who had evaluable PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: SAD: Placebo | Maximum Concentration (Cmax) of Lumasiran in Plasma | Day 1 | 39.7940 ng/mL | Standard Deviation 8.58882 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Maximum Concentration (Cmax) of Lumasiran in Plasma | Day 1 | 204.3748 ng/mL | Standard Deviation 111.68091 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Maximum Concentration (Cmax) of Lumasiran in Plasma | Day 1 | 533.4527 ng/mL | Standard Deviation 160.1106 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Maximum Concentration (Cmax) of Lumasiran in Plasma | Day 1 | 1176.1302 ng/mL | Standard Deviation 199.89797 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Maximum Concentration (Cmax) of Lumasiran in Plasma | Day 57 | 147.6780 ng/mL | Standard Deviation 67.97968 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Maximum Concentration (Cmax) of Lumasiran in Plasma | Day 1 | 324.1386 ng/mL | Standard Deviation 489.71104 |
| Part B: MAD: Placebo | Maximum Concentration (Cmax) of Lumasiran in Plasma | Day 1 | 582.4515 ng/mL | Standard Deviation 266.90105 |
| Part B: MAD: Placebo | Maximum Concentration (Cmax) of Lumasiran in Plasma | Day 57 | 701.1708 ng/mL | Standard Deviation 511.63001 |
| Part B: MAD: Lumasiran 1.0 mg/kg qM | Maximum Concentration (Cmax) of Lumasiran in Plasma | Day 85 | 411.5613 ng/mL | Standard Deviation 174.92146 |
| Part B: MAD: Lumasiran 1.0 mg/kg qM | Maximum Concentration (Cmax) of Lumasiran in Plasma | Day 1 | 432.2798 ng/mL | Standard Deviation 245.0266 |
Secondary
Percentage Change From Baseline in Plasma Glycolate Concentration
The PD outcome measure of plasma glycolate concentration could only be calculated for Part A. Due to an issue with the plasma glycolate assay at the testing laboratory the data for Part B could not be calculated.
Time frame: Part A (SAD): Days 15, 29, 57 and 85; Part B (MAD): Days 15, 29, 57, 85
Population: PD Analysis Set consisted of all participants who received at least 1 dose of study drug (lumasiran, placebo) and had at least 1 postdose blood sample available that was evaluable for PD assessments. Due to an issue with plasma glycolate assay at the testing laboratory the data for Part B could not be calculated.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: SAD: Placebo | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 15 | 18.3 percentage change from baseline | Standard Deviation 67.19 |
| Part A: SAD: Placebo | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 29 | 22.4 percentage change from baseline | Standard Deviation 46.83 |
| Part A: SAD: Placebo | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 57 | 126.7 percentage change from baseline | Standard Deviation 242.68 |
| Part A: SAD: Placebo | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 85 | 31.2 percentage change from baseline | Standard Deviation 131.04 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 15 | 58.3 percentage change from baseline | Standard Deviation 55.29 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 85 | 15.6 percentage change from baseline | Standard Deviation 100.54 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 29 | 32.9 percentage change from baseline | Standard Deviation 57.67 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 57 | 66.3 percentage change from baseline | Standard Deviation 38.07 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 85 | 40.7 percentage change from baseline | Standard Deviation 110.75 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 29 | 70.6 percentage change from baseline | Standard Deviation 82.74 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 57 | 109.8 percentage change from baseline | Standard Deviation 124.29 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 15 | 48.5 percentage change from baseline | Standard Deviation 82.99 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 15 | 56.4 percentage change from baseline | Standard Deviation 28.5 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 29 | 146.4 percentage change from baseline | Standard Deviation 81.99 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 85 | 196.2 percentage change from baseline | Standard Deviation 152.41 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 57 | 230.1 percentage change from baseline | Standard Deviation 180.36 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 85 | 731.3 percentage change from baseline | Standard Deviation 375.02 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 57 | 730.4 percentage change from baseline | Standard Deviation 439.54 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 29 | 390.1 percentage change from baseline | Standard Deviation 270.4 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Percentage Change From Baseline in Plasma Glycolate Concentration | Day 15 | 59.5 percentage change from baseline | Standard Deviation 49 |
Secondary
Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A
The endpoint was only measured in Part A.
