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Nonclinical toxicology studies that are required to support human clinical trials of new drug candidates are generally conducted in a rodent and a non-rodent species. These studies typically contain a vehicle control group and low, intermediate, and high dose test article groups. In addition, a dosing-free recovery phase is sometimes included to determine reversibility of potential toxicities observed during the dosing phase and may include additional animals in the vehicle control and one or more dose groups. Typically, reversibility is determined by comparing the test article–related changes in the dosing phase animals to concurrent recovery phase animals at the same dose level. Therefore, for interpretation of reversibility, it is not always essential to euthanize the recovery vehicle control animals. In the absence of recovery vehicle control tissues, the pathologist’s experience, historical control database, digital or glass slide repositories, or literature can be used to interpret the findings in the context of background pathology of the species/strain/age. Therefore, in most studies, the default approach could be not to euthanize recovery vehicle control animals. This article provides opinions on scenarios that may or may not necessitate euthanasia of recovery phase vehicle control animals in nonclinical toxicology studies involving dogs and nonhuman primates.

The ability to successfully develop a safe and effective vaccine for the prevention of HIV infection has proven challenging. Consequently, alternative approaches to HIV infection prevention have been pursued, and there have been a number of successes with differing levels of efficacy. At present, only two oral preexposure prophylaxis (PrEP) products are available, Truvada and Descovy. Descovy is a newer product not yet indicated in individuals at risk of HIV-1 infection from receptive vaginal sex, because it still needs to be evaluated in this population. A topical dapivirine vaginal ring is currently under regulatory review, and a long-acting (LA) injectable cabotegravir product shows strong promise. Although demonstrably effective, daily oral PrEP presents adherence challenges for many users, particularly adolescent girls and young women, key target populations. This limitation has triggered development efforts in LA HIV prevention options. This article reviews efforts supported by the Bill & Melinda Gates Foundation, as well as similar work by other groups, to identify and develop optimal LA HIV prevention products. Specifically, this article is a summary review of a meeting convened by the foundation in early 2020 that focused on the development of LA products designed for extended delivery of tenofovir alafenamide (TAF) for HIV prevention. The review broadly serves as technical guidance for preclinical development of LA HIV prevention products. The meeting examined the technical feasibility of multiple delivery technologies, in vivo pharmacokinetics, and safety of subcutaneous (SC) delivery of TAF in animal models. Ultimately, the foundation concluded that there are technologies available for long-term delivery of TAF. However, because of potentially limited efficacy and possible toxicity issues with SC delivery, the foundation will not continue investing in the development of LA, SC delivery of TAF products for HIV prevention.

Background Developmental and reproductive toxicity testing is not uniformly warranted for biopharmaceuticals that lack relevant targets in test species. However, RG7667, consisting of two monoclonal antibodies specific for human cytomegalovirus (hCMV), was intended for administration to pregnant women to prevent transmission of CMV to the developing fetus. Methods Considering the target indication, a Pilot Embryo Fetal Development/Toxicokinetic study was conducted to assess toxicokinetics in the dam and fetuses and general tolerability. Results RG7667 administered intravenously to presumed pregnant Sprague-Dawley rats was well tolerated with no clinical signs in any dam and comparable litter sizes and viability across groups. However, at cesarean section, hepatic necrosis and pancreatic edema were identified in two dams administered RG7667, with no clear dose relationship. Investigation of total protein, albumin, and transaminase activity in residual serum from TK samples demonstrated striking hypoproteinemia and elevated transaminases limited to these two dams. Overall, these pathology findings in dams were considered of uncertain relationship to RG7667; therefore, a subsequent Pivotal EFD study was conducted, which did not repeat the liver or pancreatic findings. Conclusions The results of the Pivotal study confirmed the lack of overt toxicity, teratogenicity, or effects on litter size and viability when human or humanized monoclonal antibodies that lack an endogenous target are administered IV to rats during pregnancy. With these additional data, we concluded that the unexpected pathology findings in the Pilot study were not specific to RG7667, but rather highlight some clinical pathology and macroscopic/microscopic findings that can occur during pregnancy in rats.

There has been an increased interest in and activity for the use of peptide therapeutics to treat a variety of human diseases. The number of peptide drugs entering clinical development and the market has increased significantly over the past decade despite inherent challenges of peptide therapeutic discovery, development, and patient-friendly delivery. Disparities in interpretation and application of existing regulatory guidances to innovative synthetic and conjugated peptide assets have resulted in challenges for both regulators and sponsors. The Symposium on Development and Regulatory Challenges for Peptide Therapeutics at the 40th Annual Meeting of the American College of Toxicology held in November of 2019 focused on the following specific topics: (1) peptide therapeutic progress and future directions, and approaches to discover, optimize, assess, and deliver combination peptide therapeutics for treatment of diseases; (2) toxicological considerations to advance peptide drug-device combination products for efficient development and optimal patient benefit and adherence; (3) industry and regulatory perspectives on the regulation of synthetic and conjugated peptide products, including exploration of regulatory classifications, interpretations, and application of the existing guidances International Council for Harmonisation (ICH) M3(R2) and ICH S6(R1) in determining nonclinical study recommendations; and (4) presentation of the 2016 Health and Environmental Sciences Institute’s Genetic Toxicology Technical Committee working group assessment of genotoxicity testing requirements. Perspectives were shared from industry and regulatory scientists working in the peptide therapeutics field followed by an open forum panel discussion to discuss questions drafted for the peptide therapeutics scientific community, which will be discussed in more detail.

