Promising data recently released on the AR-12 antimicrobial drug from Arno Therapeutics demonstrates that the drug has substantial potential as a new and novel therapeutic agent against infectious diseases.
“The results from the earlier and ongoing investigations of AR-12 in the antimicrobial (infectious disease) area have demonstrated a very broad scope of activity against a number of pathogens,” Dr. Alexander Zukiwski, CEO of Arno Therapeutics, told BioPrepWatch.
Specifically, these pathogens include a wide range of viruses, such as Ebola, rabies, Yellow fever, specific types of encephalitis, Influenza A, Epstein Barr and the human immunodeficiency virus (HIV), Zukiwski said.
Zukiwski said AR-12 has the potential to be extremely versatile and that the drug “has a very novel mechanism of action.”
For instance, rather than targeting a specific enzyme, such as RNA polymerase or reverse transcriptase, AR-12 targets the host cell, Zukiwski said.
“When viruses invade normal cells, in order to replicate, the virus must take control of certain normal host-cell functions to produce large amounts of different viral proteins -- viral ‘RNA or DNA’ -- and assemble these components into complete and potentially infectious viruses,” Zukiwski said.
Essentially, viruses hijack the host cells machinery to make, appropriately fold and assemble the virus proteins, Zukiwski said. During a viral infection, the host protein chaperones are used to fold the viral proteins into their active three-dimensional structure and assemble these proteins into intact viruses.
“It is important to note that if the host-cell protein-folding machinery is not controlled, the large amount of viral proteins which are produced would trigger the unfolded protein response, sending the host cell into apoptosis (programmed cell death),” Zukiwski said.
AR-12 inhibits a number of these host-cell protein chaperones and has a secondary effect of inducing autophagy in host cells, which Zukiwski said is the natural, destructive mechanism that disassembles unnecessary or dysfunctional cellular components, including viruses and intracellular bacteria.
“Thus, by acting through the described host-cell mechanisms, AR-12 has demonstrated broad and effective preclinical activity against a number of microbial pathogens, including a wide range of viruses,” Zukiwski said.
Moving forward, a single ascending dose (SAD) and multiple ascending dose (MAD) study is planned with a patented second-generation oral formulation that should decrease the tablet burden and provide for a potential single daily dose schedule, Zukiwski said.
“The development of an intravenous formulation is also planned for potential utilization in those acute/critical indications where intravenous dosing would be required,” Zukiwski said.
There are also a number of additional in vitro studies being carried out or planned, including one against additional viral species to determine the potential utility and clinical-development path for the drug, additional preclinical activities to support the overall development program and a future exploratory proof-of-concept study to test the antiviral activity of AR-12 as a single agent, Zukiwski said.
Additionally, AR-12 also has been the subject of regulatory consultations with the FDA’s Division of Anti-Infective Drug Products, the FDA’s Division of Antiviral Drug Products, and the UK Medicines and Healthcare products Regulatory Agency
While the feedback received is subject to a final review of the submitted package, it so far “indicates that the preclinical and CMC ‘package’ is adequate to proceed with AR-12 development in the infectious-disease therapeutic area,” Zukiwski said.
Later this month, Zukiwski said a poster -- titled “AR-12, a Novel First in Class Host Cell Targeting Therapeutic Candidate with Potent Activity Against HIV Multidrug Resistant Strains in Vitro” -- will be presented at the 15th European AIDS Conference, hosted by the European AIDS Clinical Society. The conference will be held Oct. 21-24 in Barcelona, Spain.