New Antibody May Suppress HIV for Up to 16 Weeks Without ART

Nicola M. Parry, DVM

April 17, 2019

Monotherapy with UB-421 may suppress human immunodeficiency virus (HIV) for up to 4 months in infected patients undergoing a short-term antiretroviral therapy (ART) pause, according to a study published online today in the New England Journal of Medicine.

"UB-421 monotherapy maintained suppression of plasma viremia (< 20 copies per milliliter) in the absence of ART for up to 8 weeks in participants receiving 10 mg per kilogram every week, and for up to 16 weeks in participants receiving 25 mg per kilogram every 2 weeks," write Chang-Yi Wang, PhD, from United Biomedical, Hauppauge, New York, and colleagues.

ART has changed HIV infection from a fatal condition to a manageable, chronic illness. However, there is growing interest in identifying new approaches to suppressing HIV.

In an interview with Medscape Medical News, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, Rockville, Maryland, highlighted three potential reasons why an individual might want to move away from taking daily ART.

First, pill fatigue is not uncommon, he explained, because some individuals do not like the idea of taking a pill every day for life — often because of the associated stigma.

Second, some individuals have virus that is resistant to the combination of drugs in their ART regimen.

And, third, some experience ART-related toxicities that they find unacceptable, said Fauci.

Although broadly neutralizing HIV-specific monoclonal antibodies have been investigated as a treatment option, emergence of antibody-resistant HIV, leading to viral rebound when ART is discontinued, remains a problem.

In contrast, UB-421 is a novel investigative broadly neutralizing monoclonal antibody.

"The unique thing about this antibody," said Fauci, "is that it is directed against the host's CD4 cell surface receptor" and thus blocks HIV entry into cells.

The antiviral activity of UB-421 has already been demonstrated in a phase 1 study and a phase 2a study in HIV-infected people who had not previously received treatment.

With this in mind, Wang and colleagues conducted a phase 2, open-label, nonrandomized study to examine whether UB-421 monotherapy can prevent plasma viremia and reversibly reduce the population of regulatory T cells, while maintaining CD4+ T-cell counts in ART-stabilized HIV-infected patients.

They enrolled 29 patients with well-controlled HIV infection who stopped their oral ART, either at the time of their first infusion or 1 week later, depending on their ART regimen. Patients entered one of two study cohorts, each of which received eight intravenous infusions of UB-421.

Cohort 1 (14 patients) received weekly infusions at a dose of 10 mg/kg, whereas Cohort 2 received infusions every other week at a dose of 25 mg/kg.

The study's primary outcome was the time to viral rebound (≥ 400 copies per milliliter) after the first UB-421 infusion.

At the end of the 8- or 16-week treatment phase, patients in both cohorts restarted their ART regimens and were followed for 8 more weeks.

No patients in either cohort experienced plasma viral rebound to more than 400 copies per milliliter.

In addition, UB-421 infusion maintained HIV suppression (< 20 copies per milliliter) in all patients (94.5% of measurements at study visits 2 through 9) during ART interruption. Although low-level viral blips occurred in eight patients (28%) across both cohorts, they did not require specific treatment.

Throughout the study, CD4+ T-cell counts remained stable, while the percentage of CD4+ regulatory T-cells dropped significantly (mean reduction, 31% to 56% from baseline), but returned to baseline levels after the treatment phase. CD8+ T-cell counts increased (P < .001) in both cohorts.

UB-421 was also generally well tolerated and safe. Of the 29 enrolled patients, two in Cohort 2 did not complete all eight infusions of UB-421 (one was lost to follow-up, and one withdrew as a result of a grade 2 skin rash).

Three patients in Cohort 1 (21%) and five (33%) in Cohort 2 experienced adverse events (AEs) of grade 2 or higher.

The most common AE that was considered drug related was rash, which was typically mild and transient. Twelve patients (41%) had a rash of grade 1, and three (10%) had a rash of grade 2.

Only 1 serious AE (a grade 1 inguinal hernia in a patient in Cohort 1) was reported.

The researchers found no evidence of HIV resistance to UB-421 but acknowledge that a study so small and of such short duration is limited in its ability to identify this.

"Future clinical studies with continued monitoring for drug-resistant strains during long-term administration of UB-421 are needed to properly assess this concern," they emphasize.

Overall, "this is an interesting study that provides successful proof of concept," concluded Fauci.

This study was supported by United Biomedical; United Biomedical Asia; United BioPharma; the Ministry of Economic Administration, Taiwan; the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Several authors have disclosed receiving personal fees from United Biomedical Inc or United BioPharma; being a cofounder of and/or salaried employers and/or shareholders at United Biomedical Inc; and holding several patents. Fauci has reported that one of the authors, Tae-Wook Chun, PhD, is an independent investigator in his laboratory; however, Fauci reports having no involvement in this study and no input into the paper. The remaining authors have disclosed no relevant financial relationships.

New Engl J Med. Published online April 17, 2019. Abstract

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