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Clinical Trials

Date: 2017-07-13

Type of information: Presentation of results at a congress

phase: 2a

Announcement: presentation of results at the 9th International Aids Society Conference (IAS 2017)

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/Aids

Therapeutic area: Infectious diseases

Country: Belgium, France, Spain

Trial details: Study ABX464-004 is designed to demonstrate the long-lasting effect of ABX464, which has been observed in preclinical studies. The study will enroll twenty eight patients whose HIV infection is already fully controlled by boosted Darunavir. ABX464 will be administered to 21 of these patients in combination with their current drug regimen, while the remaining 7 patients will be given placebo in combination with their current therapy. After 28 days, all treatment will be discontinued and the study will then measure the time elapsed until the HIV virus reappears in the blood of the ABX464-treated patients and the control group. The efficacy endpoint of the study is the time to rebound of the viral load. This rebound will originate from the HIV reservoirs, which are not affected by current combination antiretroviral treatment. (NCT02735863)

Latest news:

  • • On July 13, 2017, Abivax announced that the full data of the ABX464-004 clinical study have been accepted as late breaker presentation at the 9th International Aids Society Conference (IAS 2017), which will be held July 23-26, 2017 in Paris, France. The Late Breaker presentation ‘’ABX464 decreases Total HIV DNA in PBMC´s when administered during 28 days to HIV-infected patients who are virologically suppressed’’ further demonstrates the preliminary results communicated by Abivax on May 2, 2017 (see below). ABX464 impacted the HIV blood reservoir in this Phase IIa clinical trial, supporting its potential to become a key functional cure component for HIV.
  • A separate Phase 2a clinical trial (ABX464-005) has already begun with the goal of studying the effects of ABX464 on HIV reservoirs in blood and in gut tissues. In this previously announced study, patients in the first cohort are receiving ABX464 for 28 days in addition to their antiretroviral treatment. Rectal biopsies are being collected at certain intervals, allowing quantification of the viral reservoir and level of inflammation over time. Based on the results of the ABX464-004 study, ABIVAX has submitted a protocol amendment, with plans to extend the treatment period for the second cohort of patients in order to observe the longer-term effects of ABX464 on HIV reservoir suppression. Initial results of the first cohort are expected in the third quarter of 2017. • On May 2, 2017, Abivax announced that its lead therapeutic candidate ABX464 demonstrated the first reduction in HIV reservoirs ever observed in chronically infected HIV patients as measured by total HIV DNA detected in peripheral blood mononuclear cells (PBMCs). “This is the first time we see a signal with any therapeutic candidate that it may be possible to reduce HIV reservoirs in patients,” said Professor Linos Vandekerckhove, Head HIV Cure Research Center at the Department of Internal Medicine, at the University of Ghent, Belgium, a principal investigator involved in the study. ‘’Now we are looking forward to learn how this drug can be optimized to be part of a multitarget approach to further reduce the viral reservoir”. In the ABX464-004 trial, 30 HIV patients were enrolled in Spain, Belgium and France. Patients were enrolled in a 3:1 randomization, receiving either ABX464 or matching placebo in addition to their current antiretroviral treatment during 28 days. The viral load at the start of the study was well controlled with boosted darunavir. After the 28-day treatment period, all treatments were interrupted until viral load rebound. Baseline and day 28 blood samples were taken in order to assess the potential effect of ABX464 on the HIV reservoir in PBMCs. The clinical trial has been completed with respect to patient treatment and follow-up.
  • Safety was the primary endpoint in the trial and ABX464 was well tolerated and there were no severe adverse events in the treatment group. Amongst evaluable patients (4 placebo and 14 ABX464-treated patients), a reduction in viral DNA copies/mPBMCs was observed in 7/14 treated patients (mean change of -40%, ranging from -27% to -67%) and no responders were observed in the placebo group. Responders were defined as patients who had a decrease greater than 25% in total HIV DNA in PBMCs and a reduction of at least 50 copies.
