Non-alcoholic Steatohepatitis
Conditions
Brief summary
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of single and multiple doses of ARO-HSD in healthy adult volunteers and in patients with NASH or suspected NASH.
Interventions
DRUGARO-HSD Injection
single or multiple doses of ARO-HSD by subcutaneous (sc) injections
DRUGsterile normal saline (0.9% NaCl)
calculated volume to match active treatment, by sc injection
Sponsors
Arrowhead Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
19 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Women of child bearing potential must have a negative pregnancy test, cannot be breastfeeding and must be willing to use contraception * Willing to provide written informed consent and to comply with study requirements * On a stable diet for at least 4 weeks with no plans to significantly alter diet or weight over course of study * Normal electrocardiogram (ECG) at Screening * No abnormal finding of clinical relevance (other than NASH, suspected NASH in patients) at Screening that could adversely impact subject safety during the study or adversely impact study results.
Exclusion criteria
* Clinically significant health concerns (other than NASH, suspected NASH in patients) * Human immunodeficiency virus (HIV) infection, seropositive for Hepatitis B Virus (HBV), seropositive for Hepatitis C Virus (HCV) * Uncontrolled hypertension * Excessive use of alcohol within three months prior to Screening * Use of illicit drugs within 1 year prior to Screening, or positive urine drug screen at Screening * Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study NOTE: additional inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Possibly or Probably Related to Treatment | From first dose of study drug through Day 113 (±5 days) | Adverse event (AE)=any untoward medical occurrence that does not necessarily have to have a causal relationship with this treatment. TEAEs=AEs with onset after administration of the study drug, or when a pre-existing medical condition increases in severity or frequency after study drug administration. Serious adverse event (SAE)= an AE that results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a medically important event or reaction. |
Secondary
| Measure | Time frame |
|---|---|
| PK of ARO-HSD in Normal Healthy Volunteers: Maximum Observed Plasma Concentration (Cmax) | Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24, 48 hours postdose |
| PK of ARO-HSD in Normal Healthy Volunteers: Time to Reach Cmax (Tmax) | Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24, 48 hours postdose |
| PK of ARO-HSD in Normal Healthy Volunteers: Terminal Elimination Half-Life (t1/2) | Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24, 48 hours postdose |
| PK of ARO-HSD in Normal Healthy Volunteers: Area Under the Concentration-Time Curve From Dosing (Time 0) to the Time of the Last Measured Concentration (AUClast) | Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24, 48 hours postdose |
| PK of ARO-HSD in Normal Healthy Volunteers: Area Under the Curve From Time 0 to Infinity (AUCinf) | Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24, 48 hours postdose |
| Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Normal Healthy Volunteers: Day 1: 2 hours pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 8, 12, 18, 24; Day 2: 48 hours post-dose, Days 8, 15, 29. NASH Participants: Day 1: 2 hours pre-dose, 30 minutes, 1, 2, 24, hours post-dose, Days 8, 15, 29 |
| PK of ARO-HSD in Normal Healthy Volunteers: Apparent Volume of Distribution During the Terminal-Phase (Vz/F) | Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24, 48 hours postdose |
| Urine PK of ARO-HSD in Normal Healthy Volunteers: Amount of Unchanged Drug Recovered in Urine Over 0-24 Hours Postdose (Ae0-24h) | Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24 hours postdose |
| Urine PK of ARO-HSD in Normal Healthy Volunteers: Percentage of the Administrated Drug Recovered in Urine Over 0-24 Hours (Fe0-24h) | Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24 hours postdose |
| Urine PK of ARO-HSD in Normal Healthy Volunteers: Renal Clearance (CLr) | Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24 hours postdose |
| Secondary: PK of ARO-HSD in Normal Healthy Volunteers: Oral Clearance (CL/F) | Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24, 48 hours postdose |
Countries
New Zealand
Participant flow
Pre-assignment details
