Assessment of the Safety, Tolerability and Pharmacokinetics of AV078 in Healthy Volunteers

A Phase 1, Single and Multiple Ascending Dose, Food Effect, and Drug-Drug Interaction Study with Itraconazole, Midazolam and Fexofenadine of Orally Administered AV078 in Healthy Adults

This Phase 1 study in healthy adult volunteers is planned to evaluate the safety, tolerability, and pharmacokinetics (PK) of AV078, a selective inhibitor of mammalian target of rapamycin complex 1 (mTORC1).

The study will begin with a standard exploration of safety and tolerability in sequential single ascending dose (SAD) and multiple ascending dose (MAD) cohorts. Subsequent cohorts will collect PK data to evaluate food effects and potential drug-drug interactions relevant to AV078.

Study Overview

• Status: Completed
• Conditions: Healthy Participants
• Intervention / Treatment: Drug: AV078; Drug: Placebo; Drug: Itraconazole; Drug: Midazolam; Drug: Fexofenadine

Detailed Description

This Phase 1 study in healthy adult volunteers is planned to evaluate the safety, tolerability, and pharmacokinetics (PK) of AV078, a selective inhibitor of mammalian target of rapamycin complex 1 (mTORC1). The study will additionally explore the relationship between AV078 and pharmacodynamic biomarkers related to mTOR.

The study will begin with a standard exploration of safety and tolerability in sequential single ascending dose (SAD) and multiple ascending dose (MAD) cohorts, incorporating reviews by a dedicated Safety Review Group to guide dose escalation decisions. The study will also include a cohort using a 2-way crossover design to evaluate food effects on the PK of AV078. The study will additionally include cohorts evaluating potential drug-drug-interactions (DDIs) using coadministration of index substrates and index perpetrators typically used in DDI studies of the relevant enzymes. Specifically, one DDI cohort will assess the effects of administration of itraconazole (a strong inhibitor of CYP3A4) on the PK of AV078, and an additional DDI cohort will assess the effects of administration of AV078 on the PK of midazolam (a sensitive probe substrate for CYP3A4) and fexofenadine (a probe substrate for P-gp).

• Study Type: Interventional
• Enrollment (Actual): 89
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Herston, Queensland, Australia, 4006
      • Q-Pharm
  • Victoria
    • Melbourne, Victoria, Australia, 3220
      • Nucleus Network Pty Ltd

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Key Inclusion Criteria:

1. Healthy male or female as determined by medical evaluation including medical history, psychiatric history, and no clinically significant findings on physical examination, laboratory tests, and cardiac monitoring. Slight excursions outside of normal limits may be allowed provided they are considered not clinically significant by the investigator.
2. Ages 18-65 years (inclusive), at the time of consent.
3. At least 45 kg with a body mass index (BMI; Quetelet index) in the range 18.0-32.0, at screening.
4. Sufficient intelligence to understand the nature of the trial and any hazards of participating in it. Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of, the entire trial.
5. Willingness to give written consent to participate after reading the information and consent form, and after having the opportunity to discuss the trial with the investigator or their delegate.
6. Agree not to donate blood or blood products during the study and for up to 3 months after the last administration of the trial medication.
7. Have received at least 2 doses of the COVID vaccine (1 dose of the Janssen-Cilag vaccine is acceptable).

Key Exclusion Criteria:

