Healthy Participants
Conditions
Brief summary
To evaluate the safety and tolerability of single and multiple ascending doses of oral RO7020531 in Chinese healthy participants.
Interventions
DRUGRO7020531
4 SAD Cohorts with individual dosages of 40, 100, 140 and 170 mg hard capsules and 3 MAD Cohorts with dosages of 100 and 150mg hard capsules, will be administered orally as per the dosing schedules described above.
DRUGPlacebo
Placebo hard capsules will be administered orally as per the dosing schedules described above.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Chinese healthy male and female participants. Healthy status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, hematology, blood chemistry, and urinalysis. * A Body Mass Index (BMI) of 19 to less than 28 kg/m2 and a body weight of at least 45 kg. * Negative anti-nuclear antibody (ANA) test; or positive with dilutions not greater than 1:40 and with no associated history or symptoms of potential connective tissue disease or other immune-mediated diseases. * Women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods. * Men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and refrain from donating sperm. * Negative pregnancy test on Day -1 for female participants. * Non-smokers, or use of \< 10 cigarettes (or equivalent nicotine-containing product) per day.
Exclusion criteria
* Pregnant (positive pregnancy test) or lactating women, and male partners of women who are pregnant or lactating. * History of immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis, rheumatoid arthritis, multiple sclerosis, or any other autoimmune disease). * History or symptoms of any clinically significant disease including (but not limited to), neurological, cardiovascular, endocrine, respiratory, hepatic, ocular, or renal disorder (as per Investigator's judgment). * Personal or family history of congenital long QT syndrome or sudden cardiac death. * Evidence of an active or suspected cancer or a history of malignancy, where in the Investigator's opinion, there is a risk of recurrence. * History of having received or currently receiving any systemic anti-neoplastic (including radiation) or immune-modulatory treatment (including systemic oral or inhaled corticosteroids, IFN or PEG-IFN) within 6 months prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study. Eye drop-containing and infrequent inhaled corticosteroids are permissible up to 4 weeks prior to the first dose of study drug. * History of clinically significant thyroid disease; also, subjects with clinically significant elevated thyroid-stimulating hormone (TSH) concentrations at Screening. * Any confirmed clinically significant allergic reactions (anaphylaxis) against any drug, or multiple drug allergies (non-active hay fever is acceptable). * Abnormal renal function. * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values at Screening above ULN and judged clinically significant by the Investigator. * Positive results for anti-mitochondrial antibody (AMA), anti-smooth muscle antibody (ASMA) or thyroid peroxidase antibody. * Positive hepatitis A IgM antibody (HAV Ab IgM), hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or positive for human immunodeficiency virus (HIV) at Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events (AEs) | Screening up until 28 days after the last dose of study drug (up to 1 year). | An Adverse Event (AE) is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, any new disease or exacerbation of an existing disease, recurrence of an intermittent medical condition, any deterioration in a laboratory value or other clinical test or adverse events that are related to a protocol-mandated intervention, including those that occur prior to assignment of study treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | SAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48 hours (h) Post-dose Days 1, 2; MAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24h Post-dose Days 1, 2 and Days 13, 14; Pre-dose, 2, 6, 24hr Post-dose Days 3, 5, 7, 9 and 11. | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for AUClast will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and SAD Cohorts (1-4) (on Day 13). |
| Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | SAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48 hours (h) Post-dose Days 1, 2; MAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24h Post-dose Days 1, 2 and Days 13, 14; Pre-dose, 2, 6, 24hr Post-dose Days 3, 5, 7, 9 and 11. | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for AUCinf will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and SAD Cohorts (1-4) (on Day 13). Due to insufficient plasma concentration data for RO7020531 and RO7033805, AUCinf for these 2 compounds could not be estimated. |
| Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | SAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48 hours (h) Post-dose Days 1, 2; MAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24h Post-dose Days 1, 2 and Days 13, 14; Pre-dose, 2, 6, 24hr Post-dose Days 3, 5, 7, 9 and 11. | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Median and Full Range) for Tmax will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and SAD Cohorts (1-4) (on Day 13). |
| Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | SAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48 hours (h) Post-dose Days 1, 2; MAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24h Post-dose Days 1, 2 and Days 13, 14; Pre-dose, 2, 6, 24hr Post-dose Days 3, 5, 7, 9 and 11. | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for t1/2 will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and SAD Cohorts (1-4) (on Day 13). Due to insufficient plasma concentration data for RO7020531 and RO7033805, t1/2 for these 2 compounds could not be estimated. |
| Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | SAD: Pre-dose, 0-4, 4-8, 8-12, 12-24h Day 1 | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for Total Amount Excreted, will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and MAD Cohorts (1-4). |
| Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | SAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48 hours (h) Post-dose Days 1, 2; MAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24h Post-dose Days 1, 2 and Days 13, 14; Pre-dose, 2, 6, 24hr Post-dose Days 3, 5, 7, 9 and 11. | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for Cmax will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and SAD Cohorts (1-4) (on Day 13). |
| Renal Clearance of RO7020531, RO7011785, RO7018822 and RO7033805 | SAD: Pre-dose, 0-4, 4-8, 8-12, 12-24h Day 1 | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for Renal Clearance will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and MAD Cohorts (1-4). Due to insufficient urine concentration data for RO7020531 and RO7033805, Renal Clearance for these 2 compounds could not be estimated. |
| Mean Concentrations of Protein and Metabolite Markers of Humoral Response | SAD: Day -1, Pre-dose, 2, 6, 12, 24h Post-dose Day 1 to Day 2, 3, 5, 8; MAD: Day -1, Pre-dose 2, 6, 12, 24h Post-dose Day 1 to Day 2, Pre-dose, 2, 6, 24h Post-dose Days 3, 5, 7, 13 and 20 | Protein and metabolite markers of humoral response include interferon (IFN)-alfa, IP-10, Tumor Necrosis Factor (TNF)-alfa, interleukin (IL)-6, IL-10, IL-12p40 and Neopterin. Summary descriptive statistics will be presented for the induction of cytokines, chemokines and neopterin and of interferon-response genes separately by treatment arm. Only mean concentrations were collected for IFN-alfa and hence why this data is only presented below. |
| Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | SAD: Day -1, Pre-dose, 2, 6, 12, 24, 48 (only Neopterin), 96h (only Neopterin), Post-dose Day 1 to Day 2, 3, 5, 8; MAD: Day -1, Pre-dose 2, 6, 12, 24h Post-dose Day 1 to Day 2, Pre-dose, 2, 6, 24h Post-dose Days 3, 5, 7, 13 and 20 | Protein and metabolite markers of humoral response include interferon (IFN)-alfa, IP-10, Tumor Necrosis Factor (TNF)-alfa, interleukin (IL)-6, IL-10, IL-12p40 and Neopterin. Summary descriptive statistics will be presented for the induction of cytokines, chemokines and neopterin and of interferon-response genes separately by treatment arm. Mean fold change data is presented below. |
| Mean Fold Changes of Markers of Transcriptional Responses | SAD: Day -1, Pre-dose, 2, 6, 12, 24h Post-dose Day 1 to Day 2 and Day 8; MAD: Day -1, Pre-dose 2, 6, 12, 24h Post-dose Day 1 to Day 2, Pre-dose, 2, 6, 24h Post-dose Days 3, 5, 7, 13 and 20 | Markers of transcriptional responses includes ISG15, OAS-1, MX1 and Toll-Like Receptor (TLR)7. Summary descriptive statistics will be presented for these markers separately by treatment arm. |
| Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | SAD: Pre-dose, 0-4, 4-8, 8-12, 12-24h Day 1 | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for Fraction Excreted (Molecular Weight corrected) will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and MAD Cohorts (1-4). |
Countries
Hong Kong
Participant flow
Recruitment details
The study was conducted at 1 Center in China.
Pre-assignment details
A total of 70 Healthy Male and Female Chinese Participants were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Single Ascending Dose (SAD): Placebo In SAD Cohorts 1-4, there will be eight participants in total receiving placebo, two in each cohort. | 8 |
| SAD: Cohort 1 Eight participants will be administered 40mg RO7020531 orally on Day 1. | 8 |
| SAD: Cohort 2 Eight participants will be administered 100mg RO7020531 orally on Day 1. | 8 |
| SAD: Cohort 3 Eight participants will be administered 140mg RO7020531 orally on Day 1. | 8 |
| SAD: Cohort 4 Eight participants will be administered 170mg RO7020531 orally on Day 1. | 8 |
| Multiple Ascending Dose (MAD): Placebo In MAD Cohorts 1-3, there will be six participants in total receiving placebo, two in each cohort. | 6 |
| MAD: Cohort 1 Eight participants will be administered 100mg RO7020531 orally on Day 1 and every other day (QOD) for 14 days. | 8 |
| MAD: Cohorts 2 and 3 Sixteen participants will be administered 150mg RO7020531 orally on Day 1 and every other day (QOD) for 14 days. | 16 |
| Total | 70 |
Baseline characteristics
| Characteristic | Single Ascending Dose (SAD): Placebo | SAD: Cohort 1 | SAD: Cohort 2 | SAD: Cohort 3 | SAD: Cohort 4 | Multiple Ascending Dose (MAD): Placebo | MAD: Cohort 1 | MAD: Cohorts 2 and 3 | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 26.25 Years STANDARD_DEVIATION 6.65 | 25.25 Years STANDARD_DEVIATION 7.67 | 24.13 Years STANDARD_DEVIATION 8.58 | 23.00 Years STANDARD_DEVIATION 3.66 | 26.75 Years STANDARD_DEVIATION 9.44 | 22.50 Years STANDARD_DEVIATION 3.02 | 25.75 Years STANDARD_DEVIATION 8.24 | 23.19 Years STANDARD_DEVIATION 3.37 | 24.50 Years STANDARD_DEVIATION 6.37 |
| Race/Ethnicity, Customized Asian | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 6 Participants | 8 Participants | 16 Participants | 70 Participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 1 Participants | 4 Participants | 2 Participants | 2 Participants | 4 Participants | 3 Participants | 25 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 7 Participants | 4 Participants | 6 Participants | 4 Participants | 4 Participants | 13 Participants | 45 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 |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 6 | 0 / 8 | 0 / 16 |
| other Total, other adverse events | 3 / 8 | 3 / 8 | 2 / 8 | 4 / 8 | 7 / 8 | 6 / 6 | 8 / 8 | 15 / 16 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 1 / 8 | 0 / 6 | 0 / 8 | 0 / 16 |
Outcome results
Primary
Percentage of Participants With Adverse Events (AEs)
An Adverse Event (AE) is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, any new disease or exacerbation of an existing disease, recurrence of an intermittent medical condition, any deterioration in a laboratory value or other clinical test or adverse events that are related to a protocol-mandated intervention, including those that occur prior to assignment of study treatment.
Time frame: Screening up until 28 days after the last dose of study drug (up to 1 year).
