First in Human Study of TLC-ART 101 (ACTU 2001)

First in Human Clinical Trial of a Next Generation, Long-acting Injectable, Combination Antiretroviral Therapy Platform

This study is a prospective, open-label, single-site, first-in-human study of a long-acting, injectable combination antiretroviral therapy platform, with a pharmacologically-guided adaptive design for dose escalation, de-escalation, and study duration. The study is designed to learn whether the formulation can be used as a platform for other drugs for treatment of HIV. The formulation is a drug combination nanoparticle (DCNP). The study will be conducted by UW Positive Research. The sample size for this study is 12-16. The study population consists of healthy adults without HIV. The study duration is 57 days per participant at the start of the study.

This study is a prospective, open-label, single-site, first-in-human study of a long-acting, injectable combination antiretroviral therapy platform, with a pharmacologically-guided adaptive design for dose escalation, de-escalation, and study duration. The study has two primary aims as follows:

1. To characterize the plasma concentration-time course and pharmacokinetics (PK) of a single dose of the drug substances of TLC-ART 101 (lopinavir, ritonavir, and tenofovir) administered by subcutaneous injection within the drug combination nanoparticle.
2. To characterize the safety and tolerability of a single subcutaneous injection of TLC-ART 101.

There are 4 exploratory mechanistic objectives (with related endpoints) as follows:

1. To characterize the pharmacokinetics of the drug substances in human peripheral blood mononuclear cells (PBMCs)
2. To characterize the concentrations of intracellular TFV-diphosphate (the active moiety of TFV) in PBMCs
3. To explore whether the pharmacokinetic parameters of the 3 drug substances differ by sex following a single dose NB: This analysis not performed due to truncation of study to 3 cohorts and low ratio of female to male sex participants
4. To compare lymphoid tissue mononuclear cell versus PBMC concentrations of the drug substances in TLC-ART 101.

Inclusion Criteria:

• Healthy with a BMI between 18.5 to 29.9 kg/m2 (Amended through 31.9kg/m2)
• Non-smoker or former smoker (defined as no smoking or no vaping or no use of tobacco cessation products for greater than 1 year)
• Persons of any gender are eligible if they otherwise meet all other entry criteria.
• Assessed by the study staff as being at low risk for HIV infection and committed to maintaining behavior consistent with low risk of HIV exposure until after completing the study.
• Willing and able to give informed consent.
• If participating in sexual activity that could lead to pregnancy, individuals of reproductive potential must agree to use specific forms of contraception throughout the study. At least two of the following must be used throughout the study:
• Condom (male or female)
• Diaphragm or cervical cap
• Copper-based intrauterine device
• Vasectomy in the male partner

Note: Select participants will have a 72-hour in-patient stay at UW Medical Center.

Note: Select participants will undergo an inguinal lymph node biopsy.

Exclusion Criteria:

Note the following criteria refer to values from the screening visit

• Positive HIV-1 fourth generation antigen/antibody test
• Positive hepatitis B surface antigen test
• Active HCV infection Note: Participants that are positive for HCV antibody must have a negative HCV RNA
• Any chronic medical condition deemed significant by the investigator (e.g., asthma, severe allergies, hypertension, heart disease, diabetes mellitus, hyperlipidemia)
• Taking any chronic oral or systemic prescription medications (including indwelling hormonal implants or hormone-releasing intrauterine devices) within 30 days before the Entry visit
• Taking any chronic oral or systemic non-prescription (over the counter, OTC) medications that cannot be safely stopped
• Any clinically significant abnormal value of CBC, creatinine, AST, ALT, alkaline phosphatase, total bilirubin
• PT/INR, PTT above the upper limit of normal
• U/A with any clinically significant abnormality
• Any clinically significant finding on ECG per physician review
• Urine toxicology screen positive for any illicit drug (other than cannabis if the participant agrees to stop use of cannabis for 14 days prior to entering the study and for the duration of the study, and is believed to be credible in this promise in the opinion of the investigator)
• BP > 140 systolic or > 90 diastolic mmHg
• Known allergy/sensitivity or any hypersensitivity to LPV, RTV, TFV or either of the lipids in TLC-ART 101 (including anaphylaxis to a COVID-19 mRNA vaccine)
• Active drug or alcohol use or dependence or psychiatric illness that, in the opinion of the site investigator, would interfere with adherence to study requirements
• Acute or serious illness requiring systemic treatment, antibiotics, and/or hospitalization within 90 days prior to study entry
• Scars or tattoos on the central abdomen that would interfere with administration of a subcutaneous injection or assessment of the location where the study medication is planned to be administered (within 1 inch of the umbilicus)
• Diagnosis of syphilis, gonorrhea or chlamydia in the past year
• People who are pregnant, intend to become pregnant, or are breastfeeding

Additional Exclusion Criteria for Participants who will Undergo Lymph Node Biopsy

• Allergy to lidocaine or any related "-caine" drug
• Chronic scars or tattoos in both inguinal areas that might interfere with performance of a lymph node biopsy or increase the likelihood of a poor cosmetic result
• Anxiety or any other condition that has a high likelihood of interfering with the successful performance of a lymph node biopsy done under local anesthesia
• Any coagulopathy or condition that would increase the potential for bleeding