1. Current, or past history of any clinically significant mental or physical illness or condition that the Investigator concludes would create significant concern for participation in the study.
2. Surgery (eg stomach bypass) or medical condition that might affect absorption of medicines (cholecystectomy is allowed).
3. Presence or history of severe adverse reaction to any drug or a history of sensitivity to midazolam (Part E only), fexofenadine (Part E only) and itraconazole (Part D only), or any excipients in the tablets/solutions.
4. History of relevant atopy including any confirmed significant allergic reactions against any drug, or multiple drug allergies (non-active hay fever is acceptable)
5. History of suicidal behaviour or express or have any suicidal ideation on the C-SSRS at screening or admission.
6. Employee of the Sponsor, the CRO and/or study site or their relatives.
7. Unable or unwilling to eat a high-fat breakfast per study requirements (Part C only).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AV078; In part A, a single ascending doses of AV078 oral solution will be investigated in separate cohorts. The starting dose will be 0.5 mg and ascending doses will be determined based on data from previous cohorts. In Part B, multiple ascending doses of AV078 oral solution will be administered once daily for 14 days. Dose levels will be determined based on data from the single ascending dose study and previous cohorts in the multiple ascending dose study. In Part C the effect of food (fasting or high calorie) on the pharmacokinetics of a single dose of AV078 will be investigated. The dose will be determined from Part A of the study.	Drug: AV078; Oral solution containing active ingredient, AV078
Placebo Comparator: Placebo; In Part A, placebo oral solution (containing no active ingredient) will be administered once. In Part B, placebo oral solution (containing no active ingredient) will be administered once daily for 14 days.	Drug: Placebo; Oral solution with no active ingredients
Other: Itraconazole; In Part D, 200 mg itraconazole will be administered as an oral capsule once daily for 9 days, to investigate the effect of itraconazole on the pharmacokinetics of AV078.	Drug: Itraconazole; Once daily oral dose of 200 mg itraconazole administered for 9 days
Other: Midazolam and fexofenadine; In Part E, 2.5 mg midazolam will be administered as an oromucosal solution and 120 mg fexofenadine will be administered as an oral tablet on day 1 and day 18, to investigate the effect of AV078 on the pharmacokinetics of midazolam and fexofenadine.	Drug: Midazolam; 2.5 mg midazolam administered orally on day 1 and day 18; Drug: Fexofenadine; 120 mg fexofenadine administered orally on day 1 and day 18