Population: The Safety Population was defined as all Healthy Volunteers who have received at least one dose of the study medication, whether prematurely withdrawn from the study or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Ascending Dose (SAD): Placebo | Percentage of Participants With Adverse Events (AEs) | 37.5 Percentage of Participants |
| SAD: Cohort 1 | Percentage of Participants With Adverse Events (AEs) | 37.5 Percentage of Participants |
| SAD: Cohort 2 | Percentage of Participants With Adverse Events (AEs) | 25.0 Percentage of Participants |
| SAD: Cohort 3 | Percentage of Participants With Adverse Events (AEs) | 50.0 Percentage of Participants |
| SAD: Cohort 4 | Percentage of Participants With Adverse Events (AEs) | 100 Percentage of Participants |
| Multiple Ascending Dose (MAD): Placebo | Percentage of Participants With Adverse Events (AEs) | 100 Percentage of Participants |
| MAD: Cohort 1 | Percentage of Participants With Adverse Events (AEs) | 100 Percentage of Participants |
| MAD: Cohorts 2 and 3 | Percentage of Participants With Adverse Events (AEs) | 93.8 Percentage of Participants |
Secondary
Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805)
Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for AUCinf will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and SAD Cohorts (1-4) (on Day 13). Due to insufficient plasma concentration data for RO7020531 and RO7033805, AUCinf for these 2 compounds could not be estimated.
Time frame: SAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48 hours (h) Post-dose Days 1, 2; MAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24h Post-dose Days 1, 2 and Days 13, 14; Pre-dose, 2, 6, 24hr Post-dose Days 3, 5, 7, 9 and 11.
Population: The PK analysis population included all healthy volunteers randomised and adherent to the protocol. Participants were excluded if they significantly violated the inclusion/exclusion criteria, deviated significantly from the protocol or if data were unavailable or incomplete. Data presented is only for participants included in the actual analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Ascending Dose (SAD): Placebo | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 58.5 hr*ng/ml | Standard Deviation 22.8 |
| Single Ascending Dose (SAD): Placebo | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 714 hr*ng/ml | Standard Deviation 154 |
| SAD: Cohort 1 | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 111 hr*ng/ml | Standard Deviation 29.6 |
| SAD: Cohort 1 | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 1670 hr*ng/ml | Standard Deviation 229 |
| SAD: Cohort 2 | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 2510 hr*ng/ml | Standard Deviation 549 |
| SAD: Cohort 2 | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 204 hr*ng/ml | Standard Deviation 80.6 |
| SAD: Cohort 3 | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 245 hr*ng/ml | Standard Deviation 133 |
| SAD: Cohort 3 | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 2720 hr*ng/ml | Standard Deviation 467 |
| SAD: Cohort 4 | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7011785) | 1660 hr*ng/ml | Standard Deviation 311 |
| SAD: Cohort 4 | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7018822) | 177 hr*ng/ml | Standard Deviation 115 |
| SAD: Cohort 4 | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 241 hr*ng/ml | Standard Deviation 135 |
| SAD: Cohort 4 | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 1880 hr*ng/ml | Standard Deviation 333 |
| Multiple Ascending Dose (MAD): Placebo | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7011785) | 2510 hr*ng/ml | Standard Deviation 523 |
| Multiple Ascending Dose (MAD): Placebo | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 2660 hr*ng/ml | Standard Deviation 389 |
| Multiple Ascending Dose (MAD): Placebo | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 214 hr*ng/ml | Standard Deviation 58.7 |
| Multiple Ascending Dose (MAD): Placebo | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7018822) | 189 hr*ng/ml | Standard Deviation 52.4 |
| Unknown | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7033805) | — hr*ng/ml | — |
| Unknown | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7033805) | — hr*ng/ml | — |
| Unknown | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7020531) | — hr*ng/ml | — |
| Unknown | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7020531) | — hr*ng/ml | — |
Secondary
Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805)
Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for AUClast will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and SAD Cohorts (1-4) (on Day 13).
Time frame: SAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48 hours (h) Post-dose Days 1, 2; MAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24h Post-dose Days 1, 2 and Days 13, 14; Pre-dose, 2, 6, 24hr Post-dose Days 3, 5, 7, 9 and 11.
Population: The PK analysis population included all healthy volunteers randomised and adherent to the protocol. Participants were excluded if they significantly violated the inclusion/exclusion criteria, deviated significantly from the protocol or if data were unavailable or incomplete. Data presented is only for participants included in the actual analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Ascending Dose (SAD): Placebo | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 57.9 hr*ng/ml | Standard Deviation 22.8 |
| Single Ascending Dose (SAD): Placebo | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 707 hr*ng/ml | Standard Deviation 155 |
| Single Ascending Dose (SAD): Placebo | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7020531) | 0.00 hr*ng/ml | Standard Deviation 0 |
| Single Ascending Dose (SAD): Placebo | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7033805) | 0.00 hr*ng/ml | Standard Deviation 0 |
| SAD: Cohort 1 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7020531) | 0.00 hr*ng/ml | Standard Deviation 0 |
| SAD: Cohort 1 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 109 hr*ng/ml | Standard Deviation 29.7 |
| SAD: Cohort 1 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7033805) | 0.00 hr*ng/ml | Standard Deviation 0 |
| SAD: Cohort 1 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 1660 hr*ng/ml | Standard Deviation 229 |
| SAD: Cohort 2 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 199 hr*ng/ml | Standard Deviation 78.9 |
| SAD: Cohort 2 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7020531) | 0.02 hr*ng/ml | Standard Deviation 0.05 |
| SAD: Cohort 2 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 2500 hr*ng/ml | Standard Deviation 550 |
| SAD: Cohort 2 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7033805) | 0.02 hr*ng/ml | Standard Deviation 0.05 |
| SAD: Cohort 3 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 250 hr*ng/ml | Standard Deviation 125 |
| SAD: Cohort 3 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7033805) | 0.00 hr*ng/ml | Standard Deviation 0 |
| SAD: Cohort 3 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 2700 hr*ng/ml | Standard Deviation 467 |
| SAD: Cohort 3 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7020531) | 0.00 hr*ng/ml | Standard Deviation 0 |
| SAD: Cohort 4 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7011785) | 1650 hr*ng/ml | Standard Deviation 313 |
| SAD: Cohort 4 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 235 hr*ng/ml | Standard Deviation 125 |
| SAD: Cohort 4 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7018822) | 169 hr*ng/ml | Standard Deviation 98.8 |
| SAD: Cohort 4 | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 1870 hr*ng/ml | Standard Deviation 333 |
| Multiple Ascending Dose (MAD): Placebo | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7011785) | 2550 hr*ng/ml | Standard Deviation 521 |
| Multiple Ascending Dose (MAD): Placebo | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 2650 hr*ng/ml | Standard Deviation 389 |
| Multiple Ascending Dose (MAD): Placebo | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 211 hr*ng/ml | Standard Deviation 58.5 |
| Multiple Ascending Dose (MAD): Placebo | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7020531) | 0.92 hr*ng/ml | — |
| Multiple Ascending Dose (MAD): Placebo | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7018822) | 184 hr*ng/ml | Standard Deviation 51 |
| Multiple Ascending Dose (MAD): Placebo | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7033805) | 0.14 hr*ng/ml | — |
| Multiple Ascending Dose (MAD): Placebo | Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7020531) | 0.14 hr*ng/ml | — |
Secondary
Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805
Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for Fraction Excreted (Molecular Weight corrected) will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and MAD Cohorts (1-4).
