A Phase 1, Open Label, Dose-escalation Study of the Safety, Pharmacokinetics and Antiretroviral Activity of 3BNC117

A Phase 1, Open Label, Dose-escalation Study of the Safety, Pharmacokinetics and Antiretroviral Activity of 3BNC117 Monoclonal Antibody in HIV-infected and HIV-uninfected Volunteers

The proposed study is a first-in-man phase I study that aims to evaluate the safety, tolerability and pharmacokinetics of 3BNC117 in HIV-infected and HIV-uninfected subjects, and its antiretroviral activity in HIV-infected subjects.

In preclinical studies carried out in humanized mice and non-human primates, 3BNC117 alone or in combination with other neutralizing antibodies led to protection from HIV-1 or SHIV infection and also to sustained suppression of HIV-1 plasma viremia. The aims of this protocol are to evaluate the safety, tolerability and pharmacokinetics profile of 3BNC117 in both HIV-infected and HIV-uninfected subjects,and its antiretroviral activity in HIV-infected subjects.

Inclusion Criteria:

• Group 1 (HIV-uninfected):

  • Adult males and females, age 18 to 65
  • Amenable to HIV risk reduction counseling and agrees to maintaining behavior consistent with low risk of HIV exposure;
  • If a sexually active male or female, participating in sexual activity that could lead to pregnancy, agrees to use an effective method of contraception throughout the study.

• Groups 2-5 (HIV-infected):

  • Age 18 to 65
  • HIV infection confirmed by ELISA and immunoblot
  • Groups 2A-D - on ART with HIV-1 plasma RNA levels below 100,000 copies/ml, or off ART for at least 8 weeks with HIV-1 plasma RNA level between 2,000-100,000 copies/ml by standard assays on 2 occasions at least 1 week apart;
  • Group 2E - Untreated HIV-infected (not on ART for at least 8 weeks): HIV-1 RNA plasma levels between 2,000 - 100,000 copies/ml;
  • Group 3 - Untreated HIV controllers (not on ART for at least 8 weeks): HIV-1 RNA plasma level of < 2,000 copies/ml by standard assays, on 2 occasions, at least 1 week apart, and ART-naive.
  • Group 4 - ART treated with HIV-1 RNA plasma level of > 20 copies/ml by standard assays on 2 occasions, at least 1 week apart, while on combination antiretroviral therapy;
  • Groups 5A and 5B - ART treated with HIV-1 RNA plasma level of < 20 copies/ml by standard assays on 2 occasions, at least 1 week apart, while on combination antiretroviral therapy;
  • Current CD4 cell count > 300 cells/µl
  • If sexually active male and female, participating in sexual activity that could lead to pregnancy, agrees to use an effective method of contraception throughout the study.

Exclusion criteria:

• Group 1 (HIV-uninfected):

  • Confirmed HIV-1 or HIV-2 infection;

  • History of immunodeficiency or autoimmune disease; use of systemic corticosteroids, immunosuppressive anti-cancer, or other medications considered significant by the trial physician within the last 6 months;

  • Any clinically significant acute or chronic medical condition that in the opinion of the investigator would preclude participation;

  • Within the 12 months prior to enrollment, the volunteer has a history of sexually transmitted disease;

  • Hepatitis B (surface antigen, HbsAg) or hepatitis C (HCV antibodies);

  • Laboratory abnormalities in the parameters listed below:

    • Absolute neutrophil count ≤ 2,000
    • Hemoglobin ≤ 12 gm/dL if female; ≤ 13.5 gm/dL if male
    • Platelet count ≤ 140,000
    • ALT ≥ 1.25 x ULN
    • AST ≥ 1.25 x ULN
    • Total bilirubin ≥ 1.1 ULN
    • Creatinine ≥ 1.1 x ULN
    • Coagulation parameters (PT, PTT, INR) ≥ 1.1 x ULN

  • Pregnancy or breastfeeding;

  • Any vaccination within 14 days prior to 3BNC117 administration;

  • Receipt of any experimental HIV vaccine in the past or monoclonal antibody therapy of any kind in the past;

  • Participation in another clinical study of an investigational product currently or within past 12 weeks, or expected participation during this study.

• Groups 2-5 (HIV-infected):

  • History of AIDS-defining illness

  • History of systemic corticosteroids, immunosuppressive anti-cancer, or other medications considered significant by the trial physician within the last 6 months;

  • Any clinically significant acute or chronic medical condition, other than HIV infection, that in the opinion of the investigator would preclude participation;

  • Hepatitis B (surface antigen, HbsAg) or hepatitis C (HCV antibodies);

  • Laboratory abnormalities in the parameters listed below:

    • Absolute neutrophil count ≤ 1,300
    • Hemoglobin ≤ 10 gm/dL
    • Platelet count ≤ 125,000
    • ALT ≥ 2.0 x ULN
    • AST ≥ 2.0 x ULN
    • Total bilirubin ≥ 1.1 ULN
    • Creatinine ≥ 1.1 x ULN
    • Coagulation parameters ≥ 1.1 x ULN;

  • Current antiretroviral regimen includes either maraviroc or enfuvirtide;

  • Pregnancy or breastfeeding;

  • Any vaccination within 14 days prior to 3BNC117 administration;

  • Receipt of any experimental HIV vaccine or monoclonal antibody therapy of any kind in the past;

  • Participation in another clinical study of an investigational product currently or within past 12 weeks, or expected participation during this study.