ABX464

ABX464, a novel small and first-in-class molecule inhibiting HIV replication

ABX464 is a first-in-class, novel, small molecule inhibiting HIV replication through an entirely new mechanism. For the first time in the treatment of AIDS, this molecule could deliver a long lasting reduction of the viral load after a treatment of only a few weeks. 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.

ABX464 inhibits the biogenesis of viral RNA required for the replication of the HIV virus, a mechanism of action never before explored.

This unique mode of action and preclinical data to-date suggest that ABX464 could:

  • Induce long term control of the viral load,
  • Not induce HIV mutants that are resistant to treatment,
  • Be less frequently administered over a shorter period than standard treatments, 
  • Reduce healthcare costs and offer broader access to treatment.

ABX464 is the first candidate molecule coming from ABIVAX’s proprietary technology platform and chemical library. It has been generated from an in-depth understanding of the processing of viral RNA within the human host cell and the ability of compounds from its novel library to block the biogenesis of viral RNA.

HIV/AIDS: still a major public health problem worldwide 

35 MILLION people worldwide living with HIV (Source: WHO) 
1.6 MILLION PEOPLE DEATHS due to HIV (2012)
>2.3 MILLION PATIENTS INFECTED EU and USA (2013)

As infections continue, and effective anti-viral therapies are changing HIV into a chronic disease, the population of HIV infected patients is increasing in the developed world. There is an urgent medical need for new therapies that lead to a (functional) cure of HIV.

Clinical trials and publications

ABIVAX has completed successful Phase Ia and Ib clinical trials in healthy volunteers in order to evaluate the tolerability, safety and pharmacokinetic properties of a single, escalating dose of ABX464 (Phase Ia). The Phase Ib study evaluated the impact of food in-take and the repeated administration of ABX464 on the pharmacokinetic properties as well as tolerability and safety (Phase Ib). These studies have been finalized and the results are currently being analyzed. 

A first Phase IIa trial of ABX464 in patients with HIV infection has been completed. 66 treatment-naïve patients (never having previously received antiretroviral treatment) were recruited into this Phase IIa blinded study. The preliminary results were presented at the Conference on Retroviruses and Opportunistic Infections (CROI), February 2016 in Boston, Massachusetts. The study results evidenced in humans, a dose-dependent antiviral signal of ABX464, as well as a good safety profile.

In addition, ABIVAX is currently conducting a second Phase IIa study in patients with HIV in France, Belgium and Spain. The double-blind trial will enroll 36 patients whose disease is controlled by treatment with boostered Darunavir.

Retrovirology – 9 April 2015  

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

N. Campos, R. Myburgh, A. Garcel, A. Vautrin, L. Lapasset, E. Schläpfer Nadal, F. Mahuteau-Betzer, R. Najman, P. Fornarelli, K. Tantale, E. Basyuk, M. Séveno, J. Venables, B.Pau, E. Bertrand, M. Wainberg, R.Speck, D. Scherrer and J. Tazi 

Extract of the abstract: 

Current 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. (…)

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). (…) Read more 

 

In addition to results of preclinical research featured in the Retrovirology publication, further studies were conducted showing that:


1. ABX464 is not only active against HIV-1, but also against HIV-2; 

2. Humanized mice (HIS) infected with the YU2 strain did not have a drop in their viral load after 100 days of infection and the percentage of their CD4 of total CD45 cell count was constant over time, demonstrating that there is no target cell depletion following 100 days of infection.

The fact that ABX464 and its metabolite (ABX464-N-glucuronide), act on infected macrophages adds to the attractiveness of this molecule, as cells of myeloid lineage including macrophages are present in anatomical sanctuaries making them a difficult drug target (Schrager LK1, D'Souza MP. JAMA. 1998 Jul 1;280(1):67-71, Abbas et al. Viruses 2015, 7, 1578-1598; doi:10.3390/v7041578). ABX464 reduces the level and export of unspliced viral RNA favoring accumulation of spliced viral RNA and thereby lowering the production of infectious particles in macrophages that are capable of infecting CD4+ cells.

 

CROI 2015 – 23-26 February 2015

Presentation of Pr Jamal TAZI (University of Montpellier, France) on ABX464 

 

Know more about mode of action of ABX464 :

 

ABX464

“ABX464 could become the central element of a functional cure for AIDS."

Professor Mark Wainberg, M.D., former President of the International AIDS Society and one of the top HIV experts worldwide

About the mechanism of action