Time frame: SAD: Pre-dose, 0-4, 4-8, 8-12, 12-24h Day 1
Population: The PK analysis population included all healthy volunteers randomised and adherent to the protocol. Participants were excluded if they significantly violated the inclusion/exclusion criteria, deviated significantly from the protocol or if data were unavailable or incomplete. Data presented is only for participants included in the actual analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Ascending Dose (SAD): Placebo | Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7033805 | 0.00 Percentage | Standard Deviation 0 |
| Single Ascending Dose (SAD): Placebo | Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7011785 | 59.9 Percentage | Standard Deviation 5.3 |
| Single Ascending Dose (SAD): Placebo | Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7020531 | 0.00 Percentage | Standard Deviation 0 |
| Single Ascending Dose (SAD): Placebo | Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7018822 | 1.10 Percentage | Standard Deviation 0.4 |
| SAD: Cohort 1 | Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7020531 | 0.00 Percentage | Standard Deviation 0 |
| SAD: Cohort 1 | Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7033805 | 0.00 Percentage | Standard Deviation 0 |
| SAD: Cohort 1 | Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7018822 | 0.84 Percentage | Standard Deviation 0.18 |
| SAD: Cohort 1 | Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7011785 | 62.9 Percentage | Standard Deviation 6.77 |
| SAD: Cohort 2 | Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7020531 | 0.00 Percentage | Standard Deviation 0 |
| SAD: Cohort 2 | Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7011785 | 67.1 Percentage | Standard Deviation 7.78 |
| SAD: Cohort 2 | Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7018822 | 1.06 Percentage | Standard Deviation 0.33 |
| SAD: Cohort 2 | Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7033805 | 0.00 Percentage | Standard Deviation 0 |
| SAD: Cohort 3 | Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7018822 | 1.09 Percentage | Standard Deviation 0.34 |
| SAD: Cohort 3 | Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7011785 | 66.2 Percentage | Standard Deviation 9.47 |
Secondary
Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805)
Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for t1/2 will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and SAD Cohorts (1-4) (on Day 13). Due to insufficient plasma concentration data for RO7020531 and RO7033805, t1/2 for these 2 compounds could not be estimated.
Time frame: SAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48 hours (h) Post-dose Days 1, 2; MAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24h Post-dose Days 1, 2 and Days 13, 14; Pre-dose, 2, 6, 24hr Post-dose Days 3, 5, 7, 9 and 11.
Population: The PK analysis population included all healthy volunteers randomised and adherent to the protocol. Participants were excluded if they significantly violated the inclusion/exclusion criteria, deviated significantly from the protocol or if data were unavailable or incomplete. Data presented is only for participants included in the actual analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Ascending Dose (SAD): Placebo | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 2.92 hr | Standard Deviation 0.787 |
| Single Ascending Dose (SAD): Placebo | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 0.519 hr | Standard Deviation 0.124 |
| SAD: Cohort 1 | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 0.606 hr | Standard Deviation 0.0932 |
| SAD: Cohort 1 | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 3.38 hr | Standard Deviation 0.499 |
| SAD: Cohort 2 | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 0.642 hr | Standard Deviation 0.16 |
| SAD: Cohort 2 | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 3.96 hr | Standard Deviation 0.761 |
| SAD: Cohort 3 | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 0.612 hr | Standard Deviation 0.172 |
| SAD: Cohort 3 | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 4.24 hr | Standard Deviation 0.667 |
| SAD: Cohort 4 | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7018822) | 0.753 hr | Standard Deviation 0.189 |
| SAD: Cohort 4 | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 3.38 hr | Standard Deviation 0.976 |
| SAD: Cohort 4 | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7011785) | 3.52 hr | Standard Deviation 0.813 |
| SAD: Cohort 4 | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 0.605 hr | Standard Deviation 0.092 |
| Multiple Ascending Dose (MAD): Placebo | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 4.39 hr | Standard Deviation 0.918 |
| Multiple Ascending Dose (MAD): Placebo | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7018822) | 0.706 hr | Standard Deviation 0.315 |
| Multiple Ascending Dose (MAD): Placebo | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 0.611 hr | Standard Deviation 0.0935 |
| Multiple Ascending Dose (MAD): Placebo | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7011785) | 3.85 hr | Standard Deviation 0.807 |
| Unknown | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7033805) | — hr | — |
| Unknown | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7020531) | — hr | — |
| Unknown | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7033805) | — hr | — |
| Unknown | Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7020531) | — hr | — |
Secondary
Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805)
Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for Cmax will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and SAD Cohorts (1-4) (on Day 13).
Time frame: SAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48 hours (h) Post-dose Days 1, 2; MAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24h Post-dose Days 1, 2 and Days 13, 14; Pre-dose, 2, 6, 24hr Post-dose Days 3, 5, 7, 9 and 11.
