Toxicology a. The ingredients in the formulated product do not pose a significant risk to human or animal health.
i. No ingredient in the formulated product is a known or presumed carcinogen, mutagen, teratogen, endocrine disruptor, reproductive toxin, or neurotoxin, according to conclusions of any of the following leading regulatory bodies: United States Environmental Protection Agency (“EPA”), Canadian Pest Management Regulatory Agency (“PMRA”), Australian Pesticides and Veterinary Medicines Authority (“APVMA”); European Food Safety Authority (“EFSA”); European Chemicals Agency (“EChA”).
ii. No ingredient in the formulated product is included on Annex III of the Rotterdam Convention (PIC list) or listed in the Stockholm Convention.
b. The formulated product does not pose a significant acute toxicity/irritation hazard and has no novel acute toxicological effects.
i. Formulated product must be EPA category III or IV for acute oral, dermal and inhalation toxicity and eye/skin irritation (a maximum of ‘CAUTION’ signal word in the US). For countries outside the US, may not be classified in acute toxicity categories 1-4 for acute oral, dermal and inhalation toxicity under the Globally Harmonized System of Classification and Labeling of Chemicals (GHS) (i.e., must be GHS Categories 5, with maximum ‘WARNING’ signal word based on acute toxicity) and may not be not be classified as skin corrosive or eye/skin irritant.
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. 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. 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). PORTIONS OF THIS EXHIBIT HAVE BEEN REDACTED AND ARE SUBJECT TO A CONFIDENTIAL INFORMATION REQUEST FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION.
Toxicology. MIRV was evaluated for toxicity after a single IV injection in cross-reactive (monkey) and non- cross-reactive (mouse) species. Results of these studies supported the first-in-human (FIH) study exploring the safety and tolerability of MIRV when administered once every 3 weeks to patients with advanced solid tumors. Potential risks suggested by these studies as well as clinical experience with other maytansinoid ADCs include hematologic abnormalities, electrolyte alterations, injection site reactions, infusion reactions, immunogenicity, hepatic abnormalities, and peripheral neuropathy. Toxicology studies are further detailed in the Investigator Brochure.
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 [ ]. 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 anticipated to include [ ] of ...
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)
Toxicology. Toxicology testing is absent from our project plan. We had an Initial Targeted Engagement for Regulatory Advice on CBER products (INTERACT) meeting on May 15, 2020 with the FDA in which we discussed our overall development plan and our proposal to omit animal toxicity testing in light of the proven safety profile of MVA as a vaccine platform. Acknowledging the previous safety experience available for MVA-based vaccine platforms, the FDA concurred that no additional non-clinical and toxicology studies will be required, provided that the immune response to the ultimately chosen GeoVax vaccine construct is adequately assessed in appropriate animal models. As described below under Regulatory Path, our development program is geared toward Emergency Use Authorization (EUA) readiness. To generate the human safety and immunogenicity data required for an EUA, we will propose a Phase 1a/1b trial to FDA. The final design of the clinical trial will be determined in discussions with FDA, most importantly the Pre-IND meeting. Our draft design for this study, which can be completed in approximately four months (excluding follow-up phase), calls for a Phase 1a dose-ranging study in approximately 40 volunteers (three vaccine groups and one placebo group; 10 participants per group). Assuming that safety endpoints are met, we will choose a single dose from the dose-ranging study and test it in Phase 1b in approximately 150 volunteers (100 in vaccine group, 50 in placebo group). With this Phase 1a/1b trial, we expect to obtain adequate data to enable use of the vaccine under an EUA. In the Phase 1a/1b Clinical Trial, we will obtain safety and immunogenicity data in healthy normal volunteers. An abbreviated synopsis for this clinical trial is provided in the table below. Our trial is designed to provide initial data on safety, tolerability, and immunogenicity and to identify an optimal regimen in Phase 1a and then to obtain additional data in a larger, more diverse population in Phase 1b to enable use of our vaccine under an EUA. Group N Vaccine (target virus) Dose (TCID50) Regimen
Toxicology. In conjunction with FDA requirements, standard toxicology studies were performed with the aim of inducing and identifying drug-related toxicities. The clinically relevant toxicities observed in these studies were mechanistically based; that is, attributed to activation of the innate immune system via TLR8. The most frequent of these included transient constitutional symptoms consistent with the influenza-like response frequently seen with immunomodulatory agents. As noted in §2.3, these flu-like symptoms identified in preclinical toxicology studies have subsequently been observed in clinical trials of VTX-2337, and include pyrexia, chills, myalgia, and fatigue. As detailed in the VTX-2337 IB, organ-based toxicity was also observed in preclinical toxicology studies. Organ-based toxicities have not been observed in any clinical trial of VTX-2337 to date, and are not described herein.
