Humanised monoclonal antibody as standalone Tx

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Findings from a phase 2b trial of PRO 140, a humanised monoclonal antibody, suggest the treatment could be used as a standalone therapy in place of ART for some patients with HIV-1 infection.

“We set out to prove a hypothesis that PRO 140 monotherapy – or single-agent maintenance therapy – after ART can maintain virologic suppression in HIV-infected patients,” Dr Paul J Maddon, senior science adviser to CytoDyn, is quoted in Healio as saying. “And I think that’s what we showed. Patients treated with PRO 140 were able to maintain virologic suppression after discontinuing ART.”

In a 12-week study, researchers enrolled 40 patients aged 18 years or older who were infected exclusively with CCR5-tropic HIV-1 – a strain that is found in 80% to 90% of patients starting treatment, according to Maddon. The PRO 140 monoclonal antibody was developed to bind to the CCR5 receptor, blocking HIV from infecting target cells.

Virally suppressed patients were asked to replace their daily oral ART regimens with weekly, 350-mg subcutaneous injections of PRO 140. Maddon said many of these patients had been treated with ART for a long time, some even for decades. Those who maintained virologic suppression at 12 weeks with PRO 140 were trained to self-administer the injection for an additional 108 weeks (n = 15).

According to the researchers, 10 of the 15 patients who were allowed to continue monotherapy with PRO 140 after the initial 12 weeks have now achieved virologic suppression for approximately 1.5 years. Maddon said four patients in the extension study experienced virologic failure — three of whom were receiving concomitant medications for concurrent infections, which may have contributed to the treatment failures — and one patient who had a viral load of 40 copies/mL at last visit withdrew from the study after relocating.

“PRO 140 was considered generally well-tolerated as both an intravenous and subcutaneous injection,” Maddon said during his presentation at ASM Microbe 2016. “There were no drug-related [serious adverse events], and no pattern of toxicity was seen.”

In addition, Maddon said patient acceptability of PRO 140 was high.

The researchers will continue to develop PRO 140 as a standalone treatment, Maddon said, while an ongoing phase 3 trial will investigate the monoclonal antibody in combination with ART. So far, more than 200 patients have been evaluated in clinical trials of PRO 140.

“The PRO 140 study and the extension study are both ongoing,” Maddon said. “We plan to continue treating patients with PRO 140 monotherapy beyond the 120-week duration of the current study. For greater than a year – and we’re actually approaching 2 years – we believe PRO 140 subcutaneous monotherapy provided full virologic suppression, was well-tolerated and enabled the avoidance of potential toxicity of ART while preserving drug options.”

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.

PJ Maddon, K Dhody, U Kowalczyk, K Kazempour, N Pourhassan, J Lalezari

Healio material ASM Microbe abstract

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