This supplemental funding application proposes to address unforeseen, yet solvable issues which arose in the development of SBS-1000 which is being funded by the parent grant DA048379-01 entitled ?Arylepoxamides: A new class of potent, safer analgesics.? The parent UG3 grant provides funding for CMC development and IND-enabling toxicology studies for SBS-1000 and the UH3 funds phase 1 clinical trials. SBS-1000 is a novel analgesic acting through a newly discovered target ? the AEAr. In preclinical studies, SBS-1000 has demonstrated potent analgesia across nociceptive, neuropathic, and inflammatory pain models and has not demonstrated respiratory depression, abuse liability, or physical dependence. The initial scale up API synthesis, purification and formulation development proved challenging for Patheon/Thermo Fisher and resulted in unrecognized process impurities and a formulation that required a strong buffer and low pH. The combination of the impurities, acidic formulation, and an aggressive dosing paradigm at Charles River Labs lead to spurious results in the 7-day non-GLP rat toxicology study. These results were inconsistent with the MTD rat and dog studies, the 7-day non- GLP dog study, and 8 years of prior data accumulated from academic and industry sponsored research. Re-examination of the API and formulation indicate that the toxicity was a result of the vehicle and experimental design rather than the drug itself. This application proposes to specifically address these unforeseen events and develop a new purification method, optimize the formulation, and repeat the 7- day non-GLP rat toxicology study. We are confident that these aims are achievable given that we have already made progress in a purification method, have generated preliminary data on a new formulation, and have decided on a different dosing paradigm for the rat tox study. The supplemental funding we are requesting is critical to complete this work and address the unforeseen CMC and tox issues. The remaining funding in the parent grant is all allocated for the GMP manufacturing and GLP studies which will be required to meet the UG3 milestone and for IND submission. Beyond the complications outlined in this application there have been no drug-related issues to preclude the successful development of SBS-1000 from either the exploratory tox work, MTD studies, the 7-day non- GLP dog study, or any of the in vitro assays. NOTE: MP1000 = SBS-1000 - MP1000 was laboratory name used in original grant application. SBS-1000 the new name from Sparian Biosciences
SBS-1000 is being developed as a novel, safe analgesic and has funding through a parent UG3 award for CMC development and IND-enabling toxicology studies. Due to unrecognized process impurities, an intolerable formulation, and an aggressive dosing paradigm, there were spurious results in the 7 day non-GLP rat toxicology study. The supplemental funding application proposes to specifically address these issues by developing a new API purification method, optimizing the formulation, and repeating the 7-day non-GLP rat toxicology study.