SM88, a combination therapy including tyrosine isomers, has demonstrated anti-cancer activity with low toxicity when administered together [J Clin Oncol 31, 2013 (suppl; abstr e22095)]. We now report preclinical toxicology data.
7 day escalating dose, 28 day repeat dose in rats/dogs using the tyrosine agent of SM88. Test and control/vehicle items were administered qd or 3x/wk over 4 wks at dose levels of 25, 75 and 150mg/kg. Study parameters compared pretreatment as well as day 29 (main and recovery animals) and day 55 (recovery animals). Blood was collected days 1 and 27 at 8 time points for toxicokinetics.
All animals demonstrated consistent organ and cell volume decrease and reduced concentration of zymogenous vacuoles in the pancreas. Changes were reversible upon discontinuation of the SM88 agent. There were no changes: in other organ weights, body weight, food consumption, ECGs, ocular findings, hematology, coagulation, clinical chemistry/urinalysis, and no macroscopic or microscopic findings that could be attributed to the tyrosine at up to 150 mg/kg. Consequently the No Observed Effect Level (NOEL) was determined to be 150 mg/kg. Day 27 plasma Cmax values at 150 mg/kg were 41.7 ug/ml and 41.36 ug/ml for males and females respectively. AUC0-Tlast values were 717.7 (males) and 724.8 (females) hr*ug/ml. The difference in combined tyrosine isomer concentrations in plasma between Day 1 and 27, show that the systemic exposures to tyrosine generally increased dose-dependently, and in a slightly less than dose-proportional manner. The maximum concentration levels (Cmax) were reached at 2-6.7 hours post-dosing. After Tmax, the plasma concentrations declined gradually at a mean estimated T1/2 value of 7.9-9.3 hrs on Day 1 and from 8.4 -9.6 hrs on Day 27. There were no sex-related differences with sex ratios between 0.3 and 1.8 for all measured parameters. Over the 4-week treatment period, AUC0-Tlast and AUCINF (Cmax) accumulation ratios (Day 27/Day 1) ranged from 0.6-1.8 (0.8 to 1.6) with 25, 75 and 150 mg/kg, suggesting no accumulation when administered three (3) times per week over a 27 day period.
Pancreas changes suggest possible mechanisms and therapeutic insights to explain SM88's clinical activity, supporting clincal trials.
Clinical trial identification
Legal entity responsible for the study
Steve Hoffman, CEO, Tyme Inc
G.H. Sokol: Board position at Tyme Inc. R. Dickey IV, G. Del Priore, D. Garzon, S. Hoffman: Stock ownership, membership on an advisory board or board of directors, corporate-sponsored research, or other substantive relationships.