Didier Scherrer

Long lasting control of viral rebound with a new drug ABX464 targeting Rev - mediated viral RNA biogenesis

BackgroundCurrent therapies have succeeded in controlling AIDS pandemic. However, there is a continuing need for new drugs, in particular those acting through new and as yet unexplored mechanisms of action to achieve HIV infection cure. We took advantage of the unique feature of proviral genome to require both activation and inhibition of splicing of viral transcripts to develop molecules capable of achieving long lasting effect on viral replication in humanized mouse models through inhibition of Rev-mediated viral RNA biogenesis.ResultsCurrent HIV therapies reduce viral load during treatment but titers rebound after treatment is discontinued. We devised a new drug that has a long lasting effect after viral load reduction. We demonstrate here that ABX464 compromises HIV replication of clinical isolates of different subtypes without selecting for drug resistance in PBMCs or macrophages. ABX464 alone, also efficiently compromised viral proliferation in two humanized mouse models infected with HIV that require a combination of 3TC, Raltegravir and Tenofovir (HAART) to achieve viral inhibition in current protocols. Crucially, while viral load increased dramatically just one week after stopping HAART treatment, only slight rebound was observed following treatment cessation with ABX464 and the magnitude of the rebound was maintained below to that of HAART for two months after stopping the treatment. Using a system to visualize single HIV RNA molecules in living cells, we show that ABX464 inhibits viral replication by preventing Rev-mediated export of unspliced HIV-1 transcripts to the cytoplasm and by interacting with the Cap Binding Complex (CBC). Deep sequencing of viral RNA from treated cells established that retained viral RNA is massively spliced but importantly, normal cellular splicing is unaffected by the drug. Consistently ABX464 is non-toxic in humans and therefore represents a promising complement to current HIV therapies.ConclusionsABX464 represents a novel class of anti-HIV molecules with unique properties. ABX464 has a long lasting effect in humanized mice and neutralizes the expression of HIV-1 proviral genome of infected immune cells including reservoirs and it is therefore a promising drug toward a functional cure of HIV.

Pharmacokinetics and tolerability of ABX464, a novel first-in-class compound to treat HIV infection, in healthy HIV-uninfected subjects.

Background: An anti-HIV compound (ABX464) has been developed with a novel mechanism of activity in that it blocks viral gene expression in cells that are already infected. Objectives: A first-in-man study was conducted to determine the pharmacokinetic and safety profiles of ABX464. This was carried out as an open label, parallel group, single ascending dose, exploratory study. Methods: Twenty-four male subjects in good health without HIV infection, aged from 18 to 55 years old, with BMIs of 18–27 kg/m2 were included. A single oral dose of ABX464 (50, 100, 150 or 200 mg) was administered on the morning of day 0 after overnight fasting, with follow-up for 45 days. Safety assessments consisted of vital signs, electrocardiogram, physical examination, laboratory tests and urinalysis. Pharmacokinetic parameters were calculated for ABX464 and its main metabolite ABX-464-N-glucuronide (ABX464-NGlc). The study was registered at https://www.clinicaltrials (trial number NCT02792686). Results: ABX464 was well tolerated; the most frequent related treatment-emergent adverse events were headaches, nausea and vomiting; they were not considered as treatment-limiting effects. ABX464’s Cmax was observed approximately 2 h after administration in all groups. ABX464 was rapidly and substantially metabolized into ABX464-NGlc. The Cmax of ABX464-NGlc was observed approximately 4 h post-dose and was about 160-fold higher than that of the parent with a much longer t1/2 (90–110 h). The ratio of metabolite to parent drug was consistent across the complete dose range. Conclusions: These studies confirmed that ABX464 is well tolerated and rapidly and substantially metabolized into ABX464-NGlc in human subjects.

Safety, Pharmacokinetics, and Antiviral Activity of a Novel HIV Antiviral, ABX464, in Treatment-Naive HIV-Infected Subjects in a Phase 2 Randomized, Controlled Study

ABSTRACT We investigated the safety and antiviral effects of an anti-HIV compound (ABX464) with a unique mechanism of viral replication inhibition. This was a randomized, double-blind, placebo-controlled, dose-ranging study in treatment-naive HIV-infected patients. Participants were assigned to eight groups; each group included eight subjects receiving either the study compound, ABX464 (n = 6), or the corresponding placebo (n = 2), according to a randomization code. The first dose administered was 25 mg, given once or 3 times a day over a 2- to 3-week period. Ascending doses of up to 150 mg were delivered after review of the safety data. The primary objective of the study was to assess the safety and tolerability of ABX464 after repeated oral administrations in subjects infected by HIV. Sixty-six subjects were enrolled and were randomized. Sixty-three subjects completed the study according to the study protocol. Twenty-one adverse events (AEs) were reported by 7 subjects out of 16 (44%) who received placebo, and 158 AEs were reported by 39 subjects out of 50 (78%) who received the study drug. In the ABX464 treatment group, all of these adverse events were mild to moderate. No subjects discontinued treatment due to drug-related AEs. Administration of ABX464 at up to 150 mg once a day was safe and well tolerated in HIV-infected subjects. An efficacy signal with respect to a reduction of the viral load by ABX464 was detected, mainly in subjects treated at the highest dose. Further studies will be required to demonstrate antiviral effects in HIV-infected subjects in combination with other antiretroviral therapies. (This study is registered on the ClinicalTrials.gov website under registration no. NCT02452242.)