Population: The PK analysis population included all healthy volunteers randomised and adherent to the protocol. Participants were excluded if they significantly violated the inclusion/exclusion criteria, deviated significantly from the protocol or if data were unavailable or incomplete. Data presented is only for participants included in the actual analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Ascending Dose (SAD): Placebo | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7020531) | NA ng/ml | — |
| Single Ascending Dose (SAD): Placebo | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 640 ng/ml | Standard Deviation 227 |
| Single Ascending Dose (SAD): Placebo | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7033805) | NA ng/ml | — |
| Single Ascending Dose (SAD): Placebo | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 78.6 ng/ml | Standard Deviation 32.9 |
| SAD: Cohort 1 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 125 ng/ml | Standard Deviation 56.7 |
| SAD: Cohort 1 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7020531) | NA ng/ml | — |
| SAD: Cohort 1 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 1380 ng/ml | Standard Deviation 461 |
| SAD: Cohort 1 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7033805) | NA ng/ml | — |
| SAD: Cohort 2 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 1940 ng/ml | Standard Deviation 516 |
| SAD: Cohort 2 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 200 ng/ml | Standard Deviation 70.4 |
| SAD: Cohort 2 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7033805) | 0.14 ng/ml | Standard Deviation 0.39 |
| SAD: Cohort 2 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7020531) | 0.14 ng/ml | Standard Deviation 0.39 |
| SAD: Cohort 3 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7020531) | NA ng/ml | — |
| SAD: Cohort 3 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 247 ng/ml | Standard Deviation 112 |
| SAD: Cohort 3 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 2180 ng/ml | Standard Deviation 841 |
| SAD: Cohort 3 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7033805) | NA ng/ml | — |
| SAD: Cohort 4 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7011785) | 1110 ng/ml | Standard Deviation 480 |
| SAD: Cohort 4 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 1290 ng/ml | Standard Deviation 414 |
| SAD: Cohort 4 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 249 ng/ml | Standard Deviation 217 |
| SAD: Cohort 4 | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7018822) | 116 ng/ml | Standard Deviation 55.2 |
| Multiple Ascending Dose (MAD): Placebo | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7033805) | 1.08 ng/ml | — |
| Multiple Ascending Dose (MAD): Placebo | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7020531) | 1.56 ng/ml | — |
| Multiple Ascending Dose (MAD): Placebo | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7011785) | 1530 ng/ml | Standard Deviation 382 |
| Multiple Ascending Dose (MAD): Placebo | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 231 ng/ml | Standard Deviation 98.5 |
| Multiple Ascending Dose (MAD): Placebo | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7018822) | 155 ng/ml | Standard Deviation 50.6 |
| Multiple Ascending Dose (MAD): Placebo | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7020531) | 1.08 ng/ml | — |
| Multiple Ascending Dose (MAD): Placebo | Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 1900 ng/ml | Standard Deviation 501 |
Secondary
Mean Concentrations of Protein and Metabolite Markers of Humoral Response
Protein and metabolite markers of humoral response include interferon (IFN)-alfa, IP-10, Tumor Necrosis Factor (TNF)-alfa, interleukin (IL)-6, IL-10, IL-12p40 and Neopterin. Summary descriptive statistics will be presented for the induction of cytokines, chemokines and neopterin and of interferon-response genes separately by treatment arm. Only mean concentrations were collected for IFN-alfa and hence why this data is only presented below.
Time frame: SAD: Day -1, Pre-dose, 2, 6, 12, 24h Post-dose Day 1 to Day 2, 3, 5, 8; MAD: Day -1, Pre-dose 2, 6, 12, 24h Post-dose Day 1 to Day 2, Pre-dose, 2, 6, 24h Post-dose Days 3, 5, 7, 13 and 20
Population: The Pharmacodynamic (PD) analysis population was defined as all participants who were randomized, received at least one dose of study medication (RO7020531 or placebo), and have PD data available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Single Ascending Dose (SAD): Placebo | Mean Concentrations of Protein and Metabolite Markers of Humoral Response | 0.1232 ng/L | Standard Deviation 8.5366 |
| SAD: Cohort 1 | Mean Concentrations of Protein and Metabolite Markers of Humoral Response | 0.0433 ng/L | Standard Deviation 1.0244 |
| SAD: Cohort 2 | Mean Concentrations of Protein and Metabolite Markers of Humoral Response | 0.0707 ng/L | Standard Deviation 2.3422 |
| SAD: Cohort 3 | Mean Concentrations of Protein and Metabolite Markers of Humoral Response | 0.1316 ng/L | Standard Deviation 3.672 |
| SAD: Cohort 4 | Mean Concentrations of Protein and Metabolite Markers of Humoral Response | 0.1156 ng/L | Standard Deviation 3.6654 |
| Multiple Ascending Dose (MAD): Placebo | Mean Concentrations of Protein and Metabolite Markers of Humoral Response | 0.0455 ng/L | Standard Deviation 1.2143 |
| MAD: Cohort 1 | Mean Concentrations of Protein and Metabolite Markers of Humoral Response | 0.1339 ng/L | Standard Deviation 4.1386 |
| MAD: Cohorts 2 and 3 | Mean Concentrations of Protein and Metabolite Markers of Humoral Response | 0.3733 ng/L | Standard Deviation 6.4327 |
Secondary
Mean Fold Changes of Markers of Transcriptional Responses
Markers of transcriptional responses includes ISG15, OAS-1, MX1 and Toll-Like Receptor (TLR)7. Summary descriptive statistics will be presented for these markers separately by treatment arm.