ICA6150349, a 38-amino acid analog of glucagon, is peptidase resistant and highly selective for the glucagon receptor. ICA6150349 continuously infused SC at 50 mcg/kg/d (ED50) in DIO LE rats reduced weight (21%), fat mass (37%), and food intake (17%) and normalized triglycerides and cholesterol to lean control levels. ICA6150349 (50 mcg/kg/d) in combination with exenatide (10 mcg/kg/d) further reduced weight (38%), fat mass (70%), and food intake (52%) and also normalized glucose and lipids to lean control levels. ICA6150349 continuously infused at 50 mcg/kg/d in ZDF rats increased HbA1c (1.3%), reduced weight (29%), fat mass (42%), and food intake (13%) and normalized triglycerides (66%) and cholesterol (38%) to lean control levels. ICA6150349 (50 mcg/kg/d) in combination with exenatide (10 mcg/kg/d) decreased HbA1c (1.5%), off-setting the increase seen with ICA6150349 monotherapy. The ICA6150349 and exenatide combination reduced weight (19%), fat mass (25%), food intake (29%) cholesterol (27%) and triglycerides (41%). In rodent models of obesity/T2D, ICA6150349 in combination with exenatide can significantly reduce weight, fat mass, glucose and lipids, sometimes normalizing these parameters to lean control levels. Disclosure M. Paulik: Employee; Self; Intarcia Therapeutics, Inc.. T. Tlusty: None. M.K. Grizzle: None. M. Copeland: None. S. Weng: None. W.C. Blackwell: Employee; Self; Intarcia Therapeutics, Inc. V. Srivastava: Employee; Self; Intarcia Therapeutics, Inc. J. Way: Employee; Self; Intarcia Therapeutics, Inc. S. Roller: Employee; Self; Intarcia Therapeutics, Inc.. D. Zane: None. R. Hodge: Employee; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Intarcia Therapeutics, Inc. A.A. Young: Employee; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; GlaxoSmithKline plc. P.L. Feldman: Employee; Self; Intarcia Therapeutics, Inc..

ICA6150349, a 38-amino-acid peptide, is a glucagon analog that is highly selective for the human glucagon receptor. In a 14-day toxicity study, rats and cynomolgus monkeys received ICA6150349 at doses of 0, 0.875, 8.75, 87.5 mcg/day and 0, 17.92, 179.2, 3584 mcg/day, respectively. Animals were evaluated for reversibility of findings for an additional 14 days. The TK characteristics of ICA6150349 were also determined. In rats, there was a pharmacologically expected dose-dependent decrease in body weight (BW) gains and food consumption, which demonstrated a recovery trend. Clinical pathology and anatomic pathological changes, largely restricted to the exaggerated pharmacological effect of glucagon at high exposures, had mostly recovered during the dose-free period. ICA6150349 exposures (AUC0-24) increased dose-proportionally in male and female rats on D2. On D14, exposure was 40-60% lower than on D2 in the 0.875 and 8.75 mcg/day dose groups and similar to D2 in the 87.5 mcg/day dose group after adjustment for changes in BW. ADAs were observed in rats from all dose groups, but did not impact the TK of ICA6150349. In cynomolgus monkeys, the effects of ICA6150349 were limited to minimally decreased RBC mass (hemoglobin, red blood cell count, and hematocrit) at 3584 mcg/day with recovery. ICA6150349 exposure (AUC0-24) increased dose-proportionally on D2. On Day 14, exposures were 14-65% lower than on D2 in all groups except the 3584 mcg/day females. ADA were observed in 46.7% of treated monkeys; however, ADA status only affected TK at the 3584 mcg/day dose level. Overall, ICA6150349 was well tolerated. Nonclinical safety studies identified no adverse effects (based on the minimal magnitude of change, severity grading and reversibility) at any dose level tested with a NOAEL of 87.5 mcg/day in rats and 3584 mcg/day in monkeys. All observed effects have been non-adverse, reversible, and consistent with known actions of glucagon. Disclosure D. Zane: None. R. Singh: None. J. Shelton: None. S. Roller: Employee; Self; Intarcia Therapeutics, Inc. M. Paulik: Employee; Self; Intarcia Therapeutics, Inc. J. Way: Employee; Self; Intarcia Therapeutics, Inc. W.C. Blackwell: Employee; Self; Intarcia Therapeutics, Inc. V. Srivastava: Employee; Self; Intarcia Therapeutics, Inc. R. Hodge: Employee; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Intarcia Therapeutics, Inc. P.L. Feldman: Employee; Self; Intarcia Therapeutics, Inc. T.R. Alessi: Employee; Self; Intarcia Therapeutics, Inc..