Pharmacokinetics and Safety of SAR441236

The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of SAR441236, a tri-specific broadly neutralizing antibody against the human immunodeficiency virus (HIV).

This study evaluated the safety, tolerability, pharmacokinetics, and antiviral activity of SAR441236, a tri-specific broadly neutralizing antibody against HIV.

The study included three arms.

In Arm A, three dose cohorts (1, 3, and 10 mg/kg) of antiretroviral-treated, virologically suppressed participants were randomized (2:1, active to placebo) to receive a single intravenous (IV) dose of SAR441236 or placebo on Day 0. After Cohort 1 (1 mg/kg, lowest Arm A dose), each subsequent, higher-dose, cohort opened for enrollment only after an evaluation of safety outcomes for all participants in the previous cohort indicated it was safe to increase the dose of SAR441236. All participants in Cohorts 1-3 were followed for up to 24 weeks.

In Arm A, Cohort 4, participants were randomized (2:1, active to placebo) to receive an IV infusion of 30 mg/kg SAR441236 or placebo once every 12 weeks beginning at entry, for a total of 4 infusions. The first six Cohort 4 participants were enrolled after the safety evaluation of Cohort 3 participants and the rest of the Cohort 4 participants were accrued after a safety evaluation of the first 6 participants. The time between infusions was prolonged for some participants due to the COVID-19 pandemic, which occurred during the course of the study. Participants in this cohort were followed for up to 36 weeks after their final infusion.

Participants in Arm A continued taking non-study-provided antiretroviral treatment throughout the study.

In Arm B, two cohorts of viremic participants received a single IV dose of SAR441236 on Day 0. Cohort 5 (1 mg/kg, lowest planned Arm B dose) opened first. After reviewing the safety data from that cohort, as well as that from all Arm A cohorts (which had fully enrolled), and taking into consideration enrollment challenges, the study was redesigned to be a dose de-escalation study in Arm B only. With this redesign, the study began enrollment into the highest dose (Cohort 8, 30 mg/kg) after closing Cohort 5 enrollment. Each subsequent Arm B cohort (of lower doses) was planned to open for enrollment only after an evaluation of efficacy data from Day 14 for all participants in the previous cohort was completed. However, the highest dose cohort never fully enrolled, and no subsequent cohorts were opened. All Arm B participants were followed for up to 24 weeks.

Participants in Arm B initiated or re-initiated non-study-provided combination antiretroviral therapy (ART) (selected by their primary HIV clinician) on or before Day 28. A later version of the protocol changed the duration of SAR441236 monotherapy to no more than 14 days, however, no participants enrolled under that version.

In Arm C, two cohorts of ART-treated, virologically suppressed participants were randomized (2:1, active to placebo) to receive a single subcutaneous (SC) dose of SAR441236 or placebo on Day 0. Cohort 11 (1 mg/kg) opened for enrollment only after an evaluation of safety outcomes from Day 14 for all participants in Cohort 10 (0.3 mg/kg) and the cumulative data from that cohort indicated it was safe to dose escalate. All Arm C participants were followed for 24 weeks.

Participants in Arm C continued taking non-study-provided ART throughout the study.

The study closed to enrollment and follow-up in May 2023 due to the expiration of the available study product, despite failing to meet its enrollment targets in Arm B. There had been no enrollment to the study since October 2021, despite the team's revision of the protocol (Version 4.0) to adjust eligibility criteria to facilitate enrollment of participants with viremia. At the time of study closure, Arm A and C were fully enrolled. Two Arm B cohorts (1 mg/kg and 30 mg/kg) achieved partial enrollment. Although protocol version 4.0 was released in September 2022, the last participant was enrolled under protocol version 3.0 and completed study follow-up in April 2022.

Eligibility Criteria:
Note: The following inclusion and exclusion criteria reflect those in protocol version 3.0, the last protocol version under which participants enrolled. Although a protocol version 4.0 was released, no participants enrolled under that version.

Inclusion Criteria, Arms A, B, and C

* HIV-1 infection, documented by any licensed rapid HIV-1 test or HIV-1 enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot, Geenius assay, or a second antibody test by a method other than the initial rapid HIV-1 and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.

  * NOTE: The term "licensed" refers to a US Food and Drug Administration (FDA)-approved kit.
  * WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot, Geenius assay, or a plasma HIV-1 RNA viral load.
* The following laboratory values obtained within 45 days prior to entry by any US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent.

  * Absolute neutrophil count (ANC) greater than or equal to 1500 cells/mm\^3
  * Hemoglobin greater than or equal to 12.0 g/dL for men and greater than or equal to 11.0 g/dL for women
  * Platelet count greater than or equal to 120,000/mm\^3
  * Creatinine clearance (CrCl) greater than 60 mL/min

    * Refer to the calculator located on the FSTRF website (at https://www.frontierscience.org/): Calculated Creatinine Clearance - Cockcroft-Gault Equation (Adult).
  * Aspartate aminotransferase (AST) (SGOT) less than 1.25 x upper limit of normal (ULN)
  * Alanine aminotransferase (ALT) (SGPT) less than 1.25 x ULN
  * Alkaline phosphatase less than 2.0 x ULN
  * Total bilirubin less than 1.1 x ULN
* Hepatitis C virus (HCV) antibody negative result within 45 days prior to study entry or, for study candidates who are HCV antibody positive (based on testing performed at any time prior to study entry), a negative HCV RNA result obtained within 45 days prior to study entry.

