ABIVAX, an emerging leader in developing and commercialising novel antiviral therapies for diseases like HIV/Aids and chronic Hepatitis B (CHB), has announced positive top-line efficacy and safety results from the company’s Phase IIa clinical study (ABX464-003) in patients with HIV infection.
“These exciting preliminary data reinforce our confidence in the potential of ABX464 to become a key component of a functional cure for HIV/Aids thanks to its unique and novel mechanism of action,” said Professor Hartmut Ehrlich, CEO of ABIVAX in a Medical News Today report.
ABX464 is a first-in-class orally available antiviral drug candidate for the treatment of patients with HIV infection, the report says. It blocks HIV replication through a unique mechanism of action that leads to the destruction of viral RNA. Previously reported pre-clinical data in humanised mice demonstrated that ABX464 monotherapy had an antiviral effect which was sustained for at least 6 weeks following treatment interruption.
The ABX464-003 clinical study was a randomised, double-blind, placebo-controlled Phase IIa monotherapy dose-ranging study in HIV infected patients who have not previously received antiviral drugs. Patient cohorts were administered ABX464 in increasing doses once daily for up to 3 weeks. Each dose cohort consisted of 6 patients treated with ABX464 and 2 patients receiving placebo.
A dose-dependent increase in the response rate to ABX464 monotherapy was observed in the study. The majority of patients who received the highest dose (150 mg) showed a viral load reduction of at least 0.5 log (greater than 68% reduction) during the treatment period. No such change was observed in any of the corresponding placebo patients.
The report says the safety data from this study indicate that ABX464 was well tolerated. There were no severe and/or serious adverse events that were ABX464-related. The observed adverse events (mainly headache, nausea and emesis) were predominantly mild and sometimes moderate in nature.
“Having been associated with the development of ABX464 from the beginning, I am pleased to see the preclinical efficacy profile of this novel drug candidate now translating into clinical data, with anti-viral responses observed at the higher doses in this early stage and relatively short monotherapy study,” said Professor Mark Wainberg, head of the McGill University AIDS Centre in Montreal, Canada and member of ABIVAX’s Scientific Advisory Board. “Patients globally are in critical need of new and innovative therapies for HIV disease, and ABX464 has the potential to fill an important treatment gap.”
ABIVAX will present more detailed results from this study at several scientific conferences in the coming months, the report says.
The primary goal of ABX464 clinical development is to optimise an ABX464-based treatment regimen that could result in a long-lasting functional cure upon treatment cessation in patients who respond to ABX464.
Professor Jacques Reynes, head of the infectious diseases department at Montpellier University Hospital and principal investigator of the next study with ABX464 commented: “The results of this first study in HIV-infected patients encourage us to start the next Phase IIa study in which different doses and combination with other HIV therapies will be explored. Research on biomarkers predicting ABX464 efficacy will be part of the next and forthcoming studies”.
Current therapies have succeeded in controlling AIDS pandemic. However, there is a continuing need for new drugs, in particular those acting through new and as yet unexplored mechanisms of action to achieve HIV infection cure. We took advantage of the unique feature of proviral genome to require both activation and inhibition of splicing of viral transcripts to develop molecules capable of achieving long lasting effect on viral replication in humanized mouse models through inhibition of Rev-mediated viral RNA biogenesis.
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. We demonstrate here that ABX464 compromises HIV replication of clinical isolates of different subtypes without selecting for drug resistance in PBMCs or macrophages. ABX464 alone, also efficiently compromised viral proliferation in two humanized mouse models infected with HIV that require a combination of 3TC, Raltegravir and Tenofovir (HAART) to achieve viral inhibition in current protocols. Crucially, while viral load increased dramatically just one week after stopping HAART treatment, only slight rebound was observed following treatment cessation with ABX464 and the magnitude of the rebound was maintained below to that of HAART for two months after stopping the treatment. 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). Deep sequencing of viral RNA from treated cells established that retained viral RNA is massively spliced but importantly, normal cellular splicing is unaffected by the drug. Consistently ABX464 is non-toxic in humans and therefore represents a promising complement to current HIV therapies.
ABX464 represents a novel class of anti-HIV molecules with unique properties. ABX464 has a long lasting effect in humanized mice and neutralizes the expression of HIV-1 proviral genome of infected immune cells including reservoirs and it is therefore a promising drug toward a functional cure of HIV.