Toxicology a. The ingredients in the formulated product do not pose a significant risk to human or animal health.
Toxicology. 1. Collect required toxicological samples
Toxicology. An inventory of archived tissues and samples for each of the completed toxicology studies is included in the final study report for each study. Transfer of the storage of these samples to Bukwang needs to be discussed. • Additional samples located at Triangle include: • Thirty-two wet tissues to Trump’s fixative for electron microscopy from study TOX045 from Week 119 (one female sacrificed moribund) and from Week 148 (3 females and 4 males, control and high dose). There are 4 tissues from each animal - heart, kidney, liver, and skeletal muscle. • Photomicrographs of liver, heart, and skeletal muscle and negatives of same; lepon blocks; glass slides; and 44 vials of heart, muscle, kidney, and liver (in formalin) from the woodchuck study 98-11-A conducted by Cornell. The 44 vials contain huge chunks of issue that would not have fixed well and were removed from dead animals, and therefore may have been subject to significant autolysis. • Another set of positives (slides) and photographs taken during examination by light microscopy of skeletal muscle (myopathy) from selected monkeys from study TOX045.
Toxicology. The draft report for TOX142 “A Study of the Effects of Orally Administered TP-0239 on Pre- and Postnatal Development, Including Maternal Function, in the Rat” is due Sept. 23, 2003. The date for delivery of the final report is targeted for November 1, 2003.
Toxicology. Maximum tolerated, single IV dose escalation studies of ETX2514 performed in rats and dogs did not result in serious test article–related events. Exposure across the dose ranges evaluated were generally dose proportional, and there were no significant differences between males and females. • 7-day IV repeat-dose range-finding studies in rats and dogs at doses up to the limit dose of 2000 mg/kg/day did not identify serious test article–related findings. • In pivotal 14-day IV repeat-dose toxicity studies conducted in rats and dogs, ETX2514 administered up to the limit dose of 2000 mg/kg/day was not associated with mortality or significant changes in clinical signs, ophthalmology, urinalysis or hematology parameters, organ weight changes, or changes in gross pathology or histopathology, and there were no toxicologically significant changes in clinical chemistry parameters. Based on these findings, the no-observed-adverse-effect-level (NOAEL) was 2000 mg/kg/day in both species. The associated combined-sex mean steady state maximum plasma concentration (Cmax) and AUC from 0 to 24 hours postdose (AUC0-24) values on Day 14 in the most sensitive species, rat, at the NOAEL were 1340 µg/mL and 3140 µg⋅h/mL, respectively. The exposure margin based on AUC0-24 relative to human exposures was 6.3-fold. • In a 7-day IV repeat-dose study of ETX2514 in combination with sulbactam, minimal decreases in body weight gain were noted, and there were no adverse effects on clinical pathology parameters, organ weights, or macroscopic tissue findings. Based on the mild severity of the findings, the NOAEL was the highest combination dose tested, 400 mg/kg/day of each compound. • The toxicity of ETX2514 alone or in combination with sulbactam was evaluated in a pivotal (Good Laboratory Practice [GLP]) study in rats administered the treatments IV daily for 28 days. ETX2514 administered alone (600 mg/kg/day) was devoid of toxicity. Notable effects in rats treated with the combination of sulbactam/ETX2514 (300 or 600 mg/kg/day of each compound) were consistent with known, monitorable effects of sulbactam. Dose-related inflammatory changes noted microscopically at the infusion site and in liver and lung with both combination doses were considered adverse effects of treatment; however, inflammatory changes in liver and lung were not associated with necrosis and were not present at the end of the recovery period. Thus, while there was no NOAEL identified in the study due to inflammatory cha...
Toxicology. In preparation for the initial IND filing, Licensee will contract with qualified CRO(s) to perform oral rat and dog rising single dose + 7-day repeated-dose range-finding toxicity studies with toxicokinetics and oral rat and dog 28-day repeated-dose toxicity studies with toxicokinetics. Additionally, Licensee will contract out the performance of a standard battery of GLP genotoxicity studies, including in vitro bacterial reverse mutation test, in vitro mouse lymphoma thymidine kinase assay, and in vivo rat micronucleus test. Also, to support the single IV dose of MRI-1867 in the initial Phase I trial to determine absolute bioavailability, Licensee will contract out the performance of an in vitro hemolysis assay and an IV single species single dose local tolerance study. To support subsequent clinical trials and eventual marketing, Licensee will contract out the performance of oral rat 3-month and 6-month repeated-dose toxicity studies, oral dog 3-month and 9-month repeated-dose toxicity studies, carcinogenicity studies, and reproductive and developmental toxicity studies. Overall, the timeline and cost to complete the IND-enabling nonclinical studies is estimated at approximately[ ] and [ ]. Clinical Development Licensee will contract out clinical trial related tasks to qualified CRO(s). The initial trial (i.e., the protocol to be included in the original IND filing) is anticipated to be a Phase 1 safety, tolerability, and PK study in healthy volunteers. The study will include a single IV and oral dose to determine absolute bioavailability, followed by 28-days of oral dosing. During the latter part of the conduct of this trial, Licensee plans to contract out a Phase 1 clinical mass balance study (single oral dose of radiolabeled drug). This will allow for an early determination of relevant PK metabolites and parameters to follow in subsequent trials. Additionally, Licensee plans to collaborate with NIH to perform a Phase 1 study of MRI-1867 binding to CB1R in the brain (via positron emission tomography scanning). A-034-2016 NIH Patent License Agreement—Exclusive Following the completion of the Phase 1 safety, tolerability, and PK study in healthy volunteers, Licenseeplans to move to a Phase 1 safety, tolerance, PK, and PD study in patients with systemic sclerosis. This trial will include [ ] of oral dosing. Pending no safety concerns, Licensee plans to move to a Phase 2 safety, PK, and proof of concept trial in systemic sclerosis patients that is anticipat...
