Biopharmaceutical company Arno Therapeutics, Inc. has announced promising data demonstrating novel activity of AR-12 as a broad-spectrum, anti-microbial drug.
Results were presented over the weekend in a podium presentation and in posters at the Interscience Conference of Antimicrobial Agents and Chemotherapy / International Congress of Chemotherapy and Infection (ICAAC/ICC 2015).
“Prior AR-12 antiviral investigations demonstrate potent activity across a wide range of distinct pathogenic viruses such as Influenza A, Epstein Barr virus, and hemorrhagic fever viruses including Ebola, Marburg, Nipah, Lasa, Junin, and Yellow fever,” stated Stefan Proniuk, PhD, Chief Development Officer of Arno Therapeutics. “In the two studies we presented at ICAAC/ICC, we now show that AR-12 has a first-in-class, novel mechanism of action that enables its potential for broad-spectrum antimicrobial activity, providing additional rationale for the continued development of the compound against a number of infectious disease targets.”
Proniuk presented data on in vitro inhibition of chikungunya virus replication by AR-12 in a podium presentation on Saturday.
Results from a preclinical study assessing broad-spectrum antiviral activity of AR-12 demonstrate that the drug’s first-in-class, novel mechanism of action has the potential for a broad-spectrum antiviral activity including the Chikungunya virus and has the potential to be used in combination with existing antiviral agents which may reduce the emergence of treatment resistant viral pathogens.
Activity of AR-12 was evaluated against the wild-type and T-705 resistant chikungunya virus strains as a model. AR-12’s mechanism of action was shown to down-regulate a number of protein chaperones thus targeting the unfolded protein response. Results indicate that the combination of AR-12 with T-705 resulted in an additive antiviral effect against either the wild-type or T-705-resistant strain of chikungunya. In addition, IND-enabling toxicology studies demonstrated a remarkable preclinical safety profile and a Phase I clinical study (maximum of 33 week exposure) demonstrated that high blood levels can be achieved.
Results from a preclinical study were presented during a poster session, identifying AR-12 as the lead compound of a new class of antifungal agents with a novel mechanism of action.
In vitro cell culture studies were conducted against a broad range of fungi in mice in order to establish the antifungal spectrum of AR-12. The study established that AR-12 inhibited the growth of multiple fungal species at concentrations that have been in the previous phase 1 study.
AR-12 exhibited activity against several fungi: Paecilomyces variotii, Rhizopus oryzae, Fusarium oxysporum/solani, Scedosporium apiospermum, Lomentospora prolificans, Apophysomyces, Coccidioides immitis/posadasii, Blastomyces dermatitidis and Pneumocystis carinii/murina.
In addition, AR-12 combined with fluconazole was found to yield a fungicidal cocktail that has improved in-vivo activity against Cryptococcus neoformans compared to either agent alone. The broad spectrum in vitro activity was demonstrated against multiple fungi species tested at a concentration range previous found to be achievable.
Overall, the study demonstrated the novel antifungal in vitro mechanism of action of AR-12, broad antifungal in vitro activity as a single agent or in combination with fluconazole, and its established safety profile from a previous clinical study with up to 33 week dosing holds promise for a potential new agent to treat fungal infections.
In addition, two preclinical studies were also presented at ICAAC/ICC 2015 by investigators from the Ohio State University. The first poster (Poster F-760) demonstrated AR-12’s promise as a new antifungal agent for the treatment of mycoses caused by both opportunistic and primary fungal pathogens. The second poster (Poster B-083) showed an encapsulated form of AR-12, in combination with suboptimal gentamicin treatment, further enhanced survival of mice infected with the bacterium Francisella tularenesis, which is the causative agent of the life-threatening disease tularemia, a disease for which AR-12 was recently granted orphan designation in Europe.
AR-12 has been granted two orphan drug designations in Europe for the treatment of cryptococcosis and tularaemia. 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).