Time frame: Part A (SAD): Days 29 and 57
Population: PD Analysis Set in Part A consisted of all healthy participants who received at least 1 dose of study drug (lumasiran, placebo) and had at least 1 postdose blood and/or urine sample available that was evaluable for PD assessments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: SAD: Placebo | Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A | Day 29 | 8.1 percentage change from baseline | Standard Deviation 43.42 |
| Part A: SAD: Placebo | Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A | Day 57 | 73.8 percentage change from baseline | Standard Deviation 108.9 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A | Day 29 | 32.5 percentage change from baseline | Standard Deviation 22.6 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A | Day 57 | 38.0 percentage change from baseline | Standard Deviation 50.62 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A | Day 29 | 82.9 percentage change from baseline | Standard Deviation 65 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A | Day 57 | 47.8 percentage change from baseline | Standard Deviation 41.03 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A | Day 57 | 215.0 percentage change from baseline | Standard Deviation 178.72 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A | Day 29 | 109.1 percentage change from baseline | Standard Deviation 66.51 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A | Day 29 | 210.5 percentage change from baseline | Standard Deviation 199.3 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A | Day 57 | 310.7 percentage change from baseline | Standard Deviation 94.51 |
Secondary
Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days
The endpoint was only measured during the initial 85 days in Part B.
Time frame: Part B (MAD): 24 hour urine collections on Days 29, 57 and 85
Population: PD Analysis Set in Part B consisted of all patients with PH1 who received at least 1 dose of study drug (lumasiran, placebo) and had at least 1 postdose blood and/or urine sample available that was evaluable for PD assessments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: SAD: Placebo | Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | Day 29 | -15.1 percentage change from baseline | Standard Deviation 6.47 |
| Part A: SAD: Placebo | Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | Day 85 | -23.0 percentage change from baseline | Standard Deviation 10.45 |
| Part A: SAD: Placebo | Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | Day 57 | -13.8 percentage change from baseline | Standard Deviation 29.02 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | Day 29 | 53.1 percentage change from baseline | Standard Deviation 42.18 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | Day 85 | 71.0 percentage change from baseline | Standard Deviation 55.62 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | Day 57 | 82.3 percentage change from baseline | Standard Deviation 40.12 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | Day 57 | 42.3 percentage change from baseline | Standard Deviation 57.56 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | Day 29 | 31.4 percentage change from baseline | Standard Deviation 35.99 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | Day 85 | 43.7 percentage change from baseline | Standard Deviation 62.15 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | Day 29 | 33.0 percentage change from baseline | Standard Deviation 36.37 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | Day 85 | 42.0 percentage change from baseline | Standard Deviation 20.86 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days | Day 57 | 81.8 percentage change from baseline | Standard Deviation 35.66 |
Secondary
Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B
The endpoint was only measured in Part B.
Time frame: Part B (MAD): 24 hour urine collections on Days 29, 57, 85, 113, 141, 169, 197
Population: PD Analysis Set in Part B consisted of all patients with PH1 who received at least 1 dose of study drug (lumasiran, placebo) and had at least 1 postdose blood and/or urine sample available that was evaluable for PD assessments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: SAD: Placebo | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 85 | 9.1 percentage change from baseline | — |
| Part A: SAD: Placebo | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 57 | -27.8 percentage change from baseline | Standard Deviation 47.11 |
| Part A: SAD: Placebo | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 29 | -2.4 percentage change from baseline | — |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 113 | -61.4 percentage change from baseline | Standard Deviation 12.24 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 29 | -41.1 percentage change from baseline | Standard Deviation 24.76 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 57 | -49.7 percentage change from baseline | Standard Deviation 20.08 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 85 | -65.6 percentage change from baseline | Standard Deviation 16.64 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 141 | -64.6 percentage change from baseline | Standard Deviation 13.55 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 169 | -61.6 percentage change from baseline | Standard Deviation 14.19 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 197 | -63.8 percentage change from baseline | Standard Deviation 13.85 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 29 | -57.5 percentage change from baseline | Standard Deviation 10.84 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 197 | -71.2 percentage change from baseline | Standard Deviation 11.7 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 169 | -69.3 percentage change from baseline | Standard Deviation 9.61 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 57 | -72.5 percentage change from baseline | Standard Deviation 10.7 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 113 | -78.1 percentage change from baseline | Standard Deviation 7.8 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 141 | -73.5 percentage change from baseline | Standard Deviation 8.11 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 85 | -68.4 percentage change from baseline | Standard Deviation 10.6 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 169 | -48.7 percentage change from baseline | Standard Deviation 14.19 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 85 | -53.3 percentage change from baseline | Standard Deviation 3.66 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 113 | -59.1 percentage change from baseline | Standard Deviation 20.75 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 197 | -52.7 percentage change from baseline | Standard Deviation 6.38 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 141 | -68.4 percentage change from baseline | Standard Deviation 3.21 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 57 | -49.1 percentage change from baseline | Standard Deviation 5.82 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | Day 29 | -49.2 percentage change from baseline | Standard Deviation 5.4 |
Secondary
Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B
Time frame: Part B (MAD): Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365, 393, 421, 449