Time frame: SAD: Day -1, Pre-dose, 2, 6, 12, 24h Post-dose Day 1 to Day 2 and Day 8; MAD: Day -1, Pre-dose 2, 6, 12, 24h Post-dose Day 1 to Day 2, Pre-dose, 2, 6, 24h Post-dose Days 3, 5, 7, 13 and 20
Population: The PD analysis population was defined as all participants who were randomized, received at least one dose of study medication (RO7020531 or placebo), and have PD data available.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Single Ascending Dose (SAD): Placebo | Mean Fold Changes of Markers of Transcriptional Responses | ISG15 mRNA | 1.0538 Fold Change |
| Single Ascending Dose (SAD): Placebo | Mean Fold Changes of Markers of Transcriptional Responses | OAS-1 mRNA | 1.0739 Fold Change |
| Single Ascending Dose (SAD): Placebo | Mean Fold Changes of Markers of Transcriptional Responses | MX1 mRNA | 1.0562 Fold Change |
| Single Ascending Dose (SAD): Placebo | Mean Fold Changes of Markers of Transcriptional Responses | TLR7 mRNA | 1.0883 Fold Change |
| SAD: Cohort 1 | Mean Fold Changes of Markers of Transcriptional Responses | TLR7 mRNA | 1.1638 Fold Change |
| SAD: Cohort 1 | Mean Fold Changes of Markers of Transcriptional Responses | MX1 mRNA | 1.1742 Fold Change |
| SAD: Cohort 1 | Mean Fold Changes of Markers of Transcriptional Responses | OAS-1 mRNA | 1.1256 Fold Change |
| SAD: Cohort 1 | Mean Fold Changes of Markers of Transcriptional Responses | ISG15 mRNA | 1.0907 Fold Change |
| SAD: Cohort 2 | Mean Fold Changes of Markers of Transcriptional Responses | ISG15 mRNA | 1.9190 Fold Change |
| SAD: Cohort 2 | Mean Fold Changes of Markers of Transcriptional Responses | MX1 mRNA | 2.1984 Fold Change |
| SAD: Cohort 2 | Mean Fold Changes of Markers of Transcriptional Responses | OAS-1 mRNA | 1.6148 Fold Change |
| SAD: Cohort 2 | Mean Fold Changes of Markers of Transcriptional Responses | TLR7 mRNA | 0.9921 Fold Change |
| SAD: Cohort 3 | Mean Fold Changes of Markers of Transcriptional Responses | ISG15 mRNA | 4.0828 Fold Change |
| SAD: Cohort 3 | Mean Fold Changes of Markers of Transcriptional Responses | TLR7 mRNA | 2.0835 Fold Change |
| SAD: Cohort 3 | Mean Fold Changes of Markers of Transcriptional Responses | OAS-1 mRNA | 2.9338 Fold Change |
| SAD: Cohort 3 | Mean Fold Changes of Markers of Transcriptional Responses | MX1 mRNA | 3.8705 Fold Change |
| SAD: Cohort 4 | Mean Fold Changes of Markers of Transcriptional Responses | OAS-1 mRNA | 3.0716 Fold Change |
| SAD: Cohort 4 | Mean Fold Changes of Markers of Transcriptional Responses | ISG15 mRNA | 4.3223 Fold Change |
| SAD: Cohort 4 | Mean Fold Changes of Markers of Transcriptional Responses | MX1 mRNA | 4.3748 Fold Change |
| SAD: Cohort 4 | Mean Fold Changes of Markers of Transcriptional Responses | TLR7 mRNA | 1.3872 Fold Change |
| Multiple Ascending Dose (MAD): Placebo | Mean Fold Changes of Markers of Transcriptional Responses | MX1 mRNA | 0.7414 Fold Change |
| Multiple Ascending Dose (MAD): Placebo | Mean Fold Changes of Markers of Transcriptional Responses | TLR7 mRNA | 0.8483 Fold Change |
| Multiple Ascending Dose (MAD): Placebo | Mean Fold Changes of Markers of Transcriptional Responses | OAS-1 mRNA | 0.6315 Fold Change |
| Multiple Ascending Dose (MAD): Placebo | Mean Fold Changes of Markers of Transcriptional Responses | ISG15 mRNA | 0.6938 Fold Change |
| MAD: Cohort 1 | Mean Fold Changes of Markers of Transcriptional Responses | MX1 mRNA | 1.8317 Fold Change |
| MAD: Cohort 1 | Mean Fold Changes of Markers of Transcriptional Responses | OAS-1 mRNA | 1.9447 Fold Change |
| MAD: Cohort 1 | Mean Fold Changes of Markers of Transcriptional Responses | TLR7 mRNA | 1.4923 Fold Change |
| MAD: Cohort 1 | Mean Fold Changes of Markers of Transcriptional Responses | ISG15 mRNA | 2.0720 Fold Change |
| MAD: Cohorts 2 and 3 | Mean Fold Changes of Markers of Transcriptional Responses | ISG15 mRNA | 4.2679 Fold Change |
| MAD: Cohorts 2 and 3 | Mean Fold Changes of Markers of Transcriptional Responses | OAS-1 mRNA | 3.1327 Fold Change |
| MAD: Cohorts 2 and 3 | Mean Fold Changes of Markers of Transcriptional Responses | TLR7 mRNA | 1.5454 Fold Change |
| MAD: Cohorts 2 and 3 | Mean Fold Changes of Markers of Transcriptional Responses | MX1 mRNA | 3.0186 Fold Change |
Secondary
Mean Fold Changes of Protein and Metabolite Markers of Humoral Response
Protein and metabolite markers of humoral response include interferon (IFN)-alfa, IP-10, Tumor Necrosis Factor (TNF)-alfa, interleukin (IL)-6, IL-10, IL-12p40 and Neopterin. Summary descriptive statistics will be presented for the induction of cytokines, chemokines and neopterin and of interferon-response genes separately by treatment arm. Mean fold change data is presented below.