Following Screening, Cohorts 1 through 4 (normal healthy volunteers) enrolled eligible participants, randomly assigned 1:1 to receive a single subcutaneous (SC) dose of ARO-HSD or placebo on Day 1. Per protocol, the placebo cohorts were pooled for data analysis.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: ARO-HSD 25 mg Normal healthy volunteers randomized to double blind ARO-HSD 25 mg on Day 1 only. | 4 |
| Cohort 2: ARO-HSD 50 mg Normal healthy volunteers randomized to double blind ARO-HSD 50 mg on Day 1 only. | 4 |
| Cohort 3: ARO-HSD 100 mg Normal healthy volunteers randomized to double blind ARO-HSD 100 mg on Day 1 only. | 4 |
| Cohort 4: ARO-HSD 200 mg Normal healthy volunteers randomized to double blind ARO-HSD 200 mg on Day 1 only. | 4 |
| Cohorts 1-4: Pooled Placebo Normal healthy volunteers randomized to double blind placebo on Day 1 only. | 16 |
| Cohort 1b: ARO-HSD 25 mg Participants with suspected NASH receive open-label ARO-HSD 25 mg on Days 1 and 29. | 6 |
| Cohort 3b: ARO-HSD 100 mg Participants with suspected NASH receive open-label ARO-HSD 100 mg on Days 1 and 29. | 6 |
| Cohort 4b: ARO-HSD 200 mg Participants with suspected NASH received open-label ARO-HSD 200 mg on Days 1 and 29. | 6 |
| Total | 50 |
Baseline characteristics
| Characteristic | Cohort 1b: ARO-HSD 25 mg | Cohort 3b: ARO-HSD 100 mg | Cohort 4b: ARO-HSD 200 mg | Total | Cohort 1: ARO-HSD 25 mg | Cohort 2: ARO-HSD 50 mg | Cohort 3: ARO-HSD 100 mg | Cohort 4: ARO-HSD 200 mg | Cohorts 1-4: Pooled Placebo |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 6 Participants | 50 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 16 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 6 Participants | 6 Participants | 6 Participants | 47 Participants | 4 Participants | 3 Participants | 2 Participants | 4 Participants | 16 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 5 Participants | 4 Participants | 18 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 4 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 2 Participants | 0 Participants | 1 Participants | 23 Participants | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 11 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants | 21 Participants | 1 Participants | 2 Participants | 1 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 4 Participants | 29 Participants | 3 Participants | 2 Participants | 3 Participants | 1 Participants | 6 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 / 4 | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 16 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 4 / 4 | 1 / 4 | 4 / 4 | 3 / 4 | 10 / 16 | 3 / 6 | 2 / 6 | 4 / 6 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 16 | 0 / 6 | 0 / 6 | 1 / 6 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Possibly or Probably Related to Treatment
Adverse event (AE)=any untoward medical occurrence that does not necessarily have to have a causal relationship with this treatment. TEAEs=AEs with onset after administration of the study drug, or when a pre-existing medical condition increases in severity or frequency after study drug administration. Serious adverse event (SAE)= an AE that results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a medically important event or reaction.
Time frame: From first dose of study drug through Day 113 (±5 days)
Population: Safety Population: all enrolled participants who received at least one dose of active drug or placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: ARO-HSD 25 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Possibly or Probably Related to Treatment | 0 participants |
| Cohort 2: ARO-HSD 50 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Possibly or Probably Related to Treatment | 0 participants |
| Cohort 3: ARO-HSD 100 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Possibly or Probably Related to Treatment | 1 participants |
| Cohort 4: ARO-HSD 200 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Possibly or Probably Related to Treatment | 3 participants |
| Cohorts 1-4: Pooled Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Possibly or Probably Related to Treatment | 0 participants |
| Cohort 1b: ARO-HSD 25 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Possibly or Probably Related to Treatment | 1 participants |
| Cohort 3b: ARO-HSD 100 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Possibly or Probably Related to Treatment | 1 participants |
