ABX464Drug Class: Rev Inhibitor
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(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and ClinicalTrials.gov3)
Mechanism of Action: Rev inhibitor. ABX464 is a small molecule antiretroviral compound that acts through a novel mode of action to prevent HIV replication after proviral DNA integration. ABX464 blocks the formation of viral structural proteins that are essential for HIV replication. ABX464 binds directly to the cap binding complex (CBC) of HIV mRNA, and thereby 1) enhances viral RNA splicing and 2) inhibits Rev-mediated export of unspliced HIV RNA from the nucleus to the cytoplasm. By inducing viral RNA splicing, ABX464 may promote the formation of small, irregular viral RNA fragments, which may then be translated into small viral peptides. Once positioned on the surface of infected macrophages, these peptides may act as antigen to generate a host immune response to destroy the HIV-infected cell. ABX464 is currently being studied as a potential component of a functional HIV cure strategy.2,4-7
Half-life (T½): The half-life of ABX-464 was determined in an ascending dose-ranging study (NCT02452242) of ABX464 monotherapy (25 to 150 mg) administered orally with and without food to treatment-naive adults with HIV. In this study, the half-life of ABX464 was approximately 1 hour versus about 100 hours for its active metabolite ABX464-N-glucuronide (ABX464-NGlc).8
Metabolism/Elimination: In vivo, ABX464 is quickly metabolized and extensively converted into a single primary metabolite, ABX464-NGlc. This metabolite has demonstrated antiviral activity in macrophage cultures infected with HIV.8,9Resistance: In an in vitro study of HIV-infected cell cultures exposed to increasing concentrations of ABX464 and other ARV drugs, ABX464 did not select for any resistance mutations for up to 24 weeks of treatment. ABX464 also demonstrated in vitro efficacy against certain HIV mutants (K65R and M184V) with resistance to lamivudine.5
Select Clinical Trials
Study Identifiers: ABX464-003; NCT02452242
Sponsor: Abivax S.A.
Status: This study has been completed.
Study Purpose: The purpose of this dose-escalation trial was to evaluate the safety, pharmacokinetics, and antiviral activity of ABX464.
- Participants were treatment-naive adults with HIV-1 or HIV-2.
- Participants had HIV RNA between 5,000 and 500,000 copies/mL and CD4 counts ≥350 cells/mm3.
- Group 1: 25 mg every 3 days for 2 to 3 weeks
- Group 2: 25 mg once daily for 2 to 3 weeks
- Group 3: 50 mg once daily for 2 to 3 weeks
- Group 4: 50 mg 3 times a day for 4 weeks
- Group 5: 75 mg once daily for 2 weeks
- Group 6: 100 mg once daily for 2 to 3 weeks
- Group 7: 150 mg every 3 days for 2 to 3 weeks
- Group 8: 150 mg once daily for 2 weeks.8,10,11
Selected Study Results:
- AIDS, 2016: Antiviral activity and safety of ABX464 in HIV-infected treatment-naive patients
- Antimicrob Agents Chemother article, 2017: Safety, pharmacokinetics, and antiviral activity of a novel HIV antiviral, ABX464, in treatment-naive HIV-infected subjects in a Phase 2 randomized, controlled study
Study Identifiers: ABX464-004; NCT02735863
Sponsor: Abivax S.A.
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the safety of ABX464. The study also analyzed the effect of ABX464 on the latent HIV reservoir and on viral control during a treatment interruption of ART.
- Participants were adults with HIV who had been receiving monotherapy with boosted darunavir (either darunavir plus ritonavir or darunavir plus cobicistat) for at least 8 weeks prior to baseline.
- Participants had HIV RNA ≤50 copies/mL during the 6 months prior to screening and had CD4 counts ≥600 cells/mm3 at screening.
- Participants had HIV RNA ≤100,000 copies/mL at any time since their HIV was diagnosed (excluding during primary HIV infection) and had CD4 counts ≥250 cells/mm3 at any time since their HIV was diagnosed.
Dosing: Participants were randomized to receive either ABX464 (50 mg or 150 mg) once daily or placebo once daily, each combined with their current regimens of boosted darunavir, for 28 days.
On Day 29, treatment was stopped. During the period of ART treatment interruption, participants' viral load levels were monitored, and ART was reinitiated if a participant's viral load rebounded to greater than 1,000 copies/mL.3,12
Selected Study Results:
IAS, 2017: ABX464 decreases total HIV DNA in PBMCs when administered during 28 days to HIV-infected virologically suppressed patients
Study Identifiers: ABX464-005; NCT02990325
Sponsor: Abivax S.A.
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the systemic and mucosal immunological effects of ABX464. The study will also assess the pharmacokinetic and pharmacodynamic properties of ABX464 and the impact of ABX464 on various immunological endpoints.
- Participants are adult males with HIV and without HIV.
- Participants with HIV:
- Participants have been receiving dolutegravir or raltegravir plus either tenofovir DF/emtricitabine or abacavir/lamivudine for at least 12 months prior to screening.
- Participants have HIV RNA ≤50 copies/mL during the 6 months prior to screening. At all other times, excluding the stage of primary infection and 6 months after primary infection, participants have had HIV RNA ≤100,000 copies/mL.
