ABX464/HIV

ABX464, a small and first-in-class molecule to induce functional cure in HIV-patients

ABX464 is an oral, 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 HI-virus. These reservoirs are not affected by current antiretroviral therapies, and lead to viral load rebound once treatment is stopped.

ABX464 is the first HIV antiviral to induce a long-term control of the viral load after treatment arrest.

In HIV infected humanized mice that were treated for 50 days with either ABX464 or classical HAART (Highly Active AntiRetroviral Therapy), ABX464 was not only able to reduce the viral load over the 50 days treatment period (figure 1, grey area) but also to maintain a low viral load up to 6 weeks after treatment arrest (figure 1, green circle). By contrast, in ART treated mice the viral load fully rebounded to pre-treatment levels within 14 days after stopping the treatment (figure 1, orange circle). This data suggests that ABX464 is changing the balance between the HI-Virus and its control by the immune system. (1,2)

Figure 1

ABIVAX image

ABX464 mechanism of action

ABX464 inhibits the biogenesis of viral RNA required for the replication of the HI-Virus, a mechanism of action never explored before. By binding to the Cap Binding Complex (CBC) at the 5’ end of the mRNA coding for 3 structural proteins of the virus, ABX464 inhibits the activity of REV, a key HIV protein, thereby promoting HIV RNA splicing and thus the inhibition of HIV replication. The mechanism inducing the long-term control of the viral by ABX464 is under investigation. The current hypothesis is that the induction of HIV RNA splicing by ABX464 will generate aberrant, small HIV RNA fragments that will be translated into small peptides. Those peptides, once deposited at the outer surface of the HIV-DNA containing immune cells, are “tagging” these cells with HIV antigen and thereby trigger an immune response that will result in the elimination of these cells. (2,3)

ABIVAX image2

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 after 6 months of treatment in vitro
  • be less frequently administered 

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.

 

Publications and communications

 

1. CROI 2015 – 23-26 February 2015

Durable control of viral load rebound in humanized mice by ABX464 targeting REV functions

Noelie Campos, Renier Myburgh, Aude Garcel, Audrey Vautrin, Laure Lapasset, Katjana Tantale, Mark Wainberg, Roberto Speck, Didier Scherrer, Jamal Tazi

2. 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 

3. CROI 2016 - 25 February 2016 (Presentation)

Early Evidence of Antiviral Activity and Safety of ABX464 in HIV Treatment Naïve Patient

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

4. HIV Drug Conference – Glasgow, 23-26 October 2016 (Presentation) 

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 full data were published in Antimicrobial Agents and Chemotherapy (Antimicrob Agents Chemother 61:e00545-17) [4

The study results demonstrated in humans dose-dependent antiviral activity of ABX464, as well as a good safety profile.

In addition, ABIVAX has completed a second Phase IIa treatment interruption study in France, Belgium and Spain. This double-blind trial enrolled 30patients whose HIV infections are very well controlled by the treatment with boosted Darunavir. Patients received during 28 days ABX464 or placebo on top of boosted Darunavir. After 28 days all treatments were interrupted. The effect of ABX464 on the HIV reservoir in the blood was 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.

These results will be presented as Late Breaker at the IAS Conference in Paris (July 25, 2017)

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. Blood samples and rectal biopsies are being collected at different intervals, allowing the quantification of viral DNA and level of inflammation in blood and tissue 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 on the first cohort are expected by September 2017.

A protocol amendment was submitted in order to treat the second cohort with ABX464 for a longer period ( 84 days). This could further decrease the HIV reservoir and also increase response rate.

Top line data on the second cohort are expected by the end of H2 2018.

The results of these ABX464-004 and -005 studies will guide us in designing the phase IIb study, planned to be submitted in 2018.

[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

[4] Antimicrobial Agents and Chemotherapy Safety, Pharmacokinetics, and Antiviral Activity of a Novel HIV Antiviral, ABX464, in Treatment-Naive HIV-Infected Subjects in a Phase 2 Randomized, Controlled Study

Jean-Marc Steens, Didier Scherrer, Paul Gineste, P. Noel Barrett, Supparatpino Khuanchai, Ratanasuwan Winai, Kiat Ruxrungtham, Jamal Tazi, Robert Murphy, Hartmut Ehrlich

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