| Cohort 4b: ARO-HSD 200 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Possibly or Probably Related to Treatment | 2 participants |
Secondary
Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations
Time frame: Normal Healthy Volunteers: Day 1: 2 hours pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 8, 12, 18, 24; Day 2: 48 hours post-dose, Days 8, 15, 29. NASH Participants: Day 1: 2 hours pre-dose, 30 minutes, 1, 2, 24, hours post-dose, Days 8, 15, 29
Population: PK Analysis Set: all participants who received at least one dose of active study treatment and had sufficient plasma concentration data to characterize PK profile. Participants with sufficient data at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 18 hours post-dose | 12.5088 ng/mL | Standard Deviation 5.5194 |
| Cohort 1: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 1 hour post-dose | 66.6098 ng/mL | Standard Deviation 14.6623 |
| Cohort 1: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 30 minutes post-dose | 67.6780 ng/mL | Standard Deviation 13.9394 |
| Cohort 1: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 8 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 1: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 12 hours post-dose | 33.7875 ng/mL | Standard Deviation 6.5592 |
| Cohort 1: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 2 hours post-dose | 53.5845 ng/mL | Standard Deviation 9.4115 |
| Cohort 1: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 15 minutes post-dose | 56.7555 ng/mL | Standard Deviation 13.2117 |
| Cohort 1: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 15 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 1: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 24 hours post-dose | 2.0123 ng/mL | Standard Deviation 1.7888 |
| Cohort 1: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 48 hours post-dose | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 1: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 8 hours post-dose | 53.9558 ng/mL | Standard Deviation 12.2129 |
| Cohort 1: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 2 hours pre-dose | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 1: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 4 hours post-dose | 60.8553 ng/mL | Standard Deviation 4.2935 |
| Cohort 2: ARO-HSD 50 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 1 hour post-dose | 134.8668 ng/mL | Standard Deviation 66.4452 |
| Cohort 2: ARO-HSD 50 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 30 minutes post-dose | 116.6108 ng/mL | Standard Deviation 70.436 |
| Cohort 2: ARO-HSD 50 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 24 hours post-dose | 2.9088 ng/mL | Standard Deviation 2.3774 |
| Cohort 2: ARO-HSD 50 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 48 hours post-dose | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 2: ARO-HSD 50 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 29 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 2: ARO-HSD 50 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 18 hours post-dose | 17.7438 ng/mL | Standard Deviation 12.6477 |
| Cohort 2: ARO-HSD 50 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 2 hours pre-dose | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 2: ARO-HSD 50 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 15 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 2: ARO-HSD 50 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 2 hours post-dose | 137.1443 ng/mL | Standard Deviation 53.1775 |
| Cohort 2: ARO-HSD 50 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 8 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 2: ARO-HSD 50 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 4 hours post-dose | 157.5515 ng/mL | Standard Deviation 64.5494 |
| Cohort 2: ARO-HSD 50 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 15 minutes post-dose | 60.7480 ng/mL | Standard Deviation 52.6374 |
| Cohort 2: ARO-HSD 50 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 8 hours post-dose | 136.8678 ng/mL | Standard Deviation 49.6823 |
| Cohort 2: ARO-HSD 50 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 12 hours post-dose | 80.2873 ng/mL | Standard Deviation 26.8625 |
| Cohort 3: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 1 hour post-dose | 211.1088 ng/mL | Standard Deviation 78.3225 |