  • Total HIV DNA in PBMC has been validated as a widely accepted biomarker for measuring the HIV reservoir. Specifically, in untreated patients, total HIV DNA load influences the course of the infection and is therefore clinically relevant. In addition, a correlation exists between the pool of HIV-1 DNA and the replication-competent reservoir.Dr Jean-Marc Steens, Chief Medical Officer at ABIVAX said: “These results in patients are a first and very important step in supporting the hypothesis that ABX464 could impact the HIV reservoir. Currently approved drugs can effectively reduce and control the replication of the HIV virus in humans, allowing many patients to live with chronic treatment, but no drugs have been able to eradicate the virus in humans because it evades therapy by hiding in what have been called by the scientific community “HIV reservoirs”. In this Phase IIa clinical trial, during which patients were treated only for a short period of 28 days, we did not yet see an impact on the time to rebound after treatment interruption. Therefore, the next step will be to evaluate longer treatment duration with ABX464, which could lead to a profound reduction of the HIV reservoir and potentially become part of a functional cure for HIV patients.”A separate Phase IIa clinical trial (ABX464-005) has already started to study the effects of ABX464 on HIV reservoirs in gut tissues. In this previously announced study, patients are receiving ABX464 for 28 days in addition to their antiretroviral treatment. Rectal biopsies are being collected at certain intervals, allowing quantification of the viral load and level of inflammation in the reservoir over time. Based on the results of the ABX464-004, Abivax plans to amend the ABX464-005 protocol to extend the treatment period in order to observe the longer-term effects of ABX464 on HIV reservoir suppression. Initial results of the ABX464-005 study are expected in Q3 2017.The final data of ABX464-004 will be submitted for presentation at upcoming International HIV conferences.
  • • On December 6, 2016, Abivax provided a clinical update on the clinical development program for ABX464. Given the current pace of recruitment, which is slower than expected, Abivax anticipates to communicate the top-line results of the ongoing Phase IIa study (ABX464-004) in April 2017, which translates into a delay of four months compared with the initial estimate. This phase IIa clinical trial is currently enrolling patients in Spain, Belgium and France. One of the co-primary endpoints of the study is the long-lasting effect of ABX464 in maintaining a low viral load in the blood of infected patients, which were treated with an established antiretroviral therapy and ABX464 or placebo.On top of the ongoing ABX464-004 Phase IIa study, Abivax recently requested regulatory and ethics committee approval for a new study, which is a compartmental pharmacokinetics (PK) clinical study (ABX464-005). In this study, HIV infected patients will receive ABX464 for 28 days in addition to their antiretroviral treatment. Rectal biopsies will be collected at different intervals, allowing the effect of ABX464 on the reservoir of HIV (which primarily resides in the gut) to be examined. This study, which will be conducted at the Germans Trias i Pujol University Hospital Badalona (Barcelona, Spain) will quantify the viral load and level of inflammation in the reservoir over time and, therefore, will provide a better understanding of the long-term efficacy observed in pre-clinical models with ABX464. Following receipt of the appropriate regulatory approvals, Abivax expects to initiate this study in the first half of 2017. Finally, new preclinical data generated with ABX464 demonstrate a strong anti-inflammatory effect of the compound. In macrophages, this effect was shown to be mediated by a 50-fold increase of the expression of IL-22, a cytokine known as a potent suppressor of inflammatory processes. Inflammation is a cornerstone of the pathologies observed, not only in HIV, but also in a number of other diseases, such as inflammatory bowel disease (IBD, including ulcerative colitis and Crohn’s disease). When evaluated in a mouse model of IBD, ABX464 demonstrated a long-lasting effect in preventing the typical symptoms of inflammatory colitis, including histological changes. Based on these encouraging results, the company intends to launch a proof of concept clinical study in patients with IBD in 2017.