In this Phase IIa study, 66 participants (n = 50 ABX464; n = 16 placebo) were enrolled into 8 groups to receive either ABX464 or placebo within each group. One hundred fifty-eight adverse events (AEs) occurred among 78% of participants receiving ABX464 and 21 AEs occurred among 44% of participants receiving placebo. All of the AEs in the ABX464 groups were mild to moderate, and none resulted in study drug discontinuation. No serious adverse events (SAEs) were reported with ABX464. The most common treatment-emergent adverse events (TEAEs) related to ABX464 were headache, nausea, and vomiting. Twenty cases of upper abdominal pain were reported among 4 participants receiving ABX464. The frequency of headache, nausea, and vomiting with ABX464 appeared to be dose related, increasing in frequency starting with the 75-mg dose. Two participants who received ABX464 75 mg once daily experienced an episode of skin rash, and both cases were probably related to ABX464 treatment. Across treatment groups, the proportion of participants who experienced a TEAE was between 33% and 50% for Groups 1 to 3, and 100% for Groups 4 to 8.8
In this Phase IIa study, 30 participants were randomized to receive either ABX464 (n = 22) or placebo (n = 8). No treatment-emergent SAEs occurred during the study. One participant receiving ABX464 150 mg discontinued treatment early because of Grade 2 abdominal pain and Grade 1 epigastric pain; both were considered drug-related AEs. No participants at the 50-mg dose level had a drug-related TEAE, while 8 (50%) participants receiving ABX464 150 mg and 1 (16.7%) participant receiving placebo 150 mg experienced a drug-related TEAE. All drug-related AEs were Grade 1 or 2, except for 1 case of Grade 3 fatigue in a participant receiving ABX464 150-mg. Among participants receiving ABX464, the most frequent drug-related AEs were abdominal pain and headache.3,12,14
Drug-drug interactions associated with ABX464 are unknown.
- United States National Library of Medicine. ChemIDplus Advanced: ABX464. https://chem.nlm.nih.gov/chemidplus/rn/1258453-75-6. Accessed October 10, 2018.
- National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed October 10, 2018.
- Abivax S.A. A Multi-center, randomized, double-blind, placebo-controlled Phase IIa trial to compare the safety of ABX464 given at a fixed dose to placebo in fully controlled HIV infected patients treated with boosted protease inhibitor treatment (darunavir/ritonavir or darunavir/cobicistat). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 8, 2016. NLM Identifier: NCT02735863. https://clinicaltrials.gov/ct2/show/NCT02735863. Accessed October 10, 2018.
- Abivax website. ABX464/HIV. http://www.abivax.com/en/development-products/abx464.html. Accessed October 10, 2018.
- Campos N, Myburgh R, Garcel A, et al. Long lasting control of viral rebound with a new drug ABX464 targeting Rev – mediated viral RNA biogenesis. Retrovirology. 2015;12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422473/.
- Berkhout B, van der Velden YU. ABX464: a good drug candidate instead of a magic bullet. Retrovirology. 2015;12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515925/.
- Scherrer D, Steens J-M, Kuanchai S, et al. Early evidence of antiviral activity and safety of ABX464 in HIV treatment-naive patients. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 22–25, 2016; Boston, MA. Poster 461LB. http://www.croiconference.org/sites/default/files/posters-2016/461LB.pdf. Accessed October 10, 2018.
- Steens J-M, Scherrer D, Gineste P, et al. Safety, pharmacokinetics, and antiviral activity of a novel HIV antiviral, ABX464, in treatment-naive HIV-infected subjects in a Phase 2 randomized, controlled study. Antimicrob Agents Chemother. 2017;61(7). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487684/.
- Scherrer D, Steens J-M, Gineste P, et al. Differential efficacy of ABX464 and its primary metabolite ABX464-NGlc on HIV replication in human PBMCs and macrophages: implications for treatment strategies to eliminate virus reservoirs. J Int AIDS Soc. 2016;9(8(Suppl 7)):21487.
- Abivax S.A. A Phase 2, dose escalation, schedule comparison study to evaluate the safety, pharmacokinetics, and viral kinetics of ABX464 in untreated patients with HIV infection in mauritius. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 10, 2015. NLM Identifier: NCT02452242. https://clinicaltrials.gov/ct2/show/NCT02452242. Accessed October 10, 2018.
- Steens J-M, Kuanchai S, Winai R, et al. Antiviral activity and safety of ABX464 in HIV-infected treatment-naïve patients. Poster presented at: International AIDS Conference; Durban, South Africa; July 18-22, 2016. Poster THPEB051. http://programme.aids2016.org/PAGMaterial/eposters/0_3181.pdf. Accessed October 10, 2018.
- Paredes R, Vandekerckhove L, Clotet B, et al. ABX464 decreases total HIV DNA in PBMCs when administered during 28 Days to HIV-infected virologically suppressed patients. Poster presented at: International AIDS Society (IAS) Conference on HIV Science; Paris, France; July 23-26, 2017. Poster TULBPEB22. http://programme.ias2017.org//PAGMaterial/eposters/5650.pdf. Accessed October 10, 2018.
- Abivax S.A. An open-label study of the safety, pharmacokinetics, and pharmacodynamics of ABX464 in HIV-1 seronegative and seropositive adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 7, 2016. NLM Identifier: NCT02990325. https://clinicaltrials.gov/ct2/show/NCT02990325. Accessed October 10, 2018.
- Vandekerckhove L, Paredes R, Clotet B, et al. ABX464 decreases total HIV DNA and integrated HIV DNA in PBMCs when administered during 28 days to HIV-infected virologically suppressed patients. http://www.natap.org/2017/EACS/EACS_35.htm. Accessed October 10, 2018.
Last Reviewed: October 10, 2018