ABX464/HIV

ABX464, a small and first-in-class molecule that may lead to a functional cure in HIV-patients

ABX464 is a first-in-class, novel, small molecule inhibiting HIV replication through an entirely new mechanism of action. For the first time in the treatment of HIV, this molecule could reduce or eliminate the viral reservoirs, and thus potentially deliver a long lasting reduction in the viral load of HIV-patients. In collaboration with the team of Professor Jamal Tazi at the CNRS in Montpellier, France, and the Institute Curie, Orsay, France, ABIVAX designed ABX464 with the goal of targeting the viral reservoirs of immune cells with integrated genetic material from the HIV-virus. These reservoirs are not affected by current antiretroviral therapies, and lead to viral load rebound once treatment is stopped.

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

This unique mode of action and the preclinical data to-date suggest that ABX464 has the potential to:

  • reduce or eliminate the viral reservoirs in patients with HIV
  • induce long term control of the viral load,
  • prevent  the emergence of 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 antiviral 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.

  

In addition to preclinical research results 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 ABX464 does not induce resistant mutants after 6 months of treatment in vitro

3. ABX464 is efficacious in vitro on mutated virus

4. ABX464 reduces the level and export of unspliced viral RNA favoring accumulation of spliced viral RNA, thereby lowering the production of infectious particles that are capable of infecting CD4+ cells. 

5. In the untreated humanized mice (HIS) infected with the YU2 HIV 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). 

CROI 2015 – 23-2 6 February 2015

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

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. ABIVAX has 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 

HIV Drug Conference – Glasgow, 23-26 October 2016:

Presentation by Didier Scherrer: Differential efficacy of ABX464 and its primary metabolite ABX464- NGlc on HIV replication in human PBMC’s and macrophages: implications for treatment strategies to eliminate virus reservoirs

HIV/AIDS: still a major public health problem worldwide 

36.7 MILLION people worldwide living with HIV in 2015 (UNAIDS)
1.1 MILLION deaths in 2015 due to HIV (UNAIDS)
2.1 MILLION new HIV Infections in 2015
2.4 MILLION people living with HIV in EU and USA in 2015 (UNAIDS) 

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

Clinical trials and publication

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 published ([1],[2]). 

An initial Phase IIa trial of ABX464 in 66 treatment-naïve HIV patients (never having previously received antiretroviral treatment) has also been completed. The preliminary results were presented at the Conference on Retroviruses and Opportunistic Infections (CROI), February 2016 in Boston, Massachusetts ([3]). The study results demonstrated in humans dose-dependent antiviral activity of ABX464, as well as a good safety profile.

In addition, ABIVAX is currently finishing a second Phase IIa treatment interruption study in France, Belgium and Spain. This double-blind trial enrolled 28 patients whose HIV infections are very well controlled by the treatment with boosted Darunavir. Patients receive during 28 days ABX464 or placebo on top of boosted Darunavir. After 28 days all treatments are interrupted. The effect of ABX464 on the HIV reservoir in the blood is being measured. 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. This is the first time a signal was seen with a therapeutic candidate that it may be possible to reduce HIV reservoirs in patients.

ABIVAX has also launched a compartmental pharmacokinetics (PK) clinical study (ABX464-005) in March 2017. HIV infected patients receive ABX464 for 28 days in addition to their antiretroviral treatment. Rectal biopsies are being collected at different intervals, allowing the quantification of viral load and level of inflammation in the reservoirs over time. This study, conducted at the Germans Trias i Pujol University Hospital Badalona (Barcelona, Spain), will provide a better understanding of the long term efficacy that was observed in preclinical models with ABX464. Initial results are expected during the summer of 2017.

The results of these ABX464-004 and -005 studies will guide us in designing the phase IIb study, planned to be initiated by the end of 2017.

[1] https://www.ncbi.nlm.nih.gov/pubmed/27999038 Pharmacokinetics and tolerability of ABX464, a novel first-in-class compound to treat HIV infection, in healthy HIV-uninfected subjects.

Scherrer D, Rouzier R, Noel Barrett P, Steens JM, Gineste P, Murphy RL, Tazi J, Ehrlich HJ.

[2] https://www.ncbi.nlm.nih.gov/pubmed/27799203 Randomized Trial of Food Effect on Pharmacokinetic Parameters of ABX464 Administered Orally to Healthy Male Subjects.

Scherrer D, Rouzier R, Cardona M, Barrett PN, Steens JM, Gineste P, Murphy RL, Tazi J,Ehrlich HJ.

[3] CROI 2016 ( Boston USA ) Early Evidence of Antiviral Activity and Safety of ABX464 in HIV Treatment-Naïve Patients

Didier Scherrer, Jean-Marc Steens, Supparatpinyo Kuanchai, Ratanasuwan Winai, Kiat Ruxrungtham, Regine Rouzier, Jamal Tazi, Paul Gineste, Hartmut Ehrlich, Robert Murphy

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