Study for Evaluation of the Safety, Pharmacokinetics, and Antiviral Activity of UB-421 Subcutaneous Formulation in HIV Infected Adults

A Phase I, Open-Label, Multi-Dose Study for Evaluation of the Safety, Pharmacokinetics, and Antiviral Activity of UB-421 Subcutaneous Formulation in HIV Infected Adults

UB-421 subcutaneous formulation (UB-421 SC) is developed to provide HIV infected patients a more convenient drug delivery method. UB-421 SC injection, with significantly less injection time than IV infusions and with opportunity of self-administration or administered in general medical setting (in addition to HIV-specific clinic), can provide patient a more convenient option.

This UB-421 SC phase I study will be conducted to investigate short-term safety, pharmacokinetics and anti-viral activity of UB-421 SC at three dose levels in ART-treated aviremic subjects and treatment naive HIV-infected subjects. The current UB-421 SC formulation (125 mg/ml) is at least 10-fold more concentrated than UB-421 IV (10 mg/ml). The highly concentrated formulation makes weekly UB-421 subcutaneous injections feasible. This study will form the basis of UB-421 SC in combination with antiretroviral agents (ARV) for treating HIV infected viremic patients in the future clinical trials.

Inclusion Criteria:

ART-treated aviremic subjects who meet all inclusion criteria (A~C and 1~5) will be eligible for Part A: A. Documentation of continuous ART treatment with suppression of plasma viral level below the limit of detection for ≥1 years. Individuals with "blips" (i.e., detectable viral levels on ART) prior to the Screening Visit (SV) may be included provided they satisfy the following criteria:

1. The blips are <400 copies/mL, and
2. Succeeding viral levels return to levels below the limit of detection on subsequent testing B. Tolerated the baseline ART regimen (without major toxicity) and are expected to continue in the trial period (since SV till EOS) the same ART regimen. The change in brand or formulation but not in the 3 ARV types (eg, from 3 tablets to 1 single tablet containing the same 3 ARV drugs, or from immediate-release to extended-release tablet per day, or other similar change are allowed) are considered the same ART regimen; C. Viral load should below 50 RNA copies/mL at the SV; ART-naïve viremic subjects who meet all inclusion criteria (D~F and 1~5) will be eligible for

Part B:

D. HIV-1 viral load >200 copies/mL at the SV; E. HIV antiretroviral therapy (ART)-naïve i.e., subjects who receive no prior or current ART.

However, subjects who have previously received pre- or post-exposure prophylaxis but eventually confirmed HIV-1 seropositive can be enrolled; F. Asymptomatic (generalized lymphadenopathy can be included), defined as subjects without stage 3 defining opportunistic illnesses according to revised Surveillance Case Definition for HIV Infection published in 2014, which was determined by the Investigator based on the medical history, physical examination, ECG, and laboratory evaluations;

Inclusion criteria for both Part A and B:

1. HIV-1 seropositive, with documented HIV-1 infection by official, signed, written history (e.g.

   laboratory report);

2. Male and female, age 18 years or older;

3. CD4+ (D1) T cell count > 350 cells/mm3 at the SV;

4. Male subjects and female subjects of childbearing potential must agree to use the acceptable method of contraception during the course of the study (excluding women who are not of childbearing potential). Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at the SV; Definitions Women NOT of childbearing potential: women who are permanently or surgically sterilized or postmenopausal. Permanent sterilization includes hysterectomy, and/or bilateral oophorectomy, and/or bilateral salpingectomy and/or tubal ligation.

   Postmenopausal women: 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes. Acceptable method of birth control for WOCBP: abstinence; implant; intrauterine device; hormonal contraceptive (injectable, oral contraceptives, transdermal patches, or contraceptive rings) plus barrier method (male condom, female condom or diaphragm). Acceptable method of birth control for male subjects: abstinence; condom.

5. Subjects signed the informed consent before undergoing any study procedures.

Exclusion Criteria:

Subjects who have any of the following conditions will be excluded from both Part A and B

1. Females who are pregnant, lactating, or breastfeeding, or who plan to become pregnant during the study;
2. Subjects with acute opportunistic infection(s) or bacterial infection(s), that the delayed initiation of ART would not be allowed, as judged by the Investigator;
3. Any stage 3 defining opportunistic illnesses such as Kaposi's sarcoma according to the revised Surveillance Case Definition for HIV Infection published in 2014 within the past 12 months before the SV;
4. Serious illness requiring systemic treatment and/or hospitalization for at least 7 days prior to the SV;
5. Any previous exposure to a monoclonal antibody within 12 weeks prior to the SV;
6. Any previous hypersensitivity reaction to monoclonal antibody;
7. Have ever experienced urticaria in the previous 2 years before the SV or with ongoing dermatologic problem with rash appearance (eg. eczema, atopic dermatitis, urticaria) at the SV;
8. Any significant diseases (other than HIV-1 infection) or clinically significant findings that, in the Investigator's judgment, would potentially compromise study compliance or the ability to evaluate safety/efficacy;
9. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones);
10. Presence of hepatitis B surface antigen (HBsAg) or HCV antibody and RNA double positive at the Screening Visit or within 12 weeks prior to the SV;
11. Serum GPT/ALT value is 2.5 times or greater than the upper limit of normal (≥ 2.5 xULN) at the Screening Visit;
12. Serum GOT/AST value is 2.5 times or greater than the upper limit of normal (≥ 2.5 xULN) at the Screening Visit;
13. Serum total bilirubin (TBIL) value is 2.5 times or greater than the upper limit of normal (≥ 2.5 xULN) at the SV;
14. Serum creatinine value is greater than 1.5 times the upper limit of normal (> 1.5 x ULN) at the SV;
15. Any vaccination within 8 weeks prior to the SV;
16. Any treatment with immunomodulators, such as interleukins, interferon, cyclosporine, systemic corticosteroid, or systemic chemotherapy within 12 weeks prior to the Screening Visit; Note: Subjects received short-term low dose oral (i.e. prednisone ≤0.5mg/kg/day f or ≤ 1 - month duration), inhaled, nasal, or topical steroids will not be excluded.)
17. Prior participation in any HIV vaccine trial;
18. Receipt of other investigational study agent within 12 weeks before the SV;
19. Life expectancy of less than 12 months;
20. Any current alcohol or illicit drug use that, in the Investigator's opinion, would interfere with the subject's ability to comply with the dosing and visit schedules and protocol evaluations