| |
PRO140 SC Monotherapy (MT) Provides Long-Term, Full Virologic Suppression in HIV Patients
|
| |
| |
Reported by Jules Levin
ASM/ICAAC 2016 June 16-20, Boston, MA
Jay Lalezari, Kush Dhody, Ula Kowalczyk, Kazem Kazempour, Nader Pourhassan, and Paul J. Maddon
PRO 140.....PRO 140 belongs to a new class of HIV/AIDS therapeutics -- viral-entry
inhibitors -- that are intended to protect healthy cells from viral infection. PRO 140 is a fully humanized IgG4 monoclonal antibody directed against CCR5, a molecular portal that HIV uses to enter T-cells. PRO 140 blocks the predominant HIV (R5) subtype entry into T-cells by masking this required co-receptor, CCR5. Importantly PRO 140 does not appear to interfere with the normal function of CCR5 in mediating immune responses.
Anti-HIV-1 Activity of Weekly or Biweekly Treatment with Subcutaneous PRO 140, a CCR5 Monoclonal Antibody......
http://www.natap.org/2010/HIV/042210_01.htm........
http://www.natap.org/2009/ICCAC/ICCAC_33.htm
http://www.natap.org/2007/ICAAC/ICAAC_21.htm.......
http://www.natap.org/2008/HIV/100208_02.htm........
http://www.natap.org/2008/ICAAC/ICAAC_94.htm
PRO 140 is a humanized CCR5 monoclonal antibody that potently inhibits R5 viruses and synergizes with small-molecule CCR5 antagonists, as shown in laboratory studies [15, 16]. PRO 140 does not inhibit CXCR4-using viruses. Previously, an intravenous form of PRO 140 was tested as monotherapy in HIV-1 subjects in whom only R5 virus was detectable [17]. Single doses, ranging up to 5 mg/kg, were generally well tolerated relative to placebo and demonstrated potent and prolonged antiviral activity, with a 1.83 log10 mean reduction in HIV-1 RNA level observed at 5 mg/kg. These findings supported the development of subcutaneous formulations with the potential for patient self-administration. In the present study, we examined the antiviral effects, safety, and pharmacokinetics of subcutaneous PRO 140 administered weekly or every other week to HIV-infected individuals.
CCR5 Monoclonal Antibody PRO 140 Inhibited HIV-1 Resistant to Maraviroc, a Small Molecule CCR5 Antagonist......http://www.natap.org/2008/IAS/IAS_48.htm
program abstract
Background: In patients infected exclusively with CCR5-tropic HIV-1, PRO140 (humanized CCR5 mAb) demonstrated potent antiviral activity of ≥1.65 log10 mean viral load (VL) reduction as a weekly subcutaneous injection (SC). We evaluated PRO 140 SC monotherapy (MT) in a single-arm, open-label phase 2b extension study for long-term VL suppression following initial antiretroviral therapy (ART).
Methods: 39 adult patients (11-cohort 1, 28-cohort 2) infected exclusively with CCR5-tropic HIV-1 (Trofile® DNA Co-receptor Tropism Assay) and virologically suppressed on ART (VL <40 c/mL (LabCorp)) were switched to weekly PRO140 350 mg SC MT. After 13 weeks of viral suppression, 16 subjects in cohort 2 were trained to self-administer PRO140 SC and offered continuation of MT.
Results: Of the 15 eligible subjects (86.7% male, 20% non-white; median age 55.3 yers; median CD4 T-cell count 586 cells/mm3), 11 subjects are currently on PRO140 SC MT for >1 year of treatment (56-67 weeks). Single-copy HIV-1 RNA assay reported a median VL nadir of 0.4 c/mL (n=10; <0.5-39.9). Three subjects experienced virologic failure (VF) (2 consecutive VL ≥400 c/mL) with a median time of 169 days. VF subjects restarted ART and virologically suppressed (VL <40 c/mL) with a median time of 29 days. One patient discontinued at week 47 (with VL <40 c/mL) due to relocation.At VF, there was no change of co-receptor tropism (Trofile® RNA Assay) nor significant change in post-treatment virus inhibition for PRO 140, maraviroc, and AMD3100 compared with baseline results in VF and non-VF group of subjects.(PhenoSense® Entry Assay). No anti-PRO140 antibodies were detected in any subject. PRO140 was well tolerated with no drug-related major adverse events or treatment discontinuation reported.
Conclusions: In this phase 2b extension study, PRO140 SC provided full virologic suppression, was well tolerated, and enabled the avoidance of potential toxicity of ART while preserving drug options for >1 year. PRO140 SC may offer a simple, long-acting, single-agent maintenance therapy after initial ART in selected patients.
|
|
| |
| |
|
|
|
