EXPLORE OUR SCIENTIFIC CONTRIBUTIONS AT THE ACT MEETING

On Sunday, November 16, 2025, 12:00 – 12:55 PM, Room Grand Sonoran I, Dr. Norbert Makori, Vice President of Toxicology, and Dr. Francesca Barone, Site Director, will present on advances in nonhuman juvenile toxicology, along with innovative strategies to streamline access to appropriately aged juvenile models to support the challenging but vital development of therapies for rare diseases and genetic conditions.

This session is a commercially supported Exhibitor-Hosted Program. Although not an official part of the ACT Annual Meeting scientific program, its presentation is permitted by the College.

For over 30 years, Altasciences has taken a proactive, partner-driven approach to early drug development. By applying scientific insights at each development stage, we help sponsors make smarter, faster, and more informed decisions. 

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ABSTRACTS:

An estimated 20-25% of the population is affected by inflammatory skin diseases, such as atopic dermatitis (AD or eczema) and alopecia (“bald”) areata (“patch”) (AA), worldwide. Therapeutics/drugs are being developed to treat skin disorders, many falling into the class of Janus kinase (JAK) inhibitors with a short half-life, requiring frequent treatment. JAK1 is a protein involved in the JAK-STAT signaling pathway, which is important for controlling gene expression, cell growth, and immune responses; therefore, inhibiting/silencing JAK1 can subsequently reduce inflammation and immune overactivity and provide the potential for therapeutic treatment of inflammatory skin diseases. A silencing ribonucleic acid (siRNA) that specifically targets JAK1, ALD-102, allows for infrequent treatment due to the compound’s long-lasting properties. The goals of the studies were to demonstrate the toxicity/tolerability and feasibility/efficacy of ALD 102, currently being developed as a highly targeted, long-lasting, and efficacious treatment for inflammatory skin diseases via intradermal injection and/or transdermal delivery (in the presence of STAR Particles®). Göttingen Minipigs® were administered the pig surrogate compound, ALD-105, which was well tolerated at all dose levels and dose routes evaluated, with a striking retention in the skin and limited corresponding systemic exposure. Analysis of skin biopsies showed significant downregulation of target gene (JAK1) mRNA and/or the downstream signaling pathway in the skin out to at least 28 days following a single intradermal injection and/or trans epidermal application of ALD-105. ALD-102 is currently in Phase 1b/2a clinical trial being administered via intradermal injection to AA patients. 

This study aimed to verify the functionality of L21 telemetry implants in canines. These implants measure blood pressure (BP), electrocardiography (ECG), body temperature (BT), and left ventricular pressure (LVP). Changes in contractility were assessed following administration of Milrinone, Clonidine, and a Vehicle Control (VC) of deionized water. The in-life phase was 16 days, with dosing on days 1 (VC), 4 (Milrinone 0.05 mg/kg), 8 (Milrinone 0.25 mg/kg), 11 (Clonidine 0.015 mg/kg), and 15 (Clonidine 0.03 mg/kg). Data were continuously collected for at least 26 hours per dosing occasion using Ponemah acquisition software and analyzed using EMKA ecgAUTO. The parameters evaluated included heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), pulse pressure (PP), left ventricular end diastolic pressure (LVEDP), ±dP/dt, BT, PR-interval, RR-interval, QRS-duration, QT-interval, and corrected QT-interval (QTcH) 1. Three analyses were conducted: 1) change from baseline (BL); 2) change from VC; and 3) BL corrected VC-subtracted (delta-delta) values. Statistically significant (p< 0.05) decreases in SAP, MAP, PP, and HR were observed following 0.015 mg/kg and 0.03 mg/kg of Clonidine. Positive inotropic effects were observed, with significant (p< 0.05), dose-dependent increases in ±dP/dt, following Milrinone at 0.05 mg/kg and 0.25 mg/kg. Conversely, a reduction in contractile force was observed following Clonidine at 0.015 mg/kg and 0.03 mg/kg, with significant (p< 0.05), dose-dependent decreases in ±dP/dt. BP and HR changes were as expected based on the known mechanisms for each test article; thus, the functionality of L21 implants was verified in canines.

References

1. Holzgrefe H, Cavero I, Gleason CR, et al. (2007). Novel probabilistic method for precisely correcting the QT interval for heart rate in telemetered dogs and cynomolgus monkeys. J Pharmacol Toxicol Methods. 2007;55(2):159-175.

Antibody-drug conjugates (ADCs) are a novel class of precision cancer therapeutics, with 15 currently approved by the US FDA. Gastrointestinal (GI) adverse events (nausea, vomiting, diarrhea, colitis, and intestinal obstruction) have been reported with ADCs in clinical settings. Cynomolgus monkeys (CMs) are essential in nonclinical toxicity studies, particularly for evaluating ADCs. Baseline GI variability in different geographic origin CMs can potentially confound the interpretation of ADC-related GI findings, posing challenges to drug development. A review of FDA-approved ADCs was conducted, and 9 of 15 ADCs showed GI toxicities (mucosal irritation or inflammation, epithelial cell degeneration, diarrhea, or soft stool) in the clinic and CM models. Retrospective and comparative analysis of inherent background GI and clinical pathology data was performed in Cambodian, Vietnamese, and Mauritian CMs, including histopathologic lesion location/severity/distribution pattern, parasite burden, and fecal abnormalities. Historical control data (HCD) and reference intervals were generated from Altasciences' control database from 2020 to 2025 for 2-4-year-old CMs of 3-9 months duration using Certara’s SEND Explorer data analysis and visualization functions. Our data highlight distinct origin differences in the incidence and severity of background GI findings; Cambodian and Mauritian CMs showed similar and consistent frequency of baseline GI changes, while Vietnamese-origin monkeys had relatively lower incidence of background findings in the GI system and may offer a more predictable baseline for ADC safety studies. Identifying origin differences offers insights into optimizing model selection to improve data interpretation in pivotal ADC toxicity studies, enabling more accurate translational outcomes.

The use of miniature swine in safety assessment studies has grown in popularity over the past decade as the industry aims to minimize the use of canines and primates in support of the 3Rs initiatives.  While considerable data for several breeds of miniature swine is widely available to the research community, much of the data obtained from the Sinclair Nanopig® is proprietary to the organizations utilizing the model.  The Sinclair Nanopig® is comparable to the well-established breeds, such as Yucatan and Gottingen minipigs, in terms of physiology and metabolism, but is more similar in body weight to a beagle dog when maintained on a high-fiber, low-fat diet. This provides an advantage in using the Sinclair Nanopig® in that less test article is required for IND-enabling studies compared to the beagle dog or the Gottingen minipig.  The current study establishes reference data (body weight, hematology, serum chemistry, electrocardiography, ophthalmology, macroscopic tissue observations, and microscopic pathology) for the Sinclair Nanopig® at ages that correlate to the most common ages used in safety assessment studies. These data are critical for toxicologists and pharmacologists as a reference for normal variation among animal models used in nonclinical drug development.  This poster aims to expand upon the standard reference data for the Sinclair Nanopig® available to the entire research community.

The increased utilization of miniature swine models as an alternative to large animals in biomedical research has underscored their relevance in drug toxicity testing