Time frame: SAD: Day -1, Pre-dose, 2, 6, 12, 24, 48 (only Neopterin), 96h (only Neopterin), Post-dose Day 1 to Day 2, 3, 5, 8; MAD: Day -1, Pre-dose 2, 6, 12, 24h Post-dose Day 1 to Day 2, Pre-dose, 2, 6, 24h Post-dose Days 3, 5, 7, 13 and 20
Population: The Pharmacodynamic (PD) analysis population was defined as all participants who were randomized, received at least one dose of study medication (RO7020531 or placebo), and have PD data available.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Single Ascending Dose (SAD): Placebo | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-10 | 0.9410 Fold Change |
| Single Ascending Dose (SAD): Placebo | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Tumor Necrosis Factor (TNF)-alfa | 1.0233 Fold Change |
| Single Ascending Dose (SAD): Placebo | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Neopterin | 1.0757 Fold Change |
| Single Ascending Dose (SAD): Placebo | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IP-10 | 1.1108 Fold Change |
| Single Ascending Dose (SAD): Placebo | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-12p40 | 0.9126 Fold Change |
| Single Ascending Dose (SAD): Placebo | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-6 | 1.0699 Fold Change |
| SAD: Cohort 1 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Neopterin | 1.0175 Fold Change |
| SAD: Cohort 1 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-6 | 0.9374 Fold Change |
| SAD: Cohort 1 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IP-10 | 0.9522 Fold Change |
| SAD: Cohort 1 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-10 | 0.8394 Fold Change |
| SAD: Cohort 1 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Tumor Necrosis Factor (TNF)-alfa | 0.9286 Fold Change |
| SAD: Cohort 1 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-12p40 | 0.9872 Fold Change |
| SAD: Cohort 2 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-12p40 | 0.9844 Fold Change |
| SAD: Cohort 2 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Tumor Necrosis Factor (TNF)-alfa | 0.7816 Fold Change |
| SAD: Cohort 2 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Neopterin | 1.0408 Fold Change |
| SAD: Cohort 2 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-6 | 1.0253 Fold Change |
| SAD: Cohort 2 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-10 | 1.0561 Fold Change |
| SAD: Cohort 2 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IP-10 | 0.9987 Fold Change |
| SAD: Cohort 3 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Tumor Necrosis Factor (TNF)-alfa | 1.2098 Fold Change |
| SAD: Cohort 3 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IP-10 | 1.5327 Fold Change |
| SAD: Cohort 3 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Neopterin | 1.1615 Fold Change |
| SAD: Cohort 3 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-6 | 1.1300 Fold Change |
| SAD: Cohort 3 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-12p40 | 0.9811 Fold Change |
| SAD: Cohort 3 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-10 | 1.0567 Fold Change |
| SAD: Cohort 4 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Tumor Necrosis Factor (TNF)-alfa | 1.0947 Fold Change |
| SAD: Cohort 4 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-6 | 1.0363 Fold Change |
| SAD: Cohort 4 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Neopterin | 1.2142 Fold Change |
| SAD: Cohort 4 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-10 | 1.1666 Fold Change |
| SAD: Cohort 4 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-12p40 | 0.9781 Fold Change |
| SAD: Cohort 4 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IP-10 | 1.6229 Fold Change |
| Multiple Ascending Dose (MAD): Placebo | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Tumor Necrosis Factor (TNF)-alfa | 0.7482 Fold Change |
| Multiple Ascending Dose (MAD): Placebo | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-6 | 0.8815 Fold Change |
| Multiple Ascending Dose (MAD): Placebo | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IP-10 | 0.8087 Fold Change |
| Multiple Ascending Dose (MAD): Placebo | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-10 | 0.8262 Fold Change |
| Multiple Ascending Dose (MAD): Placebo | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-12p40 | 1.0260 Fold Change |
| Multiple Ascending Dose (MAD): Placebo | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Neopterin | 0.9003 Fold Change |
| MAD: Cohort 1 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-6 | 1.0762 Fold Change |
| MAD: Cohort 1 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-10 | 0.9641 Fold Change |
| MAD: Cohort 1 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Neopterin | 1.2012 Fold Change |
| MAD: Cohort 1 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Tumor Necrosis Factor (TNF)-alfa | 0.9661 Fold Change |
| MAD: Cohort 1 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-12p40 | 0.9384 Fold Change |
| MAD: Cohort 1 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IP-10 | 1.4014 Fold Change |
| MAD: Cohorts 2 and 3 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-6 | 1.0702 Fold Change |
| MAD: Cohorts 2 and 3 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Neopterin | 1.6792 Fold Change |
| MAD: Cohorts 2 and 3 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-12p40 | 1.0331 Fold Change |
| MAD: Cohorts 2 and 3 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Tumor Necrosis Factor (TNF)-alfa | 0.9909 Fold Change |
| MAD: Cohorts 2 and 3 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IL-10 | 0.9662 Fold Change |
| MAD: Cohorts 2 and 3 | Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | IP-10 | 2.1550 Fold Change |
Secondary
Renal Clearance of RO7020531, RO7011785, RO7018822 and RO7033805
Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for Renal Clearance will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and MAD Cohorts (1-4). Due to insufficient urine concentration data for RO7020531 and RO7033805, Renal Clearance for these 2 compounds could not be estimated.