  * NOTE: A negative HCV RNA level may result from either spontaneous clearance or from HCV therapy. Participants must have completed any HCV therapy at least 6 months prior to enrollment.
* Negative HBsAg result obtained within 45 days prior to study entry, or documented hepatitis B immunity, defined as positive hepatitis B surface antibody testing, at any time.
* Female study candidates of reproductive potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL performed at screening and again within 24 hours before study entry by any US clinic or laboratory that has a CLIA certification or its equivalent, or is using a point of care (POC)/CLIA-waived test.

  * NOTE: Reproductive potential is defined as girls who have reached menarche, and women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, and women who have not undergone surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy.
* All study candidates must agree not to participate in an assisted conception process (e.g., sperm donation, intrauterine insemination, in vitro fertilization) from screening until 12 weeks after the final study visit.
* If participating in sexual activity that could lead to pregnancy, all study candidates must agree to use at least one reliable method of contraception from study entry until 12 weeks after the final study visit. At least one of the following methods must be used appropriately:

  * Condoms (male or female) with or without a spermicidal agent. Condoms are recommended because their appropriate use is the only contraception method effective for preventing HIV transmission.
  * Diaphragm or cervical cap with spermicide.
  * Intrauterine device.
  * Hormone-based contraceptive.
* Study candidates who are not of reproductive potential are eligible without requiring the use of a contraceptive method. Acceptable documentation of sterilization, menopause, and reproductive potential is specified below.

  * Written documentation or oral communication from a clinician or clinician's staff documented in source documents of one of the following:

    * Physician report/letter
    * Operative report or other source documentation in the patient record
    * Discharge summary
    * Laboratory report of azoospermia (is required to document successful vasectomy)
    * Follicle-stimulating hormone (FSH) measurement elevated into the menopausal range as established by the reporting laboratory.
  * NOTE A: Female reproductive potential is defined in the criteria above.
  * NOTE B: Male candidates who are not of reproductive potential are defined as having documented azoospermia.
  * NOTE C: A female study candidate's oral report of her male partner's lack of reproductive potential should be recorded in the source documents if written proof is not available.
* Ability and willingness of participant to provide informed consent.

Additional Arms A- and C-specific Inclusion Criteria

* Receiving combination ART for at least 12 months prior to study entry with no changes in ART regimen within the 12 weeks prior to entry.

  * NOTE A: Use of a two-drug ART regimen within the 12 months prior to entry is exclusionary.
  * NOTE B: Although ritonavir or cobicistat may be included in a combination ART regimen, neither of these "counts" in a tally of antiretroviral agents.
* CD4+ cell count of greater than or equal to 200 cells/mm\^3 obtained within 45 days prior to study entry at any US laboratory that has a CLIA certification or its equivalent.
* Within 45 days prior to study entry, plasma HIV-1 RNA \<50 copies/mL on any FDA-approved assay with a limit of quantification of \<50 copies/mL by a US laboratory that has a CLIA certification or its equivalent.
* Within 12 months prior to study entry and before screening, at least one documented plasma HIV-1 RNA \<50 copies/mL on any FDA-approved assay with a limit of quantification of \<50 copies/mL by a US laboratory that has a CLIA certification or its equivalent.

  * NOTE: A single plasma HIV-1 RNA ≥50 but \<200 copies/mL at least 6 months prior to screening is permitted if followed within 2 months by an HIV-1 RNA \<50 copies/mL.

Additional Arm B-specific Inclusion Criteria

* Plasma HIV-1 RNA \>5000 and ≤200,000 copies/mL within 45 days prior to study entry.
* CD4+ cell count of greater than or equal to 350 cells/mm\^3 obtained within 45 days prior to study entry at any US laboratory that has a CLIA certification or its equivalent.
* Willingness and ability to start or re-start combination ART by or on Day 28 of the study.

Exclusion Criteria, Arms A, B, and C

* Breastfeeding or plans to become pregnant.
* Receipt of chimeric, humanized or human long-acting mAbs, whether licensed or investigational, within 12 months prior to entry, or receipt of chimeric, humanized or human regular mAbs, whether licensed or investigational, within 6 months prior to entry, unless reviewed and approved by the study's core team.
* Known allergy/sensitivity or any hypersensitivity to components of study treatment or its formulation (refer to the product's Investigator's Brochure).
* Vaccination within 30 days prior to entry or intent to receive an elective vaccination (e.g., hepatitis A vaccine, travel-related) during the course of the study except as noted in the study protocol.
* Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
* Acute or serious illness requiring systemic treatment and/or hospitalization within 45 days prior to entry.
* Diagnosis of AIDS-defining illness using the current list on the US Centers for Disease Control and Prevention (CDC) website within 1 year prior to entry.
* Weight greater than 115 kg within 45 days prior to study entry.
* Use of maraviroc, ibalizumab, or enfuvirtide at any time.

Additional Arms A- and C-specific Exclusion Criterion

* Within 6 months prior to study entry, any plasma HIV-1 RNA ≥50 copies/mL on any FDA-approved assay with a limit of quantification of \<50 copies/mL performed by a US laboratory that has a CLIA certification or its equivalent.

Additional Arm B-specific Exclusion Criterion

* Use of any anti-HIV ART, including FDA-approved pre-exposure prophylaxis (PrEP) within the preceding 3 months

Additional Arm C-specific Exclusion Criterion

* Presence of abdominal scarring or tattooing that could interfere with assessment of injection-site reaction.