Study of PRO 140 SC as Single Agent Maintenance Therapy in Virally Suppressed Subjects With CCR5-tropic HIV-1 Infection

A Phase 2b/3, Multicenter Study to Assess the Treatment Strategy of Using PRO 140 SC as Long-Acting Single-Agent Maintenance Therapy for 48 Weeks in Virologically Suppressed Subjects With CCR5-tropic HIV-1 Infection

This study is a Phase 2b/3, multi-center study designed to evaluate the efficacy, safety, and tolerability of the strategy of shifting clinically stable patients receiving suppressive combination antiretroviral therapy to PRO 140 monotherapy and maintaining viral suppression for 48 weeks following study entry.

Consenting patients will be shifted from combination antiretroviral regimen to weekly PRO 140 monotherapy for 48 weeks during the Treatment Phase with the one week overlap of existing retroviral regimen and PRO 140 at the beginning of the study treatment and also one week overlap at the end of the treatment in subjects who do not experience virologic failure.

The primary objective is to assess the treatment strategy of using PRO 140 SC as long-acting, single-agent maintenance therapy for the chronic suppression of CCR5-tropic HIV-1 infection. In addition, the prognostic factors of therapeutic success of PRO 140 monotherapy will be evaluated.

The secondary objective of the trial is to assess the clinical efficacy, safety and tolerability parameters following substitution of combination antiretroviral therapy with weekly PRO 140 monotherapy.

Inclusion Criteria:

1. Males and females, age ≥18 years

2. Receiving combination antiretroviral therapy for last 24 weeks

3. No change in ART within last 4 weeks prior to Screening Visit

4. Subject has two or more potential alternative approved ART drug options to consider.

5. Exclusive CCR5-tropic virus at Screening Visit

6. Plasma HIV-1 RNA < 50 copies/mL at Screening Visit

7. CD4 cell count of > 200 cells/mm3 since initiation of anti-retroviral therapy

8. CD4 cell count of > 350 cells/mm3 in preceding 24 weeks and at Screening Visit

9. Laboratory values at Screening of:

   1. Absolute neutrophil count (ANC) ≥ 750/mm3
   2. Hemoglobin (Hb) ≥ 10.5 gm/dL (male) or ≥ 9.5 gm/dL (female)
   3. Platelets ≥ 75,000 /mm3
   4. Serum alanine transaminase (SGPT/ALT) < 5 x upper limit of normal (ULN)
   5. Serum aspartate transaminase (SGOT/AST) < 5 x ULN
   6. Bilirubin (total) < 2.5 x ULN unless Gilbert's disease is present or subject is receiving atazanavir in the absence of other evidence of significant liver disease
   7. Creatinine ≤ 1.5 x ULN

10. Clinically normal resting 12-lead ECG at Screening Visit or, if abnormal, considered not clinically significant by the Principal Investigator.

11. Both male and female patients and their partners of childbearing potential must agree to use 2 medically accepted methods of contraception during the course of the study.

12. Willing and able to participate in all aspects of the study, including use of SC medication, completion of subjective evaluations, attendance at scheduled clinic visits, and compliance with all protocol requirements as evidenced by providing written informed consent.

Exclusion Criteria:

1. CXCR4-tropic virus or dual/mixed tropic (R5X4) virus determined by the Trofile™ DNA Assay

2. Hepatitis B infection as manifest by the presence of Hepatitis B surface antigen (HBsAg)

3. Any active infection or malignancy requiring acute therapy (with the exception of local cutaneous Kaposi's sarcoma)

4. Laboratory test values ≥ grade 4 DAIDS laboratory abnormality.

5. Females who are pregnant, lactating, or breastfeeding, or who plan to become pregnant during the study

6. Unexplained fever or clinically significant illness within 1 week prior to the first study dose

7. Any vaccination within 2 weeks prior to the first study dose or during the study.

8. Subjects who have failed on a maraviroc containing regimen.

9. Subjects weighing < 35kg

10. History of anaphylaxis to any oral or parenteral drugs

11. History of Bleeding Disorder or patients on anti-coagulant therapy

12. Participation in an experimental drug trial(s) within 30 days of the Screening Visit

13. Any known allergy or antibodies to the study drug or excipients

14. Treatment with any of the following:

    1. Radiation or cytotoxic chemotherapy with 30 days prior to the screening visit

    2. Immunosuppressants within 60 days prior to the screening visit

    3. Immunomodulating agents (e.g., interleukins, interferons), hydroxyurea, or foscarnet within 60 days prior to the screening visit

    4. Oral or parenteral corticosteroids within 30 days prior to the Screening Visit. Subjects on chronic steroid therapy > 5 mg/day will be excluded with the following exception:

       • Subjects on inhaled, nasal, or topical steroids will not be excluded

15. Any other clinical condition that, in the Investigator's judgment, would potentially compromise study compliance or the ability to evaluate safety/efficacy