Population: PD Analysis Set in Part B consisted of all patients with PH1 who received at least 1 dose of study drug (lumasiran, placebo) and had at least 1 postdose blood and/or urine sample available that was evaluable for PD assessments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: SAD: Placebo | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 29 | 9.019 percentage change from baseline | — |
| Part A: SAD: Placebo | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 57 | 20.184 percentage change from baseline | Standard Deviation 23.5572 |
| Part A: SAD: Placebo | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 85 | -5.945 percentage change from baseline | — |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 197 | -8.546 percentage change from baseline | Standard Deviation 13.5672 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 421 | 7.610 percentage change from baseline | Standard Deviation 11.2195 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 281 | -14.283 percentage change from baseline | Standard Deviation 22.6126 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 225 | -18.221 percentage change from baseline | Standard Deviation 14.2322 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 253 | -5.140 percentage change from baseline | Standard Deviation 19.2839 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 85 | -13.536 percentage change from baseline | Standard Deviation 22.8679 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 393 | -11.942 percentage change from baseline | Standard Deviation 45.3027 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 113 | -14.424 percentage change from baseline | Standard Deviation 24.1107 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 365 | 2.268 percentage change from baseline | Standard Deviation 33.7565 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 141 | -8.804 percentage change from baseline | Standard Deviation 27.4802 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 57 | -8.426 percentage change from baseline | Standard Deviation 19.7271 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 169 | -19.796 percentage change from baseline | Standard Deviation 31.7492 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 337 | -5.168 percentage change from baseline | Standard Deviation 31.0756 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 29 | -6.672 percentage change from baseline | Standard Deviation 11.9614 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 309 | -0.403 percentage change from baseline | Standard Deviation 34.6839 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 449 | -15.093 percentage change from baseline | Standard Deviation 10.3705 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 29 | -0.624 percentage change from baseline | Standard Deviation 15.1771 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 57 | 4.505 percentage change from baseline | Standard Deviation 35.2457 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 85 | -3.720 percentage change from baseline | Standard Deviation 22.6231 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 113 | 3.444 percentage change from baseline | Standard Deviation 29.6749 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 141 | 9.315 percentage change from baseline | Standard Deviation 27.5044 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 169 | -8.544 percentage change from baseline | Standard Deviation 14.8481 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 197 | -13.513 percentage change from baseline | Standard Deviation 25.056 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 225 | 29.013 percentage change from baseline | Standard Deviation 53.5563 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 253 | 10.232 percentage change from baseline | Standard Deviation 24.4929 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 281 | 5.841 percentage change from baseline | Standard Deviation 13.0381 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 309 | 8.441 percentage change from baseline | Standard Deviation 11.5329 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 337 | 8.688 percentage change from baseline | Standard Deviation 24.2094 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 365 | 9.201 percentage change from baseline | Standard Deviation 14.4856 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 393 | -4.484 percentage change from baseline | Standard Deviation 12.632 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 421 | -6.498 percentage change from baseline | Standard Deviation 12.9022 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 29 | 2.748 percentage change from baseline | Standard Deviation 5.6858 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 225 | -14.964 percentage change from baseline | Standard Deviation 9.913 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 113 | 7.570 percentage change from baseline | Standard Deviation 40.5928 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 197 | 28.857 percentage change from baseline | Standard Deviation 22.1891 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 57 | 37.030 percentage change from baseline | Standard Deviation 56.121 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 169 | 20.210 percentage change from baseline | — |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 85 | -6.113 percentage change from baseline | Standard Deviation 43.5441 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B | Day 141 | -30.691 percentage change from baseline | Standard Deviation 12.8912 |
Secondary
Renal Clearance (CLR) of Lumasiran
Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups.
Time frame: Part A (SAD): Day 1: pooled urine 0-4 h, 4-8 h and 8-24 h; Part B (MAD): Part B (MAD phase): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: pooled urine 0-4 h, 4-8 h, 8-12 h and 12-24 h
Population: PK Analysis Set consisted of all healthy participants and patients who received at least 1 dose of lumasiran and had at least 1 postdose sample for PK parameters and who had evaluable PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: SAD: Placebo | Renal Clearance (CLR) of Lumasiran | Day 1 | 8.7817 L/h | — |
| Part A: SAD: Lumasiran 0.3 mg/kg | Renal Clearance (CLR) of Lumasiran | Day 1 | 5.4906 L/h | Standard Deviation 2.07402 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Renal Clearance (CLR) of Lumasiran | Day 1 | 5.8211 L/h | Standard Deviation 1.31377 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Renal Clearance (CLR) of Lumasiran | Day 1 | 6.3417 L/h | Standard Deviation 1.15497 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Renal Clearance (CLR) of Lumasiran | Day 57 | 1.9610 L/h | Standard Deviation 1.11228 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Renal Clearance (CLR) of Lumasiran | Day 1 | 2.2612 L/h | Standard Deviation 1.17616 |
| Part B: MAD: Placebo | Renal Clearance (CLR) of Lumasiran | Day 1 | 2.3818 L/h | Standard Deviation 1.13067 |
| Part B: MAD: Placebo | Renal Clearance (CLR) of Lumasiran | Day 57 | 2.5150 L/h | Standard Deviation 0.80386 |
| Part B: MAD: Lumasiran 1.0 mg/kg qM | Renal Clearance (CLR) of Lumasiran | Day 85 | 3.3663 L/h | Standard Deviation 1.18371 |
| Part B: MAD: Lumasiran 1.0 mg/kg qM | Renal Clearance (CLR) of Lumasiran | Day 1 | 2.0564 L/h | Standard Deviation 1.206 |
Secondary
Terminal Half-life (t1/2) of Lumasiran in Plasma
Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups.
