Trial Outcomes & Findings for A Study to Investigate the Effect of Hepatic Impairment on the Pharmacokinetics and Safety and Tolerability of a Single Oral Dose of Risdiplam Compared to Matched Healthy Participants With Normal Hepatic Function (NCT NCT03920865)

NCT ID: NCT03920865

Last Updated: 2021-02-21

Results Overview

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 26 participants
• Primary outcome timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
• Results posted on: 2021-02-21

Participant Flow

Participant milestones

Measure	Mild Hepatic Impairment All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 1 of the study.	Moderate Hepatic Impairment All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 2 of the study.	Normal Hepatic Function All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours. Two normal function participants were matched as controls for mild hepatic impairment participants in Part 1 only; likewise, two normal function participants were matched to moderate hepatic impairment participants in Part 2 only. Six of the normal function participants were matched to mild hepatic impairment participants in Part 1 and also to moderate impairment participants in Part 2.
Overall Study STARTED	8	8	10
Overall Study COMPLETED	8	8	10
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Study to Investigate the Effect of Hepatic Impairment on the Pharmacokinetics and Safety and Tolerability of a Single Oral Dose of Risdiplam Compared to Matched Healthy Participants With Normal Hepatic Function

Baseline characteristics by cohort

Measure	Mild Hepatic Impairment n=8 Participants All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 1 of the study.	Moderate Hepatic Impairment n=8 Participants All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 2 of the study.	Normal Hepatic Function n=10 Participants All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours. Two normal function participants were matched as controls for mild hepatic impairment participants in Part 1 only; likewise, two normal function participants were matched to moderate hepatic impairment participants in Part 2 only. Six of the normal function participants were matched to mild hepatic impairment participants in Part 1 and also to moderate impairment participants in Part 2.	Total n=26 Participants Total of all reporting groups
Age, Continuous	61.5 Years STANDARD_DEVIATION 4.0 • n=5 Participants	56.6 Years STANDARD_DEVIATION 6.3 • n=7 Participants	57.3 Years STANDARD_DEVIATION 6.8 • n=5 Participants	58.4 Years STANDARD_DEVIATION 6.1 • n=4 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants	13 Participants n=4 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants	13 Participants n=4 Participants
Race/Ethnicity, Customized Hispanic or Latino	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants	14 Participants n=4 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	5 Participants n=5 Participants	4 Participants n=7 Participants	3 Participants n=5 Participants	12 Participants n=4 Participants
Race/Ethnicity, Customized Black or African American	2 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants
Race/Ethnicity, Customized White	6 Participants n=5 Participants	7 Participants n=7 Participants	10 Participants n=5 Participants	23 Participants n=4 Participants

PRIMARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Risdiplam and Its Metabolite (M1)	792 h*ng/mL Geometric Coefficient of Variation 20.0	987 h*ng/mL Geometric Coefficient of Variation 35.2	222 h*ng/mL Geometric Coefficient of Variation 36.6	263 h*ng/mL Geometric Coefficient of Variation 44.1

PRIMARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Risdiplam and M1	773 h*ng/mL Geometric Coefficient of Variation 20.3	961 h*ng/mL Geometric Coefficient of Variation 35.9	197 h*ng/mL Geometric Coefficient of Variation 39.1	245 h*ng/mL Geometric Coefficient of Variation 47.1

PRIMARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 1: Maximum Observed Plasma Concentration (Cmax) of Risdiplam and M1	21.7 ng/mL Geometric Coefficient of Variation 23.5	22.8 ng/mL Geometric Coefficient of Variation 46.9	3.73 ng/mL Geometric Coefficient of Variation 30.4	3.92 ng/mL Geometric Coefficient of Variation 36.3

PRIMARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 2: AUCinf of Risdiplam and M1	1040 h*ng/mL Geometric Coefficient of Variation 29.2	971 h*ng/mL Geometric Coefficient of Variation 30.8	261 h*ng/mL Geometric Coefficient of Variation 23.4	275 h*ng/mL Geometric Coefficient of Variation 33.1

PRIMARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 2: AUClast of Risdiplam and M1	1020 h*ng/mL Geometric Coefficient of Variation 29.7	947 h*ng/mL Geometric Coefficient of Variation 31.2	243 h*ng/mL Geometric Coefficient of Variation 24.9	259 h*ng/mL Geometric Coefficient of Variation 33.9

PRIMARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 2: Cmax of Risdiplam and M1	29.9 ng/mL Geometric Coefficient of Variation 18.8	25.0 ng/mL Geometric Coefficient of Variation 30.2	4.10 ng/mL Geometric Coefficient of Variation 24.0	4.13 ng/mL Geometric Coefficient of Variation 22.5

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 1: Time of the Maximum Observed Plasma Concentration (Tmax) of Risdiplam and M1	4.00 hours (h) Interval 2.0 to 4.0	4.00 hours (h) Interval 2.0 to 4.0	10.00 hours (h) Interval 4.0 to 24.0	10.00 hours (h) Interval 4.0 to 24.0

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment n=7 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 1: Apparent Plasma Terminal Elimination Half-Life (t1/2) of Risdiplam and M1	41.3 h Geometric Coefficient of Variation 29.1	55.0 h Geometric Coefficient of Variation 16.2	32.9 h Geometric Coefficient of Variation 19.1	38.2 h Geometric Coefficient of Variation 18.7

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment n=7 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 1: Percentage of Area Under the Plasma Concentration-Time Curve Due to Extrapolation (%AUCextrap) of Risdiplam and M1	2.34 Percentage (%) of AUCextrap Geometric Coefficient of Variation 29.1	2.53 Percentage (%) of AUCextrap Geometric Coefficient of Variation 32.8	7.49 Percentage (%) of AUCextrap Geometric Coefficient of Variation 54.0	6.28 Percentage (%) of AUCextrap Geometric Coefficient of Variation 38.7

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment n=7 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 1: Terminal Elimination Rate Constant (λz=Lambda-Z) of Risdiplam and M1	0.0168 h-1 Geometric Coefficient of Variation 29.1	0.0126 h-1 Geometric Coefficient of Variation 16.2	0.0211 h-1 Geometric Coefficient of Variation 19.1	0.0182 h-1 Geometric Coefficient of Variation 18.7

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 1: Apparent Total Clearance (CL/F) of Risdiplam	6.31 L/h Geometric Coefficient of Variation 20.0	5.07 L/h Geometric Coefficient of Variation 35.2	—	—

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=7 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1	0.258 Ratio Geometric Coefficient of Variation 22.7	0.255 Ratio Geometric Coefficient of Variation 12.0	—	—

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1	0.165 Ratio Geometric Coefficient of Variation 29.4	0.164 Ratio Geometric Coefficient of Variation 15.5	—	—

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1	0.244 Ratio Geometric Coefficient of Variation 24.8	0.245 Ratio Geometric Coefficient of Variation 13.8	—	—

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 2: Tmax of Risdiplam and M1	2.00 hours (h) Interval 1.0 to 4.0	4.00 hours (h) Interval 1.0 to 4.0	24.00 hours (h) Interval 10.0 to 24.03	11.00 hours (h) Interval 4.0 to 24.0

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 2: t1/2 of Risdiplam and M1	45.6 h Geometric Coefficient of Variation 28.0	49.9 h Geometric Coefficient of Variation 28.1	34.5 h Geometric Coefficient of Variation 24.3	35.0 h Geometric Coefficient of Variation 21.6

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 2: %AUCextrap of Risdiplam and M1	1.90 Percentage (%) of AUCextrap Geometric Coefficient of Variation 33.5	2.41 Percentage (%) of AUCextrap Geometric Coefficient of Variation 30.5	6.58 Percentage (%) of AUCextrap Geometric Coefficient of Variation 28.8	5.68 Percentage (%) of AUCextrap Geometric Coefficient of Variation 23.6