| Cohort 3: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 29 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 3: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 18 hours post-dose | 75.3893 ng/mL | Standard Deviation 32.1815 |
| Cohort 3: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 4 hours post-dose | 253.6468 ng/mL | Standard Deviation 91.559 |
| Cohort 3: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 12 hours post-dose | 180.7433 ng/mL | Standard Deviation 54.0979 |
| Cohort 3: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 2 hours pre-dose | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 3: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 24 hours post-dose | 20.6793 ng/mL | Standard Deviation 12.8362 |
| Cohort 3: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 8 hours post-dose | 255.7058 ng/mL | Standard Deviation 27.2111 |
| Cohort 3: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 15 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 3: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 48 hours post-dose | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 3: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 2 hours post-dose | 219.4920 ng/mL | Standard Deviation 108.8893 |
| Cohort 3: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 15 minutes post-dose | 101.4768 ng/mL | Standard Deviation 66.7517 |
| Cohort 3: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 8 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 3: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 30 minutes post-dose | 160.9810 ng/mL | Standard Deviation 72.2119 |
| Cohort 4: ARO-HSD 200 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 15 minutes post-dose | 275.6855 ng/mL | Standard Deviation 261.1693 |
| Cohort 4: ARO-HSD 200 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 2 hours pre-dose | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 4: ARO-HSD 200 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 30 minutes post-dose | 445.7370 ng/mL | Standard Deviation 316.1025 |
| Cohort 4: ARO-HSD 200 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 1 hour post-dose | 531.6415 ng/mL | Standard Deviation 213.0969 |
| Cohort 4: ARO-HSD 200 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 2 hours post-dose | 510.3820 ng/mL | Standard Deviation 146.3129 |
| Cohort 4: ARO-HSD 200 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 4 hours post-dose | 542.9808 ng/mL | Standard Deviation 80.1204 |
| Cohort 4: ARO-HSD 200 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 8 hours post-dose | 534.2020 ng/mL | Standard Deviation 56.0211 |
| Cohort 4: ARO-HSD 200 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 12 hours post-dose | 363.3568 ng/mL | Standard Deviation 35.9755 |
| Cohort 4: ARO-HSD 200 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 18 hours post-dose | 176.4455 ng/mL | Standard Deviation 41.8914 |
| Cohort 4: ARO-HSD 200 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 24 hours post-dose | 65.4435 ng/mL | Standard Deviation 28.6583 |
| Cohort 4: ARO-HSD 200 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 48 hours post-dose | 1.8418 ng/mL | Standard Deviation 1.2854 |
| Cohort 4: ARO-HSD 200 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 8 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 4: ARO-HSD 200 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 15 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 4: ARO-HSD 200 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 29 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohorts 1-4: Pooled Placebo | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 30 minutes post-dose | 22.13370 ng/mL | Standard Deviation 8.3169 |
| Cohorts 1-4: Pooled Placebo | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 1 hour post-dose | 29.3950 ng/mL | Standard Deviation 8.2373 |
| Cohorts 1-4: Pooled Placebo | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 2 hours post-dose | 26.4290 ng/mL | Standard Deviation 7.2923 |
| Cohorts 1-4: Pooled Placebo | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 15 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohorts 1-4: Pooled Placebo | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 2 hours pre-dose | 0.0000 ng/mL | Standard Deviation 0 |
| Cohorts 1-4: Pooled Placebo | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 24 hours post-dose | 6.7428 ng/mL | Standard Deviation 4.3051 |
