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

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).

Key Inclusion Criteria:

• 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.
• Ages 18-65 years (inclusive), at the time of consent.
• At least 45 kg with a body mass index (BMI; Quetelet index) in the range 18.0-32.0, at screening.
• 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.
• 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.
• 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.
• Have received at least 2 doses of the COVID vaccine (1 dose of the Janssen-Cilag vaccine is acceptable).

Key Exclusion Criteria:

• 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.
• Surgery (eg stomach bypass) or medical condition that might affect absorption of medicines (cholecystectomy is allowed).
• 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.
• History of relevant atopy including any confirmed significant allergic reactions against any drug, or multiple drug allergies (non-active hay fever is acceptable)
• History of suicidal behaviour or express or have any suicidal ideation on the C-SSRS at screening or admission.
• Employee of the Sponsor, the CRO and/or study site or their relatives.
• Unable or unwilling to eat a high-fat breakfast per study requirements (Part C only).