Arno Therapeutics demonstrates AR-12 has potent antiviral activity against drug-resistant HIV strains

Results were presented today in a poster presentation during the 15th European AIDS Conference, which is hosted by the European AIDS Clinical Society (EACS) and being held October 21-24 in Barcelona, Spain.

Results of the in vitro studies demonstrated that AR-12 inhibits HIV-1, HIV-2 and six drug resistant HIV-1 strains with 50% inhibitory concentrations (IC50) in the range of 240-1016 nM (nanomolar) and moderate cytotoxicity (5532 nM). The IC50s were found in this study to be consistent with the IC50s observed against other viral pathogens including Influenza A, Chikungunya, Ebola, Lassa and others.

Previous studies have demonstrated AR-12 down regulates the host cell chaperone machinery, including GRP78, HSP70, HSP90 and HSP27. GRP78 is a critical chaperone protein, whose inhibition results in the up-regulation of PERK, inducing autophagy and facilitating the clearing of intracellular viruses and/or phagocytized unfolded proteins. Interfering with the host chaperone proteins in cells infected with viruses is thought to prevent the proper folding of viral proteins and efficient viral assembly.

These findings suggest that AR-12 inhibits HIV through a mechanism of action different from other inhibitors currently on the market, encompassing the major classes of HIV drugs currently available.

These preclinical investigations confirmed that host cell targeting by AR-12 may be an effective approach to inhibit the replication of HIV at low concentrations that can be achieved in the clinical setting with an oral tablet formulation.

Arno Therapeutics chief development officer Stefan Proniuk said: "These findings indicate that AR-12’s novel antiviral mechanism of action offers a new promising approach to potentially circumvent existing resistance mechanisms, enhance existing HIV treatments through combination therapies and to potentially address co-infections with other viral pathogens.

"The results demonstrated in these in vitro studies in HIV strains are consistent with the broad spectrum antiviral activity findings we have shown in other viruses, including Ebola, Nipah, Lassa, Marburg, Junin, Tacaribe, Yellow Fever, Hepatitis C, Epstein Barr, Venezuelan equine encephalitis, Chikungunya and Influenza (H1N1, H3N2), which collectively provide insight into the depth of AR-12’s anti-viral capabilities."

Arno Therapeutics Alexander Zukiwski said: "We are pleased with the findings from these in vitro studies which further support AR-12 as a potential versatile and effective antiviral compound. Based on these results, we plan to initiate a SAD/MAD study to assess the safety of single dose and multiple doses of a new optimized formulation of AR-12."

About AR-12

AR-12 is an orally-available small molecule. Data reported previously demonstrate that the AR-12 mechanism of action may include induction of host cell autophagy and inhibition of a number of protein chaperones. AR-12 has completed Phase 1 clinical trials in patients with cancer. AR-12 has been granted two orphan drug designations in Europe for the treatment of cryptococcosis and tularaemia.

In addition, Arno also has the rights to a broad portfolio of compounds in the "AR-12 series", which have been demonstrated to have a broad spectrum antimicrobial activity. In addition, the anti-viral activity of AR-12 and various analogues against Ebola and other pathogens of biodefense interest is being evaluated under a Cooperative Research and Development Agreement (CRADA) Material Transfer Agreement with the US Army Medical Research Institute of Infectious Diseases (USAMRIID).