Time frame: Part A (SAD): Day 1: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h; Part B (MAD): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h
Population: PK Analysis Set consisted of all healthy participants and patients who received at least 1 dose of lumasiran and had at least 1 postdose sample for PK parameters and who had evaluable PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: SAD: Placebo | Terminal Half-life (t1/2) of Lumasiran in Plasma | Day 1 | 7.0655 hours | Standard Deviation 0.37379 |
| Part A: SAD: Lumasiran 0.3 mg/kg | Terminal Half-life (t1/2) of Lumasiran in Plasma | Day 1 | 5.9798 hours | Standard Deviation 1.52471 |
| Part A: SAD: Lumasiran 1.0 mg/kg | Terminal Half-life (t1/2) of Lumasiran in Plasma | Day 1 | 3.4683 hours | — |
| Part A: SAD: Lumasiran 3.0 mg/kg | Terminal Half-life (t1/2) of Lumasiran in Plasma | Day 57 | 7.8090 hours | Standard Deviation 4.52009 |
| Part A: SAD: Lumasiran 3.0 mg/kg | Terminal Half-life (t1/2) of Lumasiran in Plasma | Day 1 | 3.2670 hours | Standard Deviation 1.52759 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Terminal Half-life (t1/2) of Lumasiran in Plasma | Day 1 | 5.4574 hours | Standard Deviation 3.49432 |
| Part A: SAD: Lumasiran 6.0 mg/kg | Terminal Half-life (t1/2) of Lumasiran in Plasma | Day 57 | 5.8356 hours | Standard Deviation 3.12156 |
| Part B: MAD: Placebo | Terminal Half-life (t1/2) of Lumasiran in Plasma | Day 85 | 4.6694 hours | — |
| Part B: MAD: Placebo | Terminal Half-life (t1/2) of Lumasiran in Plasma | Day 1 | 7.8028 hours | — |
Secondary
Time to Cmax (Tmax) of Lumasiran in Plasma
Samples for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups.
Time frame: Part A (SAD): Day 1: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h; Part B (MAD): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h
Population: PK Analysis Set consisted of all healthy participants and patients who received at least 1 dose of lumasiran and had at least 1 postdose sample for PK parameters and who had evaluable PK data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: SAD: Placebo | Time to Cmax (Tmax) of Lumasiran in Plasma | Day 1 | 5.0167 hours |
| Part A: SAD: Lumasiran 0.3 mg/kg | Time to Cmax (Tmax) of Lumasiran in Plasma | Day 1 | 1.5000 hours |
| Part A: SAD: Lumasiran 1.0 mg/kg | Time to Cmax (Tmax) of Lumasiran in Plasma | Day 1 | 3.0000 hours |
| Part A: SAD: Lumasiran 3.0 mg/kg | Time to Cmax (Tmax) of Lumasiran in Plasma | Day 1 | 7.0000 hours |
| Part A: SAD: Lumasiran 6.0 mg/kg | Time to Cmax (Tmax) of Lumasiran in Plasma | Day 57 | 3.0417 hours |
| Part A: SAD: Lumasiran 6.0 mg/kg | Time to Cmax (Tmax) of Lumasiran in Plasma | Day 1 | 3.9917 hours |
| Part B: MAD: Placebo | Time to Cmax (Tmax) of Lumasiran in Plasma | Day 1 | 4.9917 hours |
| Part B: MAD: Placebo | Time to Cmax (Tmax) of Lumasiran in Plasma | Day 57 | 2.9833 hours |
| Part B: MAD: Lumasiran 1.0 mg/kg qM | Time to Cmax (Tmax) of Lumasiran in Plasma | Day 85 | 5.9833 hours |
| Part B: MAD: Lumasiran 1.0 mg/kg qM | Time to Cmax (Tmax) of Lumasiran in Plasma | Day 1 | 9.0000 hours |