Study of Lademirsen (SAR339375) in Patients With Alport Syndrome

Annualized change in eGFR was calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation (for participants with age greater than 16 years) as: eGFR=142\*min(Scr/K, 1)α\*max(Scr/K, 1)\^-1.200\*0.9938\^Age\*1.012 \[if female\], where Scr = serum creatinine in milligrams per deciliter (mg/dL), K = 0.7 for females (F) and 0.9 for males (M), α = -0.241(F) and -0.302(M); age=years, calculated at time of creatinine measurement. eGFR measurements collected from baseline to Week 48 were the response variable and included fixed effects of treatment (lademirsen or placebo), screening eGFR stratification factor (less than \[\<\]60 versus greater than or equal to \[\>=\]60 milliliters per minute per 1.73 meters squared \[mL/min/1.73 m\^2\]), time, and treatment-by-time interaction. Least square (LS) mean and standard error (SE) estimated by linear mixed effect model.

Time frame: Baseline, Week 48

Population: Analysis was performed on primary population that included all randomized participants who completed the double-blinded period (the first 48 weeks) or discontinued double-blinded period early.

Adverse event (AE): any untoward medical occurrence in a participant who received study drug and did not necessarily had to have a causal relationship with the treatment. Serious adverse event (SAE) was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs: AEs with onset after the first dose of investigational medicinal product (IMP) or existing AEs that worsened during TEAE Period (for DB Period: from first IMP administration up to first administration in OLE period for participant who entered OLE period; and up to 7 days post last IMP administration for participant not continuing OLE period; for open-label: time from 1st IMP administration in open-label to last IMP administration+ 10 weeks).

Time frame: DB: from 1st dose of IMP upto 1st dose of IMP in OLE for participant who entered OLE (Week 48); up to 7 days post last dose for participant not continuing to OLE (Week 49); OLE:1st dose of IMP (at Week 48) in OLE upto 10 weeks post last dose (Week 106)

Population: Analysis was performed on safety population that included all participants who received at least one dose or partial of a dose of the IMP, analyzed according to the treatment actually received.

eGFR was used to measure level of kidney function and determine the stage of kidney disease. eGFR was calculated using CKD-EPI Creatinine Equation as: eGFR =142\*min (Scr/K, 1) α\*max (Scr/K, 1)\^-1.200\*0.9938\^Age\*1.012 \[if female\], where Scr was serum creatinine in mg/dL, K is 0.7 for females and 0.9 for males, α was -0.241 for females and -0.302 for males. Unit of age was years, calculated to reflect the age at the time when creatinine was measured.

Time frame: Baseline, Weeks 24 and 48

Population: Analysis was performed on Intent-to-Treat (ITT) population that included all randomized participants analyzed according to the treatment group allocated by randomization. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Creatinine was the supportive biomarker assessed during the study. Change from Baseline in blood creatinine values at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Cystatine C was the supportive biomarker assessed during the study. Change from Baseline in blood cystatine C values at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Blood Lipocalin-2 was the supportive biomarker assessed during the study. Change from Baseline in blood lipocalin-2 at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Transforming growth factor beta 1 was the supportive biomarker assessed during the study. Change from Baseline in blood transforming growth factor beta 1 values at Week 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

BUN was the supportive biomarker assessed during the study. Change from Baseline in BUN at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Circulating microRNA-21 were the supportive biomarkers assessed in study.

Time frame: Baseline, Weeks 24 and 48

Population: Data for this outcome measure could not be analyzed and reported as the samples for circulating microRNA-21 at the predefined timepoints, Weeks 24 and 48 were not collected and analyzed due to early study termination.

Urine albumin and creatinine were the supportive biomarker assessed during the study. Change from Baseline in urine albumin to creatinine ratio at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Creatinine was the supportive biomarker assessed during the study. Change from Baseline in urine creatinine values at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Cystatin C and Creatinine were the supportive biomarker assessed during the study. Change from Baseline in urine cystatin C to creatinine ratio at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

EGF and creatinine were the supportive biomarker assessed during the study. Change from Baseline in urine EGF to creatinine ratio at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Lipocalin-2 and Creatinine were the supportive biomarker assessed during the study. Change from Baseline in urine lipocalin-2 to creatinine ratio at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Urine protein and creatinine were the supportive biomarker assessed during the study. Change from Baseline in urine protein to creatinine ratio at Weeks 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Transforming growth factor beta 1 and creatinine were the supportive biomarker assessed during the study. Change from Baseline in urine transforming growth factor beta 1 to creatinine ratio at Week 24 and 48 was reported in this outcome measure.