Toxicology. In preparation for the initial IND filing, Scopus Biopharma will contract with qualified CRO(s) to perform sc rat and dog rising single dose + 7-day repeated-dose range-finding toxicity studies with toxicokinetics and sc rat and dog 28-day repeated-dose toxicity studies with toxicokinetics. Scopus Biopharma will contract out the performance of an in vitro hemolysis assay and an IV two species, single dose local tolerance study. Clinical Development Scopus Biopharma will contract out clinical trial related tasks to qualified CRO(s). The initial trial (i.e., the protocol to be included in the original IND filing) is anticipated to be a Phase 1 open label dose escalation study of safety tolerance PK including bioavailability in healthy volunteers, (non-visceral injection SB-001FCDP vs comparator) to be followed by an IV version of the same study. Following the completion of two Phase 1 safety, tolerability, and PK studies in healthy volunteers, Scopus Biopharma plans to move to a Phase 2 randomized double-blind study of tolerance including dose response, safety and PK in patients (non-visceral injection SB-001FCDP vs comparator). Following the successful completion of the Phase 2 study, Scopus Biopharma intends to enter into two pivotal Phase 3 trials randomized double-blind study of efficacy, safety and population PK in patients (non-visceral injection SB-001FCDP vs comparator).
Toxicology. In preparation for the initial IND filing, Scopus Biopharma will contract with qualified CRO(s) to perform sc rat and dog rising single dose +7-day repeated-dose rangefinding toxicity studies with toxicokinetics and sc rat and dog 28-day repeated-dose toxicity studies with toxicokinetics. Scopus Biopharma will contract out the performance of an in vitro hemolysis assay and an IV two species single dose local tolerance study. Clinical Development Scopus Biopharma will contract out clinical trial related tasks to qualified CRO(s). The initial trial (i.e., the protocol to be included in the original IND filing) is anticipated to be a Phase 1 open label does escalation study of safety tolerance PK including bioavailability in healthy volunteers. Following the completion of two Phase 1 safety, tolerability, and PK study in healthy volunteers, Scopus Biopharma plans to move to a Phase 2 randomized double blind study of tolerance including dose response, safety and PK in patients. Following the successful completion of the preliminary Phase 2 study, Scopus Biopharma will enter into a Phase 2b dose response study. Following the successful completion of the Phase 2b study, 2 pivotal Phase 3 trials randomized double blind study of efficacy, safety and population PK in patients. tolerance including dose response, safety and PK in patients. Regulatory Submission At the appropriate time, Scopus Biopharma plans to file a pre-IND meeting request with FDA to confirm that the planned CMC and nonclinical tasks will support the initiation of the proposed Phase 1 clinical trial. In this way, course corrections in the development plan can be made early on, expediting development and avoiding waste of resources. Following the completion of the Phase 1 clinical studies Scopus Biopharma will for and end of phase 1 (EOP) meeting. At the completion of the Phase 2 study we will file for an EOP2 meeting. Following the completion of the Phase 3 pivotal trials a pre-NDA meeting will be requested and an NDA will be filed. Development Stage Anticipated Timeline Lead and indication selection In vivo efficacy and preliminary toxicity Complete IND enabling Pre-clinical studies Phase 1 clinical studies start Clinical studies may take between years depending on indication Phase 2 start Phase 3 start NDA NB: This development plan is subject to change based on circumstance and regulatory requirements. DEVELOPMENT PLAN (For Commercial Products) (Cannabinoid Synthetic Pathway) Following the filin...
Toxicology. 2207-006_2wk SC DRF in Monkey 2207-007_2wk SC DRF in Rat 2207-008_4wk SC repeated in NHP 2207-009_4wk SC repeated in Rat 2207-013_Validated GX-I7_ADA_ELISA_in NHP Serum 2207-014Validated GX-I7_ADA_ELISA_in Rat Serum
Toxicology. A.1 Validation chemistry pre-study stability and homogeneity of suspension. A.2 Analytical method development LC-MS/N4S (rat/dog/rabbit/human) (including validation) A.3 4 week preliminary toxicity rat A.4 26 week toxicity rat A.5 4 week preliminary toxicity dog (including supporting toxicokinetics) A.6 52 week toxicity dog (including supporting toxicokinetics) A.7 Formulation chemistry rabbit (repro) A.8 Pregnant preliminary rabbit A.9 Teratology rabbit (ICH 413) (including supporting toxicokinetics) A.10 Formulation chemistry rat (repro) A.11 Fertility rat (ICH 411) A.12 pre- and post natal rat (ICH 412) A.13 Teratology rat (ICH 413) (including supporting toxicokinetics) A.14 Acute studies in two rodent species (mouse, rat) B ADME (dog-rat)
