Study of Lumasiran in Healthy Adults and Patients With Primary Hyperoxaluria Type 1

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1/2, Single-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Safety, Tolerability, Pharmacokinetic and Pharmacodynamics Study of Subcutaneously Administered ALN-GO1 in Healthy Adult Subjects, and Patients With Primary Hyperoxaluria Type 1

Conditions
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Primary Hyperoxaluria Type 1 (PH1)

Intervention / Treatment
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* Drug: Lumasiran
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part A: SAD: Placebo<br>A single dose of matching placebo will be administered subcutaneously (SC). | Drug: Placebo<br>* 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).<br>|
| Experimental: Part A: SAD: Lumasiran 0.3 mg/kg<br>A single dose of 0.3 mg/kg lumasiran will be administered SC. | Drug: Lumasiran<br>* 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).<br>* Other names: ALN-GO1;|
| Experimental: Part A: SAD: Lumasiran 1.0 mg/kg<br>A single dose of 1.0 mg/kg lumasiran will be administered SC. | Drug: Lumasiran<br>* 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).<br>* Other names: ALN-GO1;|
| Experimental: Part A: SAD: Lumasiran 3.0 mg/kg<br>A single dose of 3.0 mg/kg lumasiran will be administered SC. | Drug: Lumasiran<br>* 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).<br>* Other names: ALN-GO1;|
| Experimental: Part A: SAD: Lumasiran 6.0 mg/kg<br>A single dose of 6.0 mg/kg lumasiran will be administered SC. | Drug: Lumasiran<br>* 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).<br>* Other names: ALN-GO1;|
| Placebo Comparator: Part B: MAD: Placebo<br>Participants with primary hyperoxaluria type 1 (PH1) will be 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 will cross over to their respective Part B lumasiran arms in the Part B: MAD Study Day 85-End of Study Period and will then be treated with lumasiran. The estimated total time on study was up to 546 days. | Drug: Placebo<br>* 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).<br>|
| Experimental: Part B: MAD: Lumasiran 1.0 mg/kg qM<br>Participants with PH1 will be treated with 1.0 mg/kg lumasiran SC once monthly (qM) on Days 1, 29 and 57. The estimated total time on study is up to 546 days. One participant from the Part B: MAD: Placebo arm will cross over to this lumasiran arm at Day 85. For this participant treatment with lumasiran starts at Day 85. | Drug: Lumasiran<br>* 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).<br>* Other names: ALN-GO1;|
| Experimental: Part B: MAD: Lumasiran 3.0 mg/kg qM<br>Participants with PH1 will be treated with 3.0 mg/kg lumasiran SC qM on Days 1, 29 and 57. The estimated total time on study is up to 546 days. One participant from the Part B: MAD: Placebo arm will cross over to this lumasiran arm at Day 85. For this participant treatment with lumasiran starts at Day 85. | Drug: Lumasiran<br>* 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).<br>* Other names: ALN-GO1;|
| Experimental: Part B: MAD: Lumasiran 3.0 mg/kg q3M<br>Participants with PH1 will be treated with 3.0 mg/kg lumasiran SC once every three months (q3M) on Days 1 and 85. The estimated total time on study is up to 546 days. One participant from the Part B: MAD: Placebo arm will cross over to this lumasiran arm at Day 85. For this participant treatment with lumasiran starts at Day 85. | Drug: Lumasiran<br>* 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).<br>* Other names: ALN-GO1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Part A (SAD): Up to 405 days; Part B (MAD): Up to 546 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | Part A (SAD): Baseline, Part B (MAD): Baseline | 
| 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. | Part A (SAD): Days 15, 29, 57 and 85; Part B (MAD): Days 15, 29, 57, 85 | 
| Baseline Spot Urine Glycolate:Creatinine Ratio in Part A | The endpoint was only measured in Part A. | Part A (SAD): Baseline | 
| Percentage Change From Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A | The endpoint was only measured in Part A. | Part A (SAD): Days 29 and 57 | 
| Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | The endpoint was only measured in Part B. | Part B (MAD): Baseline | 
| Percentage Change From Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B | The endpoint was only measured in Part B. | Part B (MAD): 24 hour urine collections on Days 29, 57, 85, 113, 141, 169, 197 | 
| 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. | Part B (MAD): Baseline | 
| 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. | Part B (MAD): 24 hour urine collections on Days 29, 57 and 85 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AGT, PH1, Primary Hyperoxaluria, RNAi therapeutic, siRNA