Time frame: Baseline, Weeks 24 and 48

Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

ESRD was defined as: eGFR \<=15 mL/min/1.73 m\^2; or initiation of hemodialysis; or receiving a renal transplantation during the double-blind treatment period.

Time frame: From Baseline up to Week 48

Population: Analysis was performed on ITT population.

Estimated glomerular filtration rate was used to measure level of kidney function and determine the stage of kidney disease. eGFR was calculated using CKD-EPI Creatinine Equation as: eGFR = 142\*min(Scr/K,1)α\*max(Scr/K,1)\^-1.200\*0.9938\^Age\*1.012 \[if female\], where Scr was serum creatinine in mg/dL, K is 0.7 for females and 0.9 for males, α was -0.241 for females and -0.302 for males. Number of participants with a reduction from baseline in eGFR value of \<10%, \<20%, \<30%, or \<40% at Weeks 24 and 48 were reported in this outcome measure.

Time frame: At Weeks 24 and 48

Population: Analysis was performed on ITT population. Here, 'number analyzed' = participants considered for the analysis for each specified category.

Criteria for potentially clinically significant ECG abnormalities: HR: \<50 bpm; \<50 bpm and DFB \>=20 bpm; \<40 bpm; \<40 bpm and DFB \>=20 bpm; \<30 bpm; \<30 bpm and DFB \>=20 bpm; \>90 bpm; \>=90 bpm and IFB \>=20 bpm; \>100 bpm; \>=100bpm and IFB \>=20 bpm; \>120 bpm; \>=120 bpm and IFB \>=20 bpm; PR Interval: \>200 millisecond(ms); \>200 ms and IFB \>=25%; \>220 ms; \>220 ms and IFB \>=25%; \>240 ms; \>240 ms and IFB\>=25%; QRS Interval: \>110 ms; \>110 ms and IFB \>=25%; \>120 ms; \>120 ms and IFB \>=25%; QT Interval: \>500 ms and QTc Fridericia (QTc F): \>450 ms; \>480 ms; \>500 ms; IFB \>30 and \<=60 ms; IFB \>60 ms.

Time frame: From Baseline up to Week 48

Population: Analysis was performed on safety population.

Criteria for potentially clinically significant vital sign abnormalities: Systolic blood pressure (SBP):\<=95 mmHg and DFB \>=20 mmHg; \>=160 mmHg and increase from baseline (IFB) \>=20 mmHg; SBP (Orthostatic): \<=-20mmHg; Diastolic blood pressure (DBP): \<=45 mmHg and DFB \>=10 mmHg; \>=110 mmHg and IFB \>=10 mmHg; DBP (Orthostatic): \<=10 mmHg; heart rate (HR): \<=50 beats per minute (bpm) and DFB \>=20 bpm; \>=120 bpm and IFB\>=20 bpm and Weight: \>=5% DFB; \>=5% IFB.

Time frame: From Baseline up to Week 48

Population: Analysis was performed on safety population.

Criteria for PCSA: Total bilirubin (TBILI): \>1.5 upper limit of normal (ULN); \>2 ULN; Alanine Aminotransferase (ALT): \>3 ULN; \>5 ULN; \>10 ULN; \>20 ULN; Aspartate aminotransferase (AST): \>3ULN; \>5 ULN; \>10 ULN; \>20 ULN; Alkaline phosphatase: \>1.5 ULN; ALT\>3 ULN and TBILI\>2 ULN and Direct Bilirubin\> 35% TBILI and TBILI\> 1.5 ULN.

Time frame: From Baseline up to Week 48

Population: Analysis was performed on safety population.

Criteria for PCSA included: Hemoglobin (Hb): \<= 115 grams per liter (g/L) (Male), \<= 95 g/L (Female); greater than or equal to (\>=) 185 g/L (18.5 g/dL) (Male), \>= 165 g/L (16.5g/dL) (Female); decrease from Baseline (DFB) = 20 g/L (2g/dL); Hematocrit: \<= 0.37 volume/volume (v/v) (Male); \<= 0.32 v/v (Female); \>= 0.55 v/v (Male); \>= 0.5 v/v (Female); Red Blood Cells (RBCs):\>=6 Tera/ liter (L) and Platelets: \<100 Giga/L; \>= 700 Giga/L.

Time frame: From Baseline up to Week 48

Population: Analysis was performed on safety population.

