Interthyr Corporation (IC) is requesting an Advanced Technology Phase II STTR award to develop a novel agent with a new therapeutic paradigm: Inhibition of Toll-like receptor (TLR) expression and signaling in non-immune cells. In pursuing studies based on its Phase I award, IC has shown that a lead compound from a family of tautomeric cyclic thiones (TCTs), phenylmethimazole (C10), is effective in multiple in vitro and/or in vivo models of autoimmune-inflammatory disease, as well as, somewhat surprisingly, cancer, e.g. pancreatic cancer. In all cases, the C10 effect appears to be due to inhibition of pathological TLR expression/signaling in non-immune human cells. IC also demonstrated that it is feasible to formulate C10 in Captisol for oral delivery, that the formulation markedly improved stability, and that the formulation was active in vivo. Having successfully completed both Aims of the Phase I STTR Award and based on the novel results, IC is applying for the Advanced Technology Phase II STTR to complete the following aims:
Aim 1 : Determine the active form of C10 in vitro and in vivo, a method for its assay, the best dosing regimen based on PKA, and metabolites that might exist, as well as evaluate cytochrome induction and inhibition. These studies will complete bioanalytic, pharmokinetic, and basic toxicity studies necessary to institute preclinical toxicity testing for an IND.
Aim 2 : Characterize the detailed mechanism of action by which C10 inhibits TLR signaling. These studies will identify the exact step(s) in the TLR signaling pathway where C10 exerts its inhibitory effect.
Aim 3 : Demonstrate that C10 inhibits TLR signaling in pancreatic cancer, that C10's mechanism of action is distinct from gemcitabine, and that its inhibitory action is the same or different from type 1 diabetes related insulitis. These studies will reveal whether the mechanism of action of C10 in pancreatic cancer is via inhibition of TLR signaling and is distinct from the mechanism of action of the drug of choice for pancreatic cancer, gemcitabine. Importantly, theses studies will also determine the feasibility of IC's current commercialization plan to gain approval for use in pancreatic cancer, a disease with the lowest barrier to approval / market entry, as a means to facilitate its approval for other diseases.
Aim 4 : Identify members of the TCT family of compounds that exhibit greater, compared to our lead compound C10, ability to inhibit TLR signaling and cancer cell growth. These studies will identify compounds that could serve as a back-up to C10 or as starting points for a second generation of therapeutics that affect the TLR pathway. At the end of this award, IC will be in a position to complete an IND and Phase I/II human trial and/or license the technology to large Pharma, having attenuated the risk of future clinical development.
In its STTR Phase I Award, Interthyr Corporation (IC) demonstrated that a novel agent with a new therapeutic paradigm, inhibition of Toll-like receptor (TLR) expression and signaling in non-immune cells, was efficacious in a variety of models of human disease. The results support the widespread applicability of such an agent as a safe, non-toxic therapeutic for multiple autoimmune-inflammatory diseases as well as cancer. The Advanced Technology STTR Phase 2 award that is requested has 4 aims: Determine (i) final oral dosing, (ii) mechanism of TLR signaling inhibition in vitro, (iii) mechanism of action in pancreatic cancer in vivo, and identify (iv) additional compounds for future development that affect the TLR pathway and exhibit an inhibitory effect on human disease. The STTR Phase II work will position IC to complete studies required for an IND and Phase I/II human trials and/or to license the technology to large Pharma, having attenuated the risk of future clinical development.
| Alapati, Anuja; Deosarkar, Sudhir P; Lanier, Olivia L et al. (2015) Simple modifications to methimazole that enhance its inhibitory effect on tumor necrosis factor-?-induced vascular cell adhesion molecule-1 expression by human endothelial cells. Eur J Pharmacol 751:59-66 |
