Ryan Bennett (OyaGen, Inc)| Susan Schader (Southern Research Institute)| Roger Ptak (Southern Research Institute)| Harold Smith (OyaGen, Inc)
OyaGen, Inc is an upstate NY biotech company that has developed Irino-L, a highly potent antiviral therapeutic for a novel HIV target with intended use in treatment for patients with an HIV infection as part of a therapeutic and/or cure strategy and for pre-exposure prophylaxis (PrEP). Irino-L is a prodrug whose active metabolite SN38-L blocks Vif mediated destruction of APOBEC3 (A3) proteins that otherwise would serve in innate immunity against HIV. A3 proteins prevent the spread of HIV infection by inducing catastrophic mutations in the viral genetic code. In the absence of SN38-L, Vif binds to A3 proteins and induces their destruction. SN38-L has a low nanomolar efficacy and an average EC50 of 17.6 nM that is well separated from cellular effects with an average selectivity index of 95 when tested in PBMCs against 21 isolates from all known viral subtypes. The prodrug strategy enables antiviral levels of SN38-L to be maintained for 24 hours with twice daily dosing. In vitro ADMET and PK analyses for Irino-L, SN38-L and an analog with similar activity, O5-SN, have been completed and show a clear path for formulation of the drug for human clinical trials. Irino-L is the lactam analog of Irinotecan derived from camptothecin. Irinotecan is a chemotherapy that is safely being used in humans as a standard of care for multiple cancer types and has been shown to be safe across a range of doses and dose intervals. Studies conducted by OyaGen and in the literature show that lactam analogs of camptothecin such as Irino-L no longer inhibit the cancer target for Irinotecan, Topoisomerase I, and therefore have less cytotoxicity by comparison. Viral resistance studies showed that HIV did not develop resistance to SN38-L in human white blood cells following 7 passages. The challenge to developing resistance to SN38-L presumably is related to Vif function in A3 degradation requiring several interactions with A3 and other host cellular proteins. Combined treatments of Irino-L and antiretroviral (ARV) drugs are anticipated to markedly enhance therapeutic efficacy, reduce the total amount of ARV required to suppress viremia and will help to mitigate the emergence of drug resistant HIV.