  • • On September 13, 2016, Abivax reported that it has completed the second key milestone of the Strategic Industrial Innovation Project CaReNa. Started in 2013, this collaborative project led by Abivax with the participation of CNRS and Theradiag intends to develop new therapeutic and diagnostic solutions targeting the protein-RNA interactions with HIV/AIDS as the primary indication. The total cost of the project is 18.2 M€, of which 13.6 M€ will be born by ABIVAX. The project benefits from the help of Bpifrance in form of refundable loans and subsidies totaling 7.3 M€, of which 5.2 M€ are used in Abivax operations. So far, the Company has received 3.4 M€ and 1.8 M€ are still to come before the end of 2018.The completion of this second key milestone of CaReNa is the consequence of the progress achieved in the development of ABX464, The compound  is currently in mid-stage clinical testing. In 2014, two Phase I studies conducted on healthy subjects demonstrated that the product was well tolerated at the anticipated therapeutic doses. In 2015, a phase 2a study in 80 patients infected with HIV provided initial evidence of the activity of ABX464 in humans. Data from this placebo controlled dose-escalation study, presented in February 2016 during CROI (Conference on Retrovirus and Opportunistic Infections) in Boston MA and in July 2016 during the 21st AIDS Conference in DurbanSouth Africa, demonstrated the safety and efficacy of ABX464 monotherapy in the treatment of naive patients infected with HIV. A reduction in the viral load of at least 0.5 log (more than 68% reduction) was observed in 1 patient out of 6 in the 75 mg group, 2 patients out of 6 in the 100 mg group and 4 patients out of 6 in the 150 mg group. There was no significant variation in the viral load in the 6  patients who received a placebo in these groups. The undesirable effects noted were those typically observed in the context of antiviral treatments. The ABX464-004 study is designed to demonstrate the long-term effect of ABX464 on the viral load that had previously been observed during preclinical trials. The study plans to recruit 28 patients suffering from HIV, whose infection is well controlled by "boosted" Darunavir. ABX464 is being administered to 21 of these patients in addition to their regular anti-retroviral treatment (ART). The 7 remaining patients receive a placebo, in addition to their ART. After 28 days, all treatments are stopped, and the study then measures the time to reappearance of the virus in the blood of the patients. The main efficacy criterion of the study is the time to viral load rebound. This rebound has been studied and shown to come from the “HIV reservoir”, or pockets of virus hidden in areas of the body that are not affected by the current combinations of ART. The preliminary results of the study will become available before the end of 2016.
  • • On May 30, 2016, Abivax announced that the first patient in the ABX464-004 study has been enrolled, effectively launching the second Phase IIa trial in HIV/AIDS patients with ABX464. The first patient treatment in this trial is scheduled to take place at University Hospital  Germans Trias i Pujol in Badalona, Barcelona, Spain. The trial will be conducted at clinical centers in Spain and Belgium, where all regulatory and ethics committees authorizations have been received, and in France where pending ethics committees approvals are expected imminently. Study ABX464-004 is the second Phase IIa trial conducted with ABX464. Preliminary results of this study are expected in Q4 2016. An increase in the time to viral load rebound would constitute the first successful attempt at providing a functional cure for the HIV infection. Large-scale pivotal clinical studies of ABX464 will be required to confirm this hypothesis. These studies could begin by early 2017.
  • • On April 19th 2016, Abivax announced that its second Phase IIa study with ABX464, a first-in-class drug candidate for the treatment of patients with HIV/AIDS, has been approved by Regulatory and Ethics Committees in Spain. Additional approvals in Belgium and France are expected in the near future. With this approval, 28 patients will be enrolled in the second Phase IIa study and initial results are expected in Q4 2016. In addition to the Phase IIa clinical trials, large-scale clinical studies are expected to begin by early 2017. The Phase IIa clinical study will be conducted, subject to all necessary regulatory clearances, in 7 excellence sites in France, Belgium and Spain. One of the primary objectives of this study is to evaluate the long-lasting effect of ABX464 in the control of the viral replication following treatment interruption.

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