A Safety, Pharmacokinetics, and Pharmacodynamics Study of ABX464 in HIV-1 Seronegative and Seropositive Adults

The purpose of the ABX464-005 study is to characterize the systemic and mucosal immunological sequelae associated with exposure to ABX464 and to explore selected immunological endpoints, compartmental pharmacokinetics, and pharmacodynamics. The site will screen and enroll 12 HIV-infected subjects who will receive 150 mg ABX464 orally once daily for 28 days (Cohort 1). Following completion of this cohort a further 24 subjects will be enrolled: 12 HIV-uninfected subjects will receive 50 mg ABX464 orally once daily for 28 days (Cohort 2) and 12 HIV-infected subjects (Cohort 3) who will 50 mg ABX464 orally once daily for 84 days.

• ABX464 150mg (Drug): ABX464 given orally at 150 mg per day from Day 0 to Day 28 (Cohort 1/ HIV infected subjects)
• ABX464 50mg (Drug): ABX464 given orally at 50 mg per day from Day 0 to Day 28 (Cohort 2 / non HIV infected subjects)
• ABX464 50mg (Drug): ABX464 given orally at 50 mg per day from Day 0 to Day 84 (Cohort 3 / HIV infected subjects)

Primary outcomes

• Area Under the Curve (AUC) of ABX464 in Sera [Day 1, Day 28 and Day 84]: Pharmacokinetic parameters
• Maximum Observed Concentration (Cmax) of ABX464 in Sera [Day 1, Day 28 and day 84]: Pharmacokinetic parameters
• Area Under the Curve (AUC) of ABX464 Metabolite (ABX464-N-Glucuronide) in Sera [Day 1, Day 28 and Day 84]: Pharmacokinetics parameters
• Maximum Observed Concentration (Cmax) of ABX464 Metabolite (ABX464-N-Glucuronide) in Sera [Day 1, Day 28 and Day 84]: Pharmacokinetic parameters
• Maximum Observed Concentration (Cmax) of ABX464 in Peripheral Blood Mononuclear Cells (PBMC) [Day 1, Day 28 and Day 84]: Pharmacokinetic parameters
• Area Under the Curve (AUC) of ABX464 in Peripheral Blood Mononuclear Cells (PBMC) [Day 1, Day 28 and Day 84]: Pharmacokinetic parameters
• Maximum Observed Concentration (Cmax) of ABX464 Metabolite (ABX464-N-Glucuronide) in Peripheral Blood Mononuclear Cells (PBMC) [Day 1, Day 28 and Day 84]: Pharmacokinetic parameters
• Area Under the Curve (AUC) of ABX464 Metabolite (ABX464-N-Glucuronide) in Peripheral Blood Mononuclear Cells (PBMC) [Day 1, Day 28 and Day 84]: Pharmacokinetic parameters
• Concentration of ABX464 in Rectal Tissue (Measured Only at Pre-infusion Timepoint) [Day 1, Day 28, Day 56, Day 84 and Day 112]: Pharmacokinetic parameters
• Concentration of ABX464 Metabolite (ABX464-N-Glucuronide) in Rectal Tissue (Measured Only at Pre-infusion Timepoint) [Day 1, Day 28, Day 56, Day 84 and Day 112]: Pharmacokinetic parameters

Secondary outcomes

• Mean Change From Baseline in Plasma Viral Load (Ultrasensitive Assay) [Day 28, Day 56, Day 84 and Day 112]: Viral Load Assessments (HIV-1 RNA copies/ml)
• CD4+ Counts (Cell/mm^3) [Day 28, Day 35, Day 56, Day 84, Day 91 and Day 112]: T-cell determinations
• Total HIV-1 DNA Reservoir in Peripheral Blood Mononuclear Cells (PBMC) [Day 28, Day 56, Day 84 and Day 112]: HIV reservoir cells (CD4+)

Sex: Male, ages: 18 Years to 65 Years, accepts healthy volunteers

Inclusion criteria:

* Males aged 18-65 years;
* Subjects with adequate hematological and biochemical laboratory parameters
* Subjects should be able and willing to comply with study visits and procedures as per protocol;
* Subjects should understand, sign and date the written voluntary informed consent form at the screening visit prior to any protocol-specific procedures being performed;
* Subjects must agree to use in addition to the condom, a second highly effective method (one for the subject and one for the partner) of contraception (defined as per the Clinical Trials Facilitation and Coordination Group (CTFG) Guidance).

For HIV positive Subjects

* Subjects with a positive HIV-1 serology at any time before the study entry.
* Subjects treated for at least 12 months prior to screening with Dolutegravir or Raltegravir combined with either Tenofovir + Emtricitabine (TDF/FTC) or Abacavir + Lamivudine (ABC/3TC);
* Subjects with HIV plasma viral load ≤ 50 copies/mL during the 6 months prior to screening with a maximum of 2 blips ≤ 1000 copies during this period;
* Subjects' HIV-1 plasma viral load to be ≤ 100,000 copies/mL at any time beyond 6 months after the estimated date of primary infection;

Exclusion Criteria:

