Clinical Trials

Date: 2017-02-02

Type of information: Publication of results in a medical journal

phase: 1

Announcement: publication of results in Journal of Antimicrobial Chemotherapy and Antimicrobial Agents and Chemotherapy.

Company: Abivax (France)

Product: ABX464

Action mechanism: splice modulating agent. ABX464 is a first-in-class, small molecule inhibiting HIV replication through the inhibition of the Rev protein activity and modulation of RNA splicing. In collaboration with the team of Professor Jamal Tazi at the CNRS in Montpellier, France, ABIVAX designed ABX464 to lead to a clinically relevant improvement in HIV therapy. Preclinical data in humanized mice demonstrated that ABX464 monotherapy had an antiviral effect that was sustained following treatment interruption (Campos et al, Retrovirology 2015 12:30). A prior food-effect study demonstrated a three-fold increase in parent drug exposure when administered with food, without a significant impact on active glucuronide metabolite.

Disease: HIV infection

Therapeutic area: Infectious diseases

Country:

Trial details:

Latest news:

• • On February 2, 2017, Abivax announced that the previously disclosed results of its two Phase I trials with ABX464 in healthy volunteers have been published in Journal of Antimicrobial Chemotherapy and, separately, Antimicrobial Agents and Chemotherapy. ABX464 inhibits the HIV REV protein, which is critical for viral replication. ABX464 has not only been demonstrated to inhibit viral replication in vitro and in vivo, but also to induce a long-lasting reduction of viral load following treatment interruption in a preclinical HIV model. As a result, ABX464 may be the first of a new class of anti-retroviral drugs, and could become a key component to developing a functional cure for patients. Moreover, ABX464 has been shown to stimulate the expression of anti-inflammatory molecules (IL-22 and miR124) in immune cells in preclinical testing. For example, ABX464 was recently shown to protect mice from the lethal effects of DSS (Dextrane Sulfate Sodium), a substance inducing severe colitis. Based on these results, ABX464 will enter into a Phase II proof-of-concept (POC) study in inflammatory bowel disease later this year. The published Phase I studies were conducted in 24 and 48 healthy volunteers, respectively. They demonstrated that, following oral administration, ABX464 was well absorbed by the intestine and well tolerated by the healthy volunteers. The administration of ABX464 with food resulted in favorable pharmacokinetic properties at the anticipated therapeutic doses. ABX464 was rapidly and substantially metabolised into ABX464-N-Glucoronide. The Cmax (maximal concentration) of the metabolite was observed approximately 4h post-dose and was about 160-fold higher than that of the parent with a much longer half-life (90-110h). It has been demonstrated in vitro that the metabolite was able to inhibit HIV replication in macrophage culture with the same IC50 as the parent drug (Ref. Campos N, Myburgh R, Garcel A, Vautrin A, Lapasset L, Nadal ES, et al. Long lasting control of viral rebound with a new drug ABX464 targeting Rev – mediated viral RNA biogenesis. Retrovirology 2015; 12:1-15).
• • On November 30, 2015, Abivax announced positive results of first clinical evaluation of ABX464 in healthy volunteers for safety and pharmacokinetics. Abivax has conducted two phase 1 clinical trials in a total of 72 healthy volunteers: first, a single ascending dose (SAD) study focusing on the pharmacokinetics and tolerability of ABX464; and, second, a study to evaluate the effect of repeated dosing and of food intake on the safety and bioavailability of ABX464. The SAD study was an open-label study performed in 24 healthy male subjects to determine pharmacokinetic and safety profiles of 4 single ascending oral doses of ABX464 (50, 100, 150 and 200 mg) under fasting conditions. A linear dose-related absorption and bioavailability of ABX464 was observed up to the 150 mg dose group, with a plateau (i.e. no additional bioavailability) observed at the 200mg dose. Pharmacokinetic analyses showed that ABX464 is rapidly metabolized into ABX464-N-glucuronide in humans. This metabolite has a long half-life (t½) of 3-4 days in humans and also has been demonstrated to be functionally active against HIV. ABX464 demonstrated good safety and was generally well tolerated. Adverse events were infrequent and observed primarily at the highest doses, consisting of mild to moderate headache and nausea/emesis. No serious adverse events related to ABX464 were observed in the study. The food effect study included a total of 48 healthy volunteers: Group 1 (24 subjects): A single oral dose of 50 mg ABX464 was administered in fed and fasted conditions separated by wash-out of 45 days. In this cross-over design, patients were their own control. Group 2 (24 subjects): 50 mg ABX464 were administered orally every 3 days over 10 days in fasted or fed conditions. 12 subjects received 4 administrations of 50 mg ABX 464 during fasted conditions 12 subjects received 4 administrations of 50 mg ABX 464 during fed conditions ABX464 was generally well tolerated and no significant adverse events related to ABX464 were reported. A 3-fold increased bioavailability, with a marginal effect on the glucuronide metabolite, was observed in Group 1 during fed conditions. The same pattern of 3-fold increased bioavailability and insignificant metabolite modification were observed in Group 2 after repeated administration of ABX464. Based on these results, Abivax is actively continuing clinical development of ABX464 in patients, administered in fed conditions, which is the most common practice for marketed HIV therapies. More detailed results from both studies are being submitted to peer reviewed journals for publication. This first trial of ABX464 in patients with HIV infection is a double-blind, placebo-controlled Phase IIa monotherapy dose-ranging trial. The study was launched in 2015, and involves up to 80 treatment-naive patients (who never have received anti-retroviral treatment), randomized into 10 dose groups of eight patients each (6 patients per group receiving daily ABX464 monotherapy for 3 weeks and 2 patients per group receiving placebo). The primary endpoint of this study is to evaluate the safety and tolerability of ABX464 after repeated oral administrations in patients infected by HIV. Secondary endpoints will examine its pharmacokinetic profile and its impact as monotherapy on the viral load of patients infected with HIV over a short 3-week treatment period.
• A first Phase IIa clinical trial of ABX464 in naive patients infected with HIV was launched in 2015 with results expected in January 2016. In addition, Abivax is currently planning a second Phase IIa study in patients with HIV, to be initiated in France, Belgium and Spain. The double-blind trial will enroll 28 patients whose disease is controlled by treatment with boostered Darunavir. Patients will be randomized 3:1 to receive daily doses of either ABX464 at the highest tolerated dose from the currently ongoing study (21 patients) or placebo (7 patients). After 4 weeks of combination treatment, all therapies will be stopped, and the time to viral load rebound will be measured and compared between groups.
• • On December 1st, 2014, Abivax, a clinical stage biotech company developing and commercialising anti-viral compounds and human vaccines, announced the successful completion of its Phase 1 first-in-man study of ABX464, which has been designed to potentially deliver a number of important clinical benefits when treating patients with HIV. The trial of ABX464 in healthy volunteers assessed pharmacokinetic properties and biological safety. The Phase 1 study was completed with single administration of 4 doses: 50, 100, 150 and 200mg, and saw no serious adverse event and no clinically significant abnormal result in physical examinations, laboratory test results, vital signs and ECG. Abivax plans to start a Phase 2 study in patients with HIV in the coming months.

Is general: Yes