Criteria for potentially clinically significant abnormalities: Creatinine: \>=150 micromol/L (adults); \>=30% change from baseline, \>=100% change from baseline; Blood urea nitrogen: \>=17 millimoles per liter (mmol/L); Uric acid: \<120 micromol/L; \>408 micromol/L; Creatinine clearance: \<15 mL/min; \>=15 to \<30 mL/min; \>=30 to \<60 mL/min; \>=60 to \<90 mL/min; \>=90 mL/min; eGFR: \< 15 mL/min/1.73m\^2; \>=15 to \<30 mL/min/1.73m\^2; \>=30 to \<60 mL/min/1.73m\^2; \>=60 to \<90 mL/min/1.73m\^2; \>=90 mL/min. Participants might be counted more than once for specified categories.

Time frame: From Baseline up to Week 48

Population: Analysis was performed on safety population.

TEAEs: AE developed/worsened/became serious during TEAE period (from first IMP administration in DB period to first administration in OLE period for those who entered OLE (i.e., up to W48), up to 7 days post last dose for those not continuing to OLE period (i.e., up to W49). TESAEs: any untoward medical occurrence that resulted in death, was life-threatening, required inpatient hospitalization/prolongation of hospitalization, resulted in persistent/significant disability, was a congenital anomaly/birth defect, or a medically important event. ADA response was categorized as treatment-induced (participant whose ADA status was positive \[ADA titer value \>=50\] anytime post-baseline and was negative/missing at baseline), treatment-boosted (participant whose ADA status was positive at baseline & ADA titer level anytime post-baseline was significantly higher). In this outcome measure, number of participants with TEAEs as per ADA responses (positive or negative) were reported.

Time frame: From first IMP administration (Day 1) up to first administration in OLE period for participant who entered OLE period (i.e., up to W48) & up to 7 days post last IMP administration for participant not continuing OLE period (i.e., up to W49)

Population: Analysis was performed on ADA population. For this outcome measure analysis was done separately for TE-ADA positive and negative participants for placebo and lademirsen arms respectively. Here, 0 in the overall number of participants analyzed signifies that no participants had ADA positive response in the placebo arm.

ADA responses were categorized as: treatment-induced, and treatment-boosted response. Participant whose ADA status was negative at baseline but positive (ADA titer value \>=50) anytime post-baseline or missing at baseline was considered to have treatment-induced ADA. Participant whose ADA status was positive at baseline (pre-existing ADA) and the ADA titer level anytime post-baseline was significantly higher (\>= twice the minimum required dilution) than that at baseline was considered to have treatment-boosted ADA.

Time frame: From first IMP administration (Day 1) up to first administration in OLE period for participant who entered OLE period (i.e., up to W48) & up to 7 days post last IMP administration for participant not continuing OLE period (i.e., up to W49)

Population: Analysis was performed on ADA population that included all randomized participants who received at least one dose of study drugs and had at least one post-baseline ADA sample.

eGFR was used to measure level of kidney function and determine the stage of kidney disease. eGFR was calculated using CKD-EPI Creatinine Equation as: eGFR =142\*min (Scr/K, 1) α\*max (Scr/K, 1)\^-1.200\*0.9938\^Age\*1.012 \[if female\], where Scr was serum creatinine in mg/dL, K is 0.7 for females and 0.9 for males, α was -0.241 for females and -0.302 for males. Unit of age was years, calculated to reflect the age at the time when creatinine was measured.

Time frame: Baseline, Weeks 24 and 48

Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category.

Post-dose (4 hours) plasma concentration of lademirsen, its active major metabolite (RG0005), and SUM (lademirsen+RG0005) on Day 1, and at Weeks 24 and 48 are reported in the outcome measure. 4-hour SUM concentrations are calculated values (sum of measured lademirsen+RG0005).

Time frame: Post-dose (4 hours) on Day 1, Weeks 24 and 48

Population: Analysis was performed on PK population that included all participants who received at least one dose of IMP and had at least one post-dose PK sample. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category. Data for this outcome measure was not planned to be collected and analyzed for placebo arm.

Ctrough was measured from the pre-dose (up to 4 hours before study drug administration) plasma samples collected at Weeks 4, 12, 24, 36 and 48. SUM concentrations (lademirsen+RG0005) are measured values (assay measures lademirsen+ RG0005).

Time frame: Pre-dose (up to 4 hours before study drug administration) on Weeks 4, 12, 24, 36 and 48

Population: Analysis was performed on PK population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category. Data for this outcome measure was not planned to be collected and analyzed for placebo arm.