IAP-086-1: A Phase 1 Single Ascending Dose First-Time in Human Study

This is a phase 1, open-label, dose-escalation, study of IAP086 in persons with HIV-1 (PWH) on antiretroviral therapy (ART). The study is designed to characterize the safety, tolerability, and pharmacokinetics (PK) of the study drug in healthy PWH suppressed on ART. The participant's standard of care ART regimen is continued throughout the study period.

The study will evaluate single ascending doses of IAP086 with a 1+3 design for cohorts 1-3, followed by a 3+3 design for cohorts 4-9. Given the focus of this study is on safety, accrual within a dose cohort will be staggered such that each participant is followed for 6 days following study drug administration prior to study drug administration in a subsequent participant. A 14-day dose-limiting toxicity (DLT) period is observed prior to escalation to the next dose cohort level. Dose escalation proceeds until cell-associated HIV RNA induction (see below) or drug-related DLT criteria to halt escalation are met.

This study is designed to limit study drug exposures to participants due to the exploratory nature of this first-in-human study and effects seen after multiple doses in non-clinical toxicology studies. An adaptive dose escalation strategy will be used.

This study will have up to 9 dose cohorts starting at 0.3 µg/kg. Participants in each dose cohort will be dosed sequentially. Each participant will be directly monitored for safety for at least 24 hours after dosing, with a 6-day period of safety observations completed prior to dosing of the next participant in the same dose cohort.

The study will evaluate single ascending doses of IAP086 by intravenous (IV) infusion with a 1+3 design for cohorts 1-3, followed by a 3+3 design for cohorts 4-9.If no dose limiting toxicities occur in the 1 participant in cohorts 1-3 or 3 participants in cohorts 4-9, the study proceeds to the next higher dose following Safety Monitoring Committee (SMC) review.

All cohorts can be expanded to include an additional +3 participants if a treatment related DLT is observed to more fully explore safety events, clinical laboratory results, and virological or biomarker data prior to escalating to the next dose cohort.

Inclusion criteria

• Able and willing to provide informed consent. Participants must be willing and able to comply with study procedures
• Able and willing to provide adequate locator information
• Able and willing to comply with all study requirements through Day 28
• Agrees not to enroll on another study of an investigational agent during the study period, defined as any unlicensed investigational drug not yet approved for use in humans
• Aged ≥ 18 years and ≤ 70 years of age, at the time of informed consent
• HIV infection documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral assay.

NOTE: The term "licensed" refers to a US FDA-approved kit, which is required for all Investigational New Drug (IND) studies. World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment.

• Plasma HIV-1 RNA viral load must meet the following conditions:

• < 50 copies/mL at 2 time points within 12 months prior to screening
• < 50 copies/mL at screening
• Not > 1000 copies/mL at any time within 6 months prior to screening
• On continuous ART for at least 24 months prior to screening and must continue ART throughout the study. Permitted ART regimens include:

• At least 3 ART drugs, one ART drug must include an integrase inhibitor or non-nucleoside reverse transcriptase inhibitor (NNRTI), efavirenz excluded (see 5.2) or
• At least 2 ART drugs including injectables, in which one drug is an integrase inhibitor that is FDA approved or recommended by Department of Health and Human Services Treatment Guidelines.

NOTE: Other potent fully suppressive antiretroviral combinations will be considered on a case-by-case basis.

NOTE: No changes or modifications of ART dosing allowed within 30 days prior to screening.

• CD4 cell count > 350 cells/mm3 at screening
• Hepatitis C virus (HCV) antibody negative or HCV RNA negative at screening
• Hepatitis B surface antigen negative at screening
• Clinical laboratory parameters obtained at screening as follows:

• Platelet count ≥ 125 × 103/µL
• Absolute neutrophil count ≥ 1.5 × 103/µL
• Absolute Lymphocyte levels ≥ 1000 cells/uL
• Hemoglobin ≥ 12 g/dL (male) and ≥ 11 g/dL (females)
• Prothrombin time or international normalized ratio (INR) ≤ 1.1 × upper limit of normal (ULN)
• Serum total bilirubin ≤ 1.5 × ULN. If total bilirubin is elevated, direct bilirubin ≤ 2 × ULN. If ART includes atazanavir, direct bilirubin must be ≤ 1.0 mg/dL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 × ULN
• Alkaline phosphatase (ALP) ≤ 1.5 × ULN
• Serum glucose (fasting or non-fasting) ≤ Grade 1
• Lipase ≤ 1.5 × ULN
• Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min as determined by the 2021 Chronic Kidney Disease Epidemiology Collaboration equation (CKD-Epi equation) found at: https://www.mdcalc.com/calc/3939/ckd-epi-equations-glomerular-filtration-rate-gfr
• Negative serum pregnancy test for women of childbearing potential (WOCBP) with a sensitivity of at least 25 milli-International Units (mIU)/mL at screening
• All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization, egg donation) starting with screening visit through 30 days after receiving study drug
• WOCBP, defined as female at birth, is not pregnant, expecting to become pregnant, or breastfeeding or participant assigned male at birth is not expecting to father children, starting with screening visit through 30 days after receiving study product
• WOCBP, not surgically sterilized (hysterectomy, bilateral salpingectomy, and bilateral oophorectomy), and not post-menopausal for at least 24 consecutive months, i.e., have had menses within the preceding 24 months, must have a negative serum pregnancy test performed within 72 hours prior to initiation of study drug
• WOCBP and male participants of reproductive potential with WOCBP partners must agree to consistently use a highly effective method of contraception and a barrier method (condom, diaphragm or cervical cap) for the duration and for 30 days afterwards. Highly effective methods include the following:

Highly effective methods include:

• Contraceptive subdermal implant
• Intrauterine device or intrauterine system
• Combined estrogen and progestogen oral contraceptive
• Injectable progestogen
• Contraceptive vaginal ring
• Percutaneous contraceptive patches
• True sexual abstinence (only if it is the participant's consistent lifestyle choice and not just trial-related).
• Sterilization of male partner with documentation of azoospermia prior to the participant's entry into the study, and this individual is the sole partner for the participant. The documentation of partner sterility can come from the site personnel's review of medical records, medical examination and/or semen analysis, or medical history interview provided by the participant or the partner. Self-reported documentation of reproductive potential should be entered in the source documents.

Barrier method may include:

• Male or female condoms with or without a cream or gel that kills sperm
• Diaphragm or cervical cap with a cream or gel that kills sperm
• Sponge
• Participants not of reproductive potential are eligible without requiring the use of contraceptives. Acceptable documentation are specified below.

NOTE: Men who have sex with men only will not be required to use contraception NOTE: Women who have sex with women only will not be required to use contraception

NOTE: Written/oral documentation communicated by clinician/clinician's staff of one of the following:

• Physician report/letter
• Operative report or other source documentation in the patient record (a laboratory report of azoospermia is required to document successful vasectomy)
• Discharge summary
• Follicle stimulating hormone-release factor (FSH) measurement elevated into the menopausal range as established by the reporting laboratory
• Willingness to defer vaccinations, including influenza and Coronavirus Disease (COVID-19) vaccines, from 30 days prior to Day -1 through Day 28 post-infusion
• Willingness to abstain from alcohol, illicit drugs and grapefruit juice and limit caffeine intake from 24 hours prior to study treatment through Day 7
• Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, and laboratory tests
• Body mass index of less than 35

Exclusion criteria

• Current use of moderate or strong CYP3A inhibitors or inducers for any indication including current use of a protease inhibitor, ritonavir, cobicistat, or efavirenz as part of ART regimen (See Section 6.1.1)
• Significant history or presence of respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, neurological disorders, immunodeficiency other than HIV-1, or clinical condition capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention or interfering with the interpretation of data
• Unstable asthma (e.g. sudden acute attacks occurring without an obvious trigger) or asthma requiring:

• Daily steroid or long-acting beta-agonist prevention
• Hospitalization in the last two years
• Clinically significant cardiovascular disease within 12 months prior to screening including but not limited to:

• Myocardial infarction or unstable angina
• Cardiac arrhythmias
• Uncontrolled hypertension at screening: systolic blood pressure > 180 mmHg, diastolic blood pressure >100 mmHg that is sustained on repeat measurement (without intervention)
• Cerebrovascular accident
• Congestive heart failure, New York Heart Association class II-IV
• QTc >450 msec at screening NOTE: QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF), and/or another method, machine-read or manually over-read
• Diabetes mellitus ≥ Grade 3 per DAIDS criteria (defined as uncontrolled despite treatment modification or hospitalization for immediate glucose control indicated)
• History of malignancy within the last 3 years NOTE: History of non-melanoma skin cancer (e.g., basal cell carcinoma or squamous cell skin cancer) is not exclusionary with documentation of resolution per topical treatment or complete resection as determined by a dermatologist at least 3 months prior to screening
• Evidence of active viral, bacterial, or systemic fungal infection requiring parenteral antibiotic, antiviral, or antifungal treatment within 14 days prior to the initiation of study drug.
• History of coagulopathy or other bleeding disorder or current or anticipated need for chronic anti-coagulation
• An underlying skin disease or disorder including, but not limited to, inflammation, dermatitis, eczema, drug rash, drug allergy, psoriasis, food allergy, urticaria, or tattoo that would interfere with assessment of infusion sites
• History of severe allergic reaction with generalized urticarial, angioedema, or anaphylaxis
• Use of any prescription or non-prescription drugs or dietary supplements that are prohibited (See Section 6.11), within 7 days prior to dosing
• Use of any immunosuppressive, immunomodulatory or cytokine therapy within 90 days prior to entry. Not Exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3] topical steroids for mild, uncomplicated dermatitis unless it interferes with assessment of infusion site reactions; or [4] a single course of oral /parenteral prednisone or equivalent at doses <20mg/day and length of therapy <14 days with completion at least 30 days prior to enrollment.
• Use of any other investigational treatment within 6 months prior to enrollment, with the exception of Phase II or higher studies of antiretroviral agents
• Regular use (daily to weekly) of known drugs of abuse within 3 months of enrollment
• Increased alcohol consumption within 6 months prior to screening, defined as an average weekly intake of >14 units for males or >7 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
• Current tobacco use or current use of nicotine-containing products (e.g. nicotine patches or vaporizing devices) within 6 months prior to screening
• Known sensitivity to any of the study interventions, or components thereof, or study drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study
• Any other clinical condition, behavior or prior therapy that, in the opinion of the Investigator, would make the participant unsuitable for the study; unable to comply with dosing requirements; or unable to comply with study visits