| Cohorts 1-4: Pooled Placebo | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 29 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 1b: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 15 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 1b: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 2 hours post-dose | 166.2240 ng/mL | Standard Deviation 45.4507 |
| Cohort 1b: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 8 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 1b: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 1 hour post-dose | 158.0703 ng/mL | Standard Deviation 36.7514 |
| Cohort 1b: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 2 hours pre-dose | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 1b: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 30 minutes post-dose | 123.2292 ng/mL | Standard Deviation 11.5639 |
| Cohort 1b: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 29 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 1b: ARO-HSD 25 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 24 hours post-dose | 25.5277 ng/mL | Standard Deviation 9.082 |
| Cohort 3b: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 2 hours post-dose | 286.9603 ng/mL | Standard Deviation 103.4747 |
| Cohort 3b: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 1 hour post-dose | 251.3230 ng/mL | Standard Deviation 133.5201 |
| Cohort 3b: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 8 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 3b: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 29 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 3b: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 24 hours post-dose | 84.2982 ng/mL | Standard Deviation 28.8905 |
| Cohort 3b: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | Day 15 | 0.0000 ng/mL | Standard Deviation 0 |
| Cohort 3b: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 30 minutes post-dose | 174.1368 ng/mL | Standard Deviation 127.8926 |
| Cohort 3b: ARO-HSD 100 mg | Pharmacokinetics (PK) of ARO-HSD: Plasma Concentrations | 2 hours pre-dose | 0.0000 ng/mL | Standard Deviation 0 |
Secondary
PK of ARO-HSD in Normal Healthy Volunteers: Apparent Volume of Distribution During the Terminal-Phase (Vz/F)
Time frame: Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24, 48 hours postdose
Population: PK Analysis Set: all participants who received at least one dose of active study treatment and had sufficient plasma concentration data to characterize PK profile. Normal healthy volunteer cohorts only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ARO-HSD 25 mg | PK of ARO-HSD in Normal Healthy Volunteers: Apparent Volume of Distribution During the Terminal-Phase (Vz/F) | 148 L | Standard Deviation 38.7 |
| Cohort 2: ARO-HSD 50 mg | PK of ARO-HSD in Normal Healthy Volunteers: Apparent Volume of Distribution During the Terminal-Phase (Vz/F) | 99.9 L | Standard Deviation 29.3 |
| Cohort 3: ARO-HSD 100 mg | PK of ARO-HSD in Normal Healthy Volunteers: Apparent Volume of Distribution During the Terminal-Phase (Vz/F) | 141 L | Standard Deviation 37.6 |
| Cohort 4: ARO-HSD 200 mg | PK of ARO-HSD in Normal Healthy Volunteers: Apparent Volume of Distribution During the Terminal-Phase (Vz/F) | 153 L | Standard Deviation 27.7 |
Secondary
PK of ARO-HSD in Normal Healthy Volunteers: Area Under the Concentration-Time Curve From Dosing (Time 0) to the Time of the Last Measured Concentration (AUClast)
Time frame: Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24, 48 hours postdose
Population: PK Analysis Set: all participants who received at least one dose of active study treatment and had sufficient plasma concentration data to characterize PK profile. Normal healthy volunteer cohorts only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ARO-HSD 25 mg | PK of ARO-HSD in Normal Healthy Volunteers: Area Under the Concentration-Time Curve From Dosing (Time 0) to the Time of the Last Measured Concentration (AUClast) | 788 h*ng/mL | Standard Deviation 43.5 |
| Cohort 2: ARO-HSD 50 mg | PK of ARO-HSD in Normal Healthy Volunteers: Area Under the Concentration-Time Curve From Dosing (Time 0) to the Time of the Last Measured Concentration (AUClast) | 1830 h*ng/mL | Standard Deviation 346 |
| Cohort 3: ARO-HSD 100 mg | PK of ARO-HSD in Normal Healthy Volunteers: Area Under the Concentration-Time Curve From Dosing (Time 0) to the Time of the Last Measured Concentration (AUClast) | 3670 h*ng/mL | Standard Deviation 549 |
