A First-In-Human Study of ARO-INHBE in Adults With Obesity With and Without Type 2 Diabetes Mellitus

Official title

A Phase 1/2a Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ARO-INHBE in Adult Volunteers With Obesity With and Without Diabetes Mellitus

Overview

This is a Phase 1/2a double-blind dose-escalating study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of ARO-INHBE in adult participants with obesity (in Part 1), the safety, tolerability, PK, and PD of multiple doses of ARO-INHBE either as monotherapy, or in combination with tirzepatide, in adult participants with obesity with and without type 2 diabetes mellitus (in Part 2 and Part 3).

Interventions

• Drug ARO-INHBE
  Subcutaneous (SC) injection
• Drug Placebo
  Calculated volume to match active treatment by SC injection
• Drug Tirzepatide
  SC injection

Primary outcome measures

• Number of Participants with Treatment-Emergent Adverse Events (TEAEs) [Time frame: Up to Day 365]

Secondary outcome measures (11)

• PK of ARO-INHBE: Maximum observed Plasma Concentration (Cmax) [Time frame: Part 1: single dose (Day 1): Through 48 hours post-dose; Part 1: multiple dose (Day 1, Day 29): Through 48 hours post first and second dose; Part 3: multiple dose (Day 1, Day 85): Through 48 hours post first and second dose]
• PK of ARO-INHBE: Time to Maximum Observed Plasma Concentration (Tmax) [Time frame: Part 1: single dose (Day 1): Through 48 hours post-dose; Part 1: multiple dose (Day 1, Day 29); Part 3: multiple dose (Day 1, Day 85): Through 48 hours post first and second dose]
• PK of ARO-INHBE: Area Under the Plasma Concentration Versus Time Curve from Zero to 24 Hours (AUC0-24) [Time frame: Part 1: single dose (Day 1): Through 48 hours post-dose; Part 1: multiple dose (Day 1, Day 29); Part 3: multiple dose (Day 1, Day 85): Through 48 hours post first and second dose]
• PK of ARO-INHBE: Area Under the Plasma Concentration Versus Time Curve from Zero to the Last Quantifiable Plasma Concentration (AUC0-t) [Time frame: Part 1: single dose (Day 1): Through 48 hours post-dose; Part 1: multiple dose (Day 1, Day 29); Part 3: multiple dose (Day 1, Day 85): Through 48 hours post first and second dose]
• PK of ARO-INHBE: Area Under the Plasma Concentration Versus Time Curve from Zero to Infinity (AUC0-∞) [Time frame: Part 1: single dose (Day 1): Through 48 hours post-dose; Part 1: multiple dose (Day 1, Day 29); Part 3: multiple dose (Day 1, Day 85): Through 48 hours post first and second dose]
• PK of ARO-INHBE: Terminal Half-life (t1/2) [Time frame: Part 1: single dose (Day 1): Through 48 hours post-dose; Part 1: multiple dose (Day 1, Day 29); Part 3: multiple dose (Day 1, Day 85): Through 48 hours post first and second dose]
• PK of ARO-INHBE: Apparent Systemic Clearance (CL/F) [Time frame: Part 1: single dose (Day 1): Through 48 hours post-dose; Part 1: multiple dose (Day 1, Day 29); Part 3: multiple dose (Day 1, Day 85): Through 48 hours post first and second dose]
• PK of ARO-INHBE: Apparent Terminal-phase Volume of Distribution (Vz/F) [Time frame: Part 1: single dose (Day 1): Through 48 hours post-dose; Part 1: multiple dose (Day 1, Day 29); Part 3: multiple dose (Day 1, Day 85): Through 48 hours post first and second dose]
• PK of ARO-INHBE: Recovery of Unchanged Drug in Urine from Time 0 to 24 Hours after dosing (amount excreted: Ae) [Time frame: Part 1: single dose (Day 1): Through 48 hours post-dose; Part 1: multiple dose (Day 1, Day 29); Part 3: multiple dose (Day 1, Day 85): Through 48 hours post first and second dose]
• PK of ARO-INHBE: Fraction or Percentage of Administered Drug Excreted in Urine from Time 0 to 24 Hours after Dosing (Fe) [Time frame: Part 1: single dose (Day 1): Through 48 hours post-dose; Part 1: multiple dose (Day 1, Day 29); Part 3: multiple dose (Day 1, Day 85): Through 48 hours post first and second dose]
• PK of ARO-INHBE: Renal Clearance (CLr) [Time frame: Part 1: single dose (Day 1): Through 48 hours post-dose; Part 1: multiple dose (Day 1, Day 29); Part 3: multiple dose (Day 1, Day 85): Through 48 hours post first and second dose]

Eligibility criteria

Inclusion criteria

• Obesity, defined as Body Mass Index (BMI) between 30 to 50 kilograms (kg)/square meter (m\^2) at Screening
• At least one self-reported, unsuccessful attempt at weight loss with lifestyle modification
• Type 2 diabetes mellitus for at least 6 months prior to Screening, with glycated hemoglobin (HgbA1c) between 6.0% (42 millimole \[mmol\]/mole \[mol\]) and 9.5% (80 mmol/mol) at Screening, on a stable diabetes medication regimen for at least 3 months (select Part 2 and Part 3 cohorts only)
• Willing, able and motivated to comply with all study assessments and adhere to the protocol schedule, including adherence to a stable diet and exercise routine for the duration of the study
• No abnormal finding of clinical relevance at Screening that, in the opinion of investigator, could adversely impact participant safety or adversely impact study results
• Participants of childbearing potential must agree to use highly effective contraception during the study and for at least 90 days following the end of the study or last dose of study medication, whichever is later. Participants must not donate sperm or eggs during the study and for at least 90 days following the end of the study or last dose of study medication, whichever is later.

Exclusion criteria

• Self-reported (or documented) weight gain or loss >5% within 3 months prior to Screening
• Use of glucagon-like protein 1 receptor (GLP1R) agonists (liraglutide, semaglutide, etc.) for any indication within 6 months prior to Screening
• Use of non-GLP1R medications for weight loss within 3 months prior to Screening, including but not limited to naltrexone/bupropion, orlistat, phentermine/topiramate, and other prescription or over-the-counter medication or supplements taken for weight loss
• Obesity attributable, in the investigator's opinion, to medication use, monogenic, or endocrinologic disorders (other than polycystic ovary syndrome)
• History or prior surgical or device-based therapy for obesity
• Use of medications strongly associated with weight gain within 3 months prior to Screening
• Type 1 diabetes mellitus
• History of hyperthyroidism or thyroid-stimulating hormone (TSH) levels <0.4 or >6.0 milli-international units (mIU)/liter (L) at Screening
• Evidence of clinically significant end-organ disease

Note: Other Inclusion/Exclusion criteria may apply per protocol

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

New Zealand · 5 centers

• Research Site 1 — Grafton
• Research Site 5 — Auckland
• Research Site 3 — Auckland
• Research Site 2 — Christchurch
• Research Site 4 — Hamilton

Identifiers

NCT: NCT06700538 · AROINHBE-1001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