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 2: λz of Risdiplam and M1	0.0152 h-1 Geometric Coefficient of Variation 28.0	0.0139 h-1 Geometric Coefficient of Variation 28.1	0.0201 h-1 Geometric Coefficient of Variation 24.3	0.0198 h-1 Geometric Coefficient of Variation 21.6

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 2: CL/F of Risdiplam and M1	4.79 L/h Geometric Coefficient of Variation 29.2	5.15 L/h Geometric Coefficient of Variation 30.8	—	—

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1	0.239 Ratio Geometric Coefficient of Variation 16.8	0.271 Ratio Geometric Coefficient of Variation 10.3	—	—

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1	0.131 Ratio Geometric Coefficient of Variation 16.3	0.158 Ratio Geometric Coefficient of Variation 15.0	—	—

SECONDARY outcome

Timeframe: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose

Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1	0.227 Ratio Geometric Coefficient of Variation 16.8	0.262 Ratio Geometric Coefficient of Variation 10.0	—	—

SECONDARY outcome

Timeframe: Up to 31 Days

Population: The safety population included all participants who received a dose of risdiplam.

An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

Outcome measures

Measure	Risdiplam - Mild Hepatic Impairment n=8 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam - Normal Hepatic Function n=8 Participants Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Mild Hepatic Impairment n=10 Participants Participants with mild hepatic impairment received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.	Risdiplam M1 Metabolite - Normal Hepatic Function Participants with normal hepatic function received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours.
Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) With at least one AE	62.5 Percentage of Participants	12.5 Percentage of Participants	0.0 Percentage of Participants	—
Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) With at least one SAE	0.0 Percentage of Participants	12.5 Percentage of Participants	0.0 Percentage of Participants	—

Adverse Events

Mild Hepatic Impairment

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Moderate Hepatic Impairment

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Normal Hepatic Function

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Measure	Mild Hepatic Impairment n=8 participants at risk All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 1 of the study.	Moderate Hepatic Impairment n=8 participants at risk All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 2 of the study.	Normal Hepatic Function n=10 participants at risk All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours. Two normal function participants were matched as controls for mild hepatic impairment participants in Part 1 only; likewise, two normal function participants were matched to moderate hepatic impairment participants in Part 2 only. Six of the normal function participants were matched to mild hepatic impairment participants in Part 1 and also to moderate impairment participants in Part 2.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/8 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.	12.5% 1/8 • Number of events 1 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.	0.00% 0/10 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.

Other adverse events

Measure	Mild Hepatic Impairment n=8 participants at risk All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 1 of the study.	Moderate Hepatic Impairment n=8 participants at risk All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 2 of the study.	Normal Hepatic Function n=10 participants at risk All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours. Two normal function participants were matched as controls for mild hepatic impairment participants in Part 1 only; likewise, two normal function participants were matched to moderate hepatic impairment participants in Part 2 only. Six of the normal function participants were matched to mild hepatic impairment participants in Part 1 and also to moderate impairment participants in Part 2.
Gastrointestinal disorders Vomiting	25.0% 2/8 • Number of events 2 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.	0.00% 0/8 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.	0.00% 0/10 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.
Ear and labyrinth disorders Ear pain	12.5% 1/8 • Number of events 1 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.	0.00% 0/8 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.	0.00% 0/10 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.
Gastrointestinal disorders Diarrhoea	12.5% 1/8 • Number of events 1 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.	0.00% 0/8 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.	0.00% 0/10 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.
Gastrointestinal disorders Dyspepsia	12.5% 1/8 • Number of events 1 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.	0.00% 0/8 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.	0.00% 0/10 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.
General disorders Chest discomfort	12.5% 1/8 • Number of events 1 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.	0.00% 0/8 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.	0.00% 0/10 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.
Skin and subcutaneous tissue disorders Pruritus	12.5% 1/8 • Number of events 1 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.	0.00% 0/8 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.	0.00% 0/10 • Up to 31 days post-dose The safety population included all participants who received a dose of risdiplam.

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800 821-8590

Email: genentech@druginfo.com

Results disclosure agreements

• Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights
• Publication restrictions are in place

Restriction type: OTHER