* History of allergic disease, anaphylaxis or reactions likely to be triggered or exacerbated by any component of investigational products;
* Acute or chronic infectious disease other than HIV infection (include but not limited to viral hepatitis such as hepatitis B, hepatitis C, active tuberculosis, active syphilis \[i.e. currently treated\].
* Acute, chronic or history of clinically relevant pulmonary, cardiovascular, gastrointestinal, hepatic, pancreatic or renal functional abnormality, encephalopathy, neuropathy or unstable Central Nervous System (CNS) pathology, angina or cardiac arrhythmias, or any other clinically significant medical problems as determined by physical examination and/or laboratory screening tests and/or medical history;
* Severe hepatic impairment;
* Acute, chronic or history of immunodeficiency or autoimmune disease other than HIV infection;

Participant flow

Outcome results

• Area Under the Curve (AUC) of ABX464 in Sera (Primary), Geometric mean, ng*h/mL: ABX464 150mg 306.0 +/- 46.5; ABX464 50mg for 28 Days 63.7 +/- 39.9; ABX464 50mg for 84 Days 63.7 +/- 77.4
• Maximum Observed Concentration (Cmax) of ABX464 in Sera (Primary), Geometric mean, ng/mL: ABX464 150mg 106.1 +/- 54.5; ABX464 50mg for 28 Days 23.1 +/- 45.2; ABX464 50mg for 84 Days 24.5 +/- 75.5
• Area Under the Curve (AUC) of ABX464 Metabolite (ABX464-N-Glucuronide) in Sera (Primary), Geometric mean, ng*h/mL: ABX461 150mg 50115.8 +/- 41.5; ABX464 50mg for 28 Days 8282.3 +/- 37.0; ABX464 50mg for 84 Days 11209.6 +/- 66.5
• Maximum Observed Concentration (Cmax) of ABX464 Metabolite (ABX464-N-Glucuronide) in Sera (Primary), Geometric mean, ng/mL: ABX464 150mg 9918.2 +/- 33.5; ABX464 50mg for 28 Days 1626.8 +/- 36.9; ABX464 50mg for 84 Days 2036.2 +/- 62.8
• Maximum Observed Concentration (Cmax) of ABX464 in Peripheral Blood Mononuclear Cells (PBMC) (Primary), Geometric mean, ng/mL: ABX464 150mg 463.3 +/- 55.0; ABX464 50mg for 28 Days 209.4 +/- 54.4; ABX464 50mg for 84 Days 203.8 +/- 81.0
• Area Under the Curve (AUC) of ABX464 in Peripheral Blood Mononuclear Cells (PBMC) (Primary), Geometric mean, ng*h/mL: ABX464 150mg 1120.7 +/- 52.6; ABX464 50mg for 28 Days 594.2 +/- 53.2; ABX464 50mg for 84 Days 481.5 +/- 78.9
• Maximum Observed Concentration (Cmax) of ABX464 Metabolite (ABX464-N-Glucuronide) in Peripheral Blood Mononuclear Cells (PBMC) (Primary), Geometric mean, ng/mL: ABX464 150mg 585.5 +/- 60.3; ABX464 50mg for 28 Days 39.7 +/- 90.5; ABX464 50mg for 84 Days 230.0 +/- 153.9
• Area Under the Curve (AUC) of ABX464 Metabolite (ABX464-N-Glucuronide) in Peripheral Blood Mononuclear Cells (PBMC) (Primary), Geometric mean, ng*h/mL: ABX464 150mg 2133.7 +/- 42.2; ABX464 50mg for 28 Days 39.2 +/- 186.7; ABX464 50mg for 84 Days 835.3 +/- 116.0
• Concentration of ABX464 in Rectal Tissue (Measured Only at Pre-infusion Timepoint) (Primary), Mean, ng/mL: ABX464 150mg 0.0 +/- 0.00; ABX464 50mg for 28 Days 0.0 +/- 0.00; ABX464 50mg for 84 Days 0.0 +/- 0.00
• Concentration of ABX464 Metabolite (ABX464-N-Glucuronide) in Rectal Tissue (Measured Only at Pre-infusion Timepoint) (Primary), Mean, ng/mL: ABX464 150mg 0.0 +/- 0.00; ABX464 50mg for 28 Days 0.1 +/- 0.08; ABX464 50mg for 84 Days 0.0 +/- 0.00
• Mean Change From Baseline in Plasma Viral Load (Ultrasensitive Assay) (Secondary), Mean, copies/mL: ABX464 150mg -0.9 (-1.9 to 0.1); ABX464 50mg -2.0 (-4.3 to 0.2)
• CD4+ Counts (Cell/mm^3) (Secondary), Mean, cells/mm^3: ABX464 150mg -130.6 (-217.5 to -43.6); ABX464 50mg -34.6 (-167.7 to 98.5)
• Total HIV-1 DNA Reservoir in Peripheral Blood Mononuclear Cells (PBMC) (Secondary), Mean, copies/10^6 cells: ABX464 150mg -86.8 (-172.2 to -1.3); ABX464 50mg 22.3 (-21.7 to 66.4)

Adverse events

Time frame: From baseline up to 112 days

Other adverse events by term

• Results publication: Moron-Lopez S, Bernal S, Wong JK, Martinez-Picado J, Yukl SA. ABX464 Decreases the Total Human Immunodeficiency Virus (HIV) Reservoir and HIV Transcription Initiation in CD4+ T Cells From Antiretroviral Therapy-Suppressed Individuals Living With HIV. Clin Infect Dis. 2022 Jun 10;74(11):2044-2049. doi: 10.1093/cid/ciab733. PMID 34436569

• Study Protocol (PDF, 2018-09-04)
• Statistical Analysis Plan (PDF, 2019-04-29)

• Paul GINESTE, PhD, Study director, Abivax S.A.