Time frame: SAD: Pre-dose, 0-4, 4-8, 8-12, 12-24h Day 1
Population: The PK analysis population included all healthy volunteers randomised and adherent to the protocol. Participants were excluded if they significantly violated the inclusion/exclusion criteria, deviated significantly from the protocol or if data were unavailable or incomplete. Data presented is only for participants included in the actual analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Ascending Dose (SAD): Placebo | Renal Clearance of RO7020531, RO7011785, RO7018822 and RO7033805 | RO7011785 | 536 CLr (mL/min) | Standard Deviation 101 |
| Single Ascending Dose (SAD): Placebo | Renal Clearance of RO7020531, RO7011785, RO7018822 and RO7033805 | RO7018822 | 115.31 CLr (mL/min) | Standard Deviation 48.54 |
| SAD: Cohort 1 | Renal Clearance of RO7020531, RO7011785, RO7018822 and RO7033805 | RO7018822 | 116.30 CLr (mL/min) | Standard Deviation 36.41 |
| SAD: Cohort 1 | Renal Clearance of RO7020531, RO7011785, RO7018822 and RO7033805 | RO7011785 | 590 CLr (mL/min) | Standard Deviation 78.4 |
| SAD: Cohort 2 | Renal Clearance of RO7020531, RO7011785, RO7018822 and RO7033805 | RO7018822 | 117.80 CLr (mL/min) | Standard Deviation 42.15 |
| SAD: Cohort 2 | Renal Clearance of RO7020531, RO7011785, RO7018822 and RO7033805 | RO7011785 | 600 CLr (mL/min) | Standard Deviation 136 |
| SAD: Cohort 3 | Renal Clearance of RO7020531, RO7011785, RO7018822 and RO7033805 | RO7018822 | 119.99 CLr (mL/min) | Standard Deviation 36.54 |
| SAD: Cohort 3 | Renal Clearance of RO7020531, RO7011785, RO7018822 and RO7033805 | RO7011785 | 659 CLr (mL/min) | Standard Deviation 157 |
| Unknown | Renal Clearance of RO7020531, RO7011785, RO7018822 and RO7033805 | RO7033805 | — CLr (mL/min) | — |
| Unknown | Renal Clearance of RO7020531, RO7011785, RO7018822 and RO7033805 | RO7020531 | — CLr (mL/min) | — |
Secondary
Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805)
Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Median and Full Range) for Tmax will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and SAD Cohorts (1-4) (on Day 13).
Time frame: SAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48 hours (h) Post-dose Days 1, 2; MAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24h Post-dose Days 1, 2 and Days 13, 14; Pre-dose, 2, 6, 24hr Post-dose Days 3, 5, 7, 9 and 11.
Population: The PK analysis population included all healthy volunteers randomised and adherent to the protocol. Participants were excluded if they significantly violated the inclusion/exclusion criteria, deviated significantly from the protocol or if data were unavailable or incomplete. Data presented is only for participants included in the actual analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Single Ascending Dose (SAD): Placebo | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 0.50 hr |
| Single Ascending Dose (SAD): Placebo | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 0.50 hr |
| SAD: Cohort 1 | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 0.50 hr |
| SAD: Cohort 1 | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 0.75 hr |
| SAD: Cohort 2 | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7020531) | 0.50 hr |
| SAD: Cohort 2 | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 0.50 hr |
| SAD: Cohort 2 | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 0.50 hr |
| SAD: Cohort 2 | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7033805) | 0.50 hr |
| SAD: Cohort 3 | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 0.50 hr |
| SAD: Cohort 3 | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 0.50 hr |
| SAD: Cohort 4 | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7018822) | 1.00 hr |
| SAD: Cohort 4 | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 1.50 hr |
| SAD: Cohort 4 | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 0.50 hr |
| SAD: Cohort 4 | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7011785) | 1.00 hr |
| Multiple Ascending Dose (MAD): Placebo | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7011785) | 0.52 hr |
| Multiple Ascending Dose (MAD): Placebo | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7018822) | 0.50 hr |
| Multiple Ascending Dose (MAD): Placebo | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 1 (RO7020531) | 0.25 hr |
| Multiple Ascending Dose (MAD): Placebo | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7011785) | 1.00 hr |
| Multiple Ascending Dose (MAD): Placebo | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7018822) | 0.50 hr |
| Multiple Ascending Dose (MAD): Placebo | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7020531) | 0.50 hr |
| Multiple Ascending Dose (MAD): Placebo | Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Day 13 (RO7033805) | 0.50 hr |
Secondary
Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805
Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for Total Amount Excreted, will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and MAD Cohorts (1-4).
Time frame: SAD: Pre-dose, 0-4, 4-8, 8-12, 12-24h Day 1
Population: The PK analysis population included all healthy volunteers randomised and adherent to the protocol. Participants were excluded if they significantly violated the inclusion/exclusion criteria, deviated significantly from the protocol or if data were unavailable or incomplete. Data presented is only for participants included in the actual analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Ascending Dose (SAD): Placebo | Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7020531 | 0.00 mg | Standard Deviation 0 |
| Single Ascending Dose (SAD): Placebo | Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7011785 | 22.2 mg | Standard Deviation 1.96 |
| Single Ascending Dose (SAD): Placebo | Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7018822 | 0.39 mg | Standard Deviation 0.14 |
| Single Ascending Dose (SAD): Placebo | Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7033805 | 0.00 mg | Standard Deviation 0 |
| SAD: Cohort 1 | Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7018822 | 0.74 mg | Standard Deviation 0.16 |
| SAD: Cohort 1 | Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7011785 | 58.3 mg | Standard Deviation 6.27 |
| SAD: Cohort 1 | Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7020531 | 0.00 mg | Standard Deviation 0 |
| SAD: Cohort 1 | Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7033805 | 0.00 mg | Standard Deviation 0 |
| SAD: Cohort 2 | Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7033805 | 0.00 mg | Standard Deviation 0 |
| SAD: Cohort 2 | Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7011785 | 87.0 mg | Standard Deviation 10.1 |
| SAD: Cohort 2 | Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7018822 | 1.31 mg | Standard Deviation 0.4 |
| SAD: Cohort 2 | Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7020531 | 0.00 mg | Standard Deviation 0 |
| SAD: Cohort 3 | Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7011785 | 104 mg | Standard Deviation 14.9 |
| SAD: Cohort 3 | Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | RO7018822 | 1.63 mg | Standard Deviation 0.51 |