| Cohort 4: ARO-HSD 200 mg | PK of ARO-HSD in Normal Healthy Volunteers: Area Under the Concentration-Time Curve From Dosing (Time 0) to the Time of the Last Measured Concentration (AUClast) | 8450 h*ng/mL | Standard Deviation 479 |
Secondary
PK of ARO-HSD in Normal Healthy Volunteers: Area Under the Curve From Time 0 to Infinity (AUCinf)
Time frame: Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24, 48 hours postdose
Population: PK Analysis Set: all participants who received at least one dose of active study treatment and had sufficient plasma concentration data to characterize PK profile. Normal healthy volunteer cohorts only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ARO-HSD 25 mg | PK of ARO-HSD in Normal Healthy Volunteers: Area Under the Curve From Time 0 to Infinity (AUCinf) | 806 h*ng/mL | Standard Deviation 38.4 |
| Cohort 2: ARO-HSD 50 mg | PK of ARO-HSD in Normal Healthy Volunteers: Area Under the Curve From Time 0 to Infinity (AUCinf) | 1840 h*ng/mL | Standard Deviation 343 |
| Cohort 3: ARO-HSD 100 mg | PK of ARO-HSD in Normal Healthy Volunteers: Area Under the Curve From Time 0 to Infinity (AUCinf) | 3790 h*ng/mL | Standard Deviation 587 |
| Cohort 4: ARO-HSD 200 mg | PK of ARO-HSD in Normal Healthy Volunteers: Area Under the Curve From Time 0 to Infinity (AUCinf) | 8500 h*ng/mL | Standard Deviation 506 |
Secondary
PK of ARO-HSD in Normal Healthy Volunteers: Maximum Observed Plasma Concentration (Cmax)
Time frame: Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24, 48 hours postdose
Population: PK Analysis Set: all participants who received at least one dose of active study treatment and had sufficient plasma concentration data to characterize PK profile. Normal healthy volunteer cohorts only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ARO-HSD 25 mg | PK of ARO-HSD in Normal Healthy Volunteers: Maximum Observed Plasma Concentration (Cmax) | 74.0 ng/mL | Standard Deviation 11.5 |
| Cohort 2: ARO-HSD 50 mg | PK of ARO-HSD in Normal Healthy Volunteers: Maximum Observed Plasma Concentration (Cmax) | 184 ng/mL | Standard Deviation 52.2 |
| Cohort 3: ARO-HSD 100 mg | PK of ARO-HSD in Normal Healthy Volunteers: Maximum Observed Plasma Concentration (Cmax) | 294 ng/mL | Standard Deviation 60.3 |
| Cohort 4: ARO-HSD 200 mg | PK of ARO-HSD in Normal Healthy Volunteers: Maximum Observed Plasma Concentration (Cmax) | 644 ng/mL | Standard Deviation 183 |
Secondary
PK of ARO-HSD in Normal Healthy Volunteers: Terminal Elimination Half-Life (t1/2)
Time frame: Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24, 48 hours postdose
Population: PK Analysis Set: all participants who received at least one dose of active study treatment and had sufficient plasma concentration data to characterize PK profile. Normal healthy volunteer cohorts only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ARO-HSD 25 mg | PK of ARO-HSD in Normal Healthy Volunteers: Terminal Elimination Half-Life (t1/2) | 3.3 hours | Standard Deviation 0.9 |
| Cohort 2: ARO-HSD 50 mg | PK of ARO-HSD in Normal Healthy Volunteers: Terminal Elimination Half-Life (t1/2) | 2.5 hours | Standard Deviation 0.6 |
| Cohort 3: ARO-HSD 100 mg | PK of ARO-HSD in Normal Healthy Volunteers: Terminal Elimination Half-Life (t1/2) | 3.7 hours | Standard Deviation 0.9 |
| Cohort 4: ARO-HSD 200 mg | PK of ARO-HSD in Normal Healthy Volunteers: Terminal Elimination Half-Life (t1/2) | 4.5 hours | Standard Deviation 0.7 |
Secondary
PK of ARO-HSD in Normal Healthy Volunteers: Time to Reach Cmax (Tmax)
Time frame: Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24, 48 hours postdose
Population: PK Analysis Set: all participants who received at least one dose of active study treatment and had sufficient plasma concentration data to characterize PK profile. Normal healthy volunteer cohorts only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: ARO-HSD 25 mg | PK of ARO-HSD in Normal Healthy Volunteers: Time to Reach Cmax (Tmax) | 2.5 hours |
| Cohort 2: ARO-HSD 50 mg | PK of ARO-HSD in Normal Healthy Volunteers: Time to Reach Cmax (Tmax) | 3.0 hours |
| Cohort 3: ARO-HSD 100 mg | PK of ARO-HSD in Normal Healthy Volunteers: Time to Reach Cmax (Tmax) | 8.0 hours |
| Cohort 4: ARO-HSD 200 mg | PK of ARO-HSD in Normal Healthy Volunteers: Time to Reach Cmax (Tmax) | 3.0 hours |
Secondary
Secondary: PK of ARO-HSD in Normal Healthy Volunteers: Oral Clearance (CL/F)
Time frame: Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24, 48 hours postdose