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of treatment emergent adverse events (TEAEs).		From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Occurrence of clinically significant changes in physical examination (including neurological assessment).	Abnormal physical examination findings will be listed.	From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Change in blood haematology values.	Haematology data will be summarised by treatment	From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Change in blood biochemisty values.	Biochemistry data will be summarised by treatment	From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Change in urinalysis values.	Urinalysis data will be summarised by treatment	From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Change in lipid panel values.	Lipid panel data will be summarised by treatment	From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Change in blood coagulation values.	Blood coagulation data will be summarised by treatment	From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Clinically significant ECG findings.	Occurrence of clinically significant ECG findings will be listed.	From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Monitor for the emergence of suicidal ideation and behaviour using the Columbia-Suicide Severity Rating Scale (C-SSRS).	C-SSRS will be listed and summarised for each visit.	From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Pharmacokinetics measured by area under the concentration-time curve in fasted and fed state.	To determine the effect of food on the pharmacokinetic profile of AV078.	Day 1 to Day 7 post-dose and final follow-up visit (Day 14)
Pharmacokinetics measured by the maximum plasma concentration (Cmax) in fasted and fed state.	To determine the effect of food on the pharmacokinetic profile of AV078.	Day 1 to Day 7 post-dose and final follow-up visit (Day 14)
Effects of itraconazole on the pharmacokinetics of AV078 measured by area under the concentration-time curve.		Day 1 to Day 15 post-dose and final follow-up visit (Day 23)
Effects of itraconazole on the pharmacokinetics of AV078 measured by the maximum plasma concentration (Cmax).		Day 1 to Day 15 post-dose and final follow-up visit (Day 23)
Effects of AV078 on the pharmacokinetics of midazolam and fexofenadine measured by area under the concentration-time curve.		Day 1, 2, 18 and 19 post-dose (midazolam) or Day 1-3, 18 and 19 post-dose (fexofenadine)
Effects of AV078 on the pharmacokinetics of midazolam and fexofenadine measured by the maximum plasma concentration (Cmax).		Day 1, 2, 18 and 19 post-dose (midazolam) or Day 1-3, 18 and 19 post-dose (fexofenadine)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of AV078 measured by the area under the concentration-time curve.		Day 1 to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Pharmacokinetics of AV078 measured by the maximum plasma concentration (Cmax).		Day 1 to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Pharmacokinetics of AV078 measured by time of maximum plasma/whole blood concentration.		Day 1 to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Pharmacokinetics of AV078 measured by terminal elimination half-life.		Day 1 to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Pharmacokinetics of AV078 measured by fraction of drug excreted in urine.		Day 1 to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Pharmacokinetics of AV078 measured by renal clearance from plasma/whole blood.		Day 1 to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Change from baseline and placebo-corrected change from baseline in ECG parameter, QTcF including exposure response.		Part A: Screening (Day -42) to Day 5 post-dose, and final follow-up visit (Day 14). Part B: Screening (Day -42) to Day 2 post-dose, then Day 4, 7, 10, 14, 15 and 18 post-dose, and final follow-up visit (Day 42)]
Change from baseline and placebo-corrected change from baseline in ECG parameter - heart rate (HR)	ECG parameters will be descriptively summarised at each time point.	Part A: Screening (Day -42) to Day 5 post-dose, and final follow-up visit (Day 14). Part B: Screening (Day -42) to Day 2 post-dose, then Day 4, 7, 10, 14, 15 and 18 post-dose, and final follow-up visit (Day 42)]
Change from baseline and placebo-corrected change from baseline in ECG parameter - PR interval	ECG parameters will be descriptively summarised at each time point.	Part A: Screening (Day -42) to Day 5 post-dose, and final follow-up visit (Day 14). Part B: Screening (Day -42) to Day 2 post-dose, then Day 4, 7, 10, 14, 15 and 18 post-dose, and final follow-up visit (Day 42)]
Change from baseline and placebo-corrected change from baseline in ECG parameter - QRS interval	ECG parameters will be descriptively summarised at each time point.	Part A: Screening (Day -42) to Day 5 post-dose, and final follow-up visit (Day 14). Part B: Screening (Day -42) to Day 2 post-dose, then Day 4, 7, 10, 14, 15 and 18 post-dose, and final follow-up visit (Day 42)]
Incidence and severity of treatment emergent adverse events (TEAEs)	Assessed for single doses of AV078 taken fasted or after a high-fat breakfast and repeated oral doses of AV078	From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E)
Occurrence of clinically significant changes in physical examination (including neurological assessment).	Abnormal physical examination findings will be listed.	From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E)
Change in blood haematology values	Haematology data will be summarised by treatment.	From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E)
Change in blood biochemistry values	Biochemistry data will be summarised by treatment.	From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E)
Change in urinalysis values	Urinalysis data will be summarised by treatment.	From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E)
Change in lipid panel values	Lipid panel data will be summarised by treatment.	From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E)
Change in blood coagulation values	Coagulation data will be summarised by treatment.	From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E)
Monitor for the emergence of suicidal ideation and behaviour using the Columbia-Suicide Severity Rating Scale (C-SSRS)	C-SSRS will be listed and summarised for each visit	From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E)

Collaborators and Investigators

• Sponsor: Aeovian Pharmaceuticals, Inc.
• Investigators: Study Director: Davis Ryman, Chief Medical Officer, Aeovian Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2024
• Primary Completion (Actual): February 8, 2025
• Study Completion (Actual): February 8, 2025

Study Registration Dates

• First Submitted: December 19, 2023
• First Submitted That Met QC Criteria: January 3, 2024
• First Posted (Actual): January 16, 2024

Study Record Updates

• Last Update Posted (Estimated): March 26, 2025
• Last Update Submitted That Met QC Criteria: March 24, 2025
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: mTOR
• Additional Relevant MeSH Terms: Anti-Infective Agents; Antifungal Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Enzyme Inhibitors; Anesthetics; Central Nervous System Depressants; Histamine Antagonists; Histamine Agents; Neurotransmitter Agents; Adjuvants, Anesthesia; Hypnotics and Sedatives; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; GABA Modulators; GABA Agents; Steroid Synthesis Inhibitors; Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Anti-Allergic Agents; Cytochrome P-450 CYP3A Inhibitors; Histamine H1 Antagonists; 14-alpha Demethylase Inhibitors; Histamine H1 Antagonists, Non-Sedating; Midazolam; Itraconazole; Fexofenadine
• Other Study ID Numbers: CL-078-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No