Randomized Trial of Food Effect on Pharmacokinetic Parameters of ABX464 Administered Orally to Healthy Male Subjects

ABSTRACT ABX464 is an antiviral that provides a novel approach to the reduction and control of HIV infection. Investigation of food influence is important in the optimization of treatment. An open-label, food effect, randomized study which included 2 groups of 24 subjects each was carried out to assess the bioavailability and safety of single (group 1) and repeated (group 2) oral doses of ABX464 (50 mg) under fed or fasted conditions. The maximum concentration (Cmax) and the area under the concentration-time curve from time zero to infinity (AUC0–∞) of ABX464 were demonstrated to increase with food after a single dose of ABX464 (219% and 188%, respectively). The apparent terminal elimination half-lives (t1/2s) under fed and fasted conditions were comparable, at about 0.80 h. The median time to maximum concentration (Tmax) was delayed from 1.5 to 2.8 h, and the ratio of the AUC0–∞ obtained under fed conditions to the AUC0–∞ obtained under fasted conditions (Frel) was 2.69. Comparable results were obtained on day 1 and day 10 in group 2. The increases in Cmax and AUC0–∞ of the metabolite ABX464–N-glucuronide (ABX464-NGlc) were, however, much more limited when ABX464 was given with food. The t1/2s were also comparable under the two conditions (around 100 h). Between day 1 and day 10, the Cmax increased by 5% under the fasted condition and by 25% under the fed condition. The most common related treatment-emergent adverse events were headaches, vomiting, and nausea. It was concluded that food has a significant impact on the levels of ABX464 in plasma with a delay in absorption and increased relative bioavailability, with a lesser impact on its biotransformation into ABX464-NGlc. ABX464 was well tolerated under both fasted and fed conditions. (This study has been registered at ClinicalTrials.gov under registration no. NCT02731885.)

The Anti-Hiv Candidate Abx464 Dampens Intestinal Inflammation by Triggering Il-22 Production in Activated Macrophages

The progression of human immunodeficiency virus (HIV) is associated with mucosal damage in the gastrointestinal (GI) tract. This damage enables bacterial translocation from the gut and leads to subsequent inflammation. Dextran sulfate sodium (DSS-exposure) is an established animal model for experimental colitis that was recently shown to recapitulate the link between GI-tract damage and pathogenic features of SIV infection. The current study tested the protective properties of ABX464, a first-in-class anti-HIV drug candidate currently in phase II clinical trials. ABX464 treatment strongly attenuated DSS-induced colitis in mice and produced a long-term protection against prolonged DSS-exposure after drug cessation. Consistently, ABX464 reduced the colonic production of the inflammatory cytokines IL-6 and TNFα as well as that of the chemoattractant MCP-1. However, RNA profiling analysis revealed the capacity of ABX464 to induce the expression of IL-22, a cytokine involved in colitis tissue repair, both in DSS-treated mice and in LPS-stimulated bone marrow-derived macrophages. Importantly, anti-IL-22 antibodies significantly reduced the protective effect of ABX464 on colitis in DSS-treated mice. Because reduced IL-22 production in the gut mucosa is an established factor of HIV and DSS-induced immunopathogenesis, our data suggest that the anti-inflammatory properties of ABX464 warrant exploration in both HIV and inflammatory ulcerative colitis (UC) disease.

RNA sequencing analysis of activated macrophages treated with the anti-HIV ABX464 in intestinal inflammation

RNA-Seq enables the generation of extensive transcriptome information providing the capability to characterize transcripts (including alternative isoforms and polymorphism), to quantify expression and to identify differential regulation in a single experiment. To reveal the capacity of new anti-HIV ABX464 candidate in modulating the expression of genes, datasets were generated and validated using RNA-seq approach. This comprehensive dataset will be useful to deepen the comprehensive understanding of the progression of human immunodeficiency virus (HIV) associated with mucosal damage in the gastrointestinal (GI) tract and subsequent inflammation, providing an opportunity to generate new therapies, diagnoses, and preventive strategies.