Population: PK Analysis Set: all participants who received at least one dose of active study treatment and had sufficient plasma concentration data to characterize PK profile. Normal healthy volunteer cohorts only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ARO-HSD 25 mg | Secondary: PK of ARO-HSD in Normal Healthy Volunteers: Oral Clearance (CL/F) | 31.1 L/hour | Standard Deviation 1.48 |
| Cohort 2: ARO-HSD 50 mg | Secondary: PK of ARO-HSD in Normal Healthy Volunteers: Oral Clearance (CL/F) | 27.9 L/hour | Standard Deviation 4.96 |
| Cohort 3: ARO-HSD 100 mg | Secondary: PK of ARO-HSD in Normal Healthy Volunteers: Oral Clearance (CL/F) | 26.8 L/hour | Standard Deviation 3.65 |
| Cohort 4: ARO-HSD 200 mg | Secondary: PK of ARO-HSD in Normal Healthy Volunteers: Oral Clearance (CL/F) | 23.6 L/hour | Standard Deviation 1.43 |
Secondary
Urine PK of ARO-HSD in Normal Healthy Volunteers: Amount of Unchanged Drug Recovered in Urine Over 0-24 Hours Postdose (Ae0-24h)
Time frame: Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24 hours postdose
Population: PK Analysis Set: all participants who received at least one dose of active study treatment and had sufficient plasma concentration data to characterize PK profile. Normal healthy volunteer cohorts only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ARO-HSD 25 mg | Urine PK of ARO-HSD in Normal Healthy Volunteers: Amount of Unchanged Drug Recovered in Urine Over 0-24 Hours Postdose (Ae0-24h) | 1.56 mg | Standard Deviation 0.12 |
| Cohort 2: ARO-HSD 50 mg | Urine PK of ARO-HSD in Normal Healthy Volunteers: Amount of Unchanged Drug Recovered in Urine Over 0-24 Hours Postdose (Ae0-24h) | 3.64 mg | Standard Deviation 0.75 |
| Cohort 3: ARO-HSD 100 mg | Urine PK of ARO-HSD in Normal Healthy Volunteers: Amount of Unchanged Drug Recovered in Urine Over 0-24 Hours Postdose (Ae0-24h) | 6.67 mg | Standard Deviation 3.21 |
| Cohort 4: ARO-HSD 200 mg | Urine PK of ARO-HSD in Normal Healthy Volunteers: Amount of Unchanged Drug Recovered in Urine Over 0-24 Hours Postdose (Ae0-24h) | 45.8 mg | Standard Deviation 9.66 |
Secondary
Urine PK of ARO-HSD in Normal Healthy Volunteers: Percentage of the Administrated Drug Recovered in Urine Over 0-24 Hours (Fe0-24h)
Time frame: Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24 hours postdose
Population: PK Analysis Set: all participants who received at least one dose of active study treatment and had sufficient plasma concentration data to characterize PK profile. Normal healthy volunteer cohorts only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ARO-HSD 25 mg | Urine PK of ARO-HSD in Normal Healthy Volunteers: Percentage of the Administrated Drug Recovered in Urine Over 0-24 Hours (Fe0-24h) | 6.23 percentage of study drug | Standard Deviation 0.47 |
| Cohort 2: ARO-HSD 50 mg | Urine PK of ARO-HSD in Normal Healthy Volunteers: Percentage of the Administrated Drug Recovered in Urine Over 0-24 Hours (Fe0-24h) | 7.29 percentage of study drug | Standard Deviation 1.5 |
| Cohort 3: ARO-HSD 100 mg | Urine PK of ARO-HSD in Normal Healthy Volunteers: Percentage of the Administrated Drug Recovered in Urine Over 0-24 Hours (Fe0-24h) | 6.67 percentage of study drug | Standard Deviation 3.21 |
| Cohort 4: ARO-HSD 200 mg | Urine PK of ARO-HSD in Normal Healthy Volunteers: Percentage of the Administrated Drug Recovered in Urine Over 0-24 Hours (Fe0-24h) | 22.9 percentage of study drug | Standard Deviation 4.83 |
Secondary
Urine PK of ARO-HSD in Normal Healthy Volunteers: Renal Clearance (CLr)
Time frame: Day 1: Predose, 15 minutes, 30 minutes, 1, 2, 4, 8 12, 18, 24 hours postdose
Population: PK Analysis Set: all participants who received at least one dose of active study treatment and had sufficient plasma concentration data to characterize PK profile. Normal healthy volunteer cohorts only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ARO-HSD 25 mg | Urine PK of ARO-HSD in Normal Healthy Volunteers: Renal Clearance (CLr) | 1.97 L/hour | Standard Deviation 0.14 |
| Cohort 2: ARO-HSD 50 mg | Urine PK of ARO-HSD in Normal Healthy Volunteers: Renal Clearance (CLr) | 1.99 L/hour | Standard Deviation 0.17 |
| Cohort 3: ARO-HSD 100 mg | Urine PK of ARO-HSD in Normal Healthy Volunteers: Renal Clearance (CLr) | 1.82 L/hour | Standard Deviation 0.88 |
| Cohort 4: ARO-HSD 200 mg | Urine PK of ARO-HSD in Normal Healthy Volunteers: Renal Clearance (CLr) | 5.75 L/hour | Standard Deviation 1.43 |