Experimental Antibody Maintains HIV Suppression Without ART

Neil Osterweil

June 22, 2016

BOSTON — An experimental monoclonal antibody that blocks HIV from entering and infecting healthy immune cells successfully maintained viral suppression for more than a year in a subset of HIV-positive patients, allowing them an extended holiday from the adverse effects of antiretroviral therapy (ART).

In the extension arm of a phase 2b study, 10 of 15 patients infected with HIV-1 who had achieved full viral suppression while receiving antiretroviral therapy (ART) and who were then maintained on once-weekly subcutaneous injections of the antibody PRO 140 (CytoDyn) remained on study for 70 weeks, reported Paul J. Maddon, MD, PhD, here at the American Society for Microbiology (ASM) Microbe 2016 meeting.

"The longest patient is currently out to 96 weeks. I think anything beyond a year, to me, is a home run." Dr Maddon said in an interview. Dr Maddon is an inventor of the antibody and a senior science advisor to CytoDyn, which is developing the antibody.

Four of the 15 patients in the extension group had virologic failure, and one withdrew consent. All four of the patients with virologic failure resumed ART and regained full viral suppression with no additional consequences, Dr Maddon told Medscape Medical News.

 
Anything beyond a year, to me, is a home run. Dr Paul J. Maddon
 

The fully humanized immunoglobulin G4 (IgG4) antibody, named PRO 140, binds with high affinity to CCR5, an entry co-receptor for the most prevalent strains of HIV-1.

A naturally occurring CCR5delta32 mutation, which causes expression of a truncated and nonfunctioning form of the CCR5 protein, has been shown to be protective against HIV infection. The mutation came to light when a man named Timothy Brown, known as "the Berlin patient," was apparently cured of HIV infection after a bone marrow transplant from a donor who had the mutation.

During his presentation, Dr Maddon reported on a cohort of 28 patients aged 18 years and older who were infected with R5-tropic HIV-1 and had been receiving a stable ART regimen for 12 months with no changes within the 4 weeks before screening.

All patients had plasma HIV-1 RNA less than 100 copies/mL at screening, and no detectable viral loads within the last 12 months.

The participants suspended their ART and were placed on weekly 350-mg subcutaneous injections of PRO 140 monotherapy (with a 1-week overlap between ART and PRO 140) for up to 12 weeks.

Fifteen of the 28 patients remained in viral suppression at 12 weeks and were then trained to self-administer PRO 140 and were continued for an additional 108 weeks in the extension protocol. The remaining patients in the cohort restarted ART and regained viral suppression, Dr Maddon said.

As noted before, four of the 15 patients had virologic failure, one withdrew consent because of relocation, and 10 patients remained on study after completing 70 weeks of PRO-140 monotherapy. Of this group, seven patients had undetectable viral loads on a standard HIV-1 RNA assay (Abbott Real Time), and the remaining three had loads lower than 40 copies/mL.

Similarly, a single-copy HIV-1 RNA assay performed at the University of Pittsburgh showed that six patients had fewer than 1 copy/mL, two had between 2 and 4 copies, and one had 39.9 copies/mL. This assay was not performed in one patient.

"CD4 cell counts remained stable throughout the study; there were no detectable antibodies to PRO 140. It also showed a favorable pharmacology profile, and importantly, there was no change in co-receptor tropism for the duration of the study," Dr Maddon said.

An analysis of safety data on 40 patients in the main study and the 15 patients in the extension group showed that all of the adverse events deemed to be related to the monoclonal antibody were injection-site reactions and were either mild or moderate in severity.

The antibody has been generally well tolerated in both intravenous and subcutaneous forms, with no drug-related serious adverse events, no pattern of toxicity, and non-dose-limiting toxicities, he said.

Asked why a substantial proportion of the patients in the original 28-patient cohort had virologic failure, Dr Maddon said, "we're looking into factors beyond the viral resistance, which we've already measured, and we don't see any changes in viral resistance or viral susceptibility to PRO 140 from these subjects."

He suggested that larger studies will give investigators a better idea about potential pharmacologic or viral dynamic reasons that could explain why the benefit is durable in some patients, but not others. A phase 3 trial is currently in the planning stages.

"Ideally, we would develop a simple assay that would be able to screen for patients that would have prolonged success," he said.

An AIDS and HIV infection specialist who was not involved in the study told Medscape Medical News that the approach is promising, but that clearly further work is needed to determine which patients might benefit.

"I think it's intriguing, the idea that you can have longer-acting antivirals through a distinct mechanism," said Rajesh Tim Gandhi, MD, from the Department of Infectious Diseases at Massachusetts General Hospital in Boston.

"What the true success rate is still needs to be determined. This was too small a study to know, and it sounds like there were some early failures. If you don't have early failures, it seems that a reasonable proportion of people maintain suppression. I would like to know more about why people fail and what the basis of that failure was," he said in an interview.

The study was supported by CytoDyn. Dr. Maddon is senior science advisor to CytoDyn, founder and vice chairman of Progenics Pharmaceuticals, and serves as a director and consultant to several biotechnology and specialty pharmaceutical companies. Dr. Gandhi has disclosed no relevant financial relationships.

American Society for Microbiology (ASM) Microbe 2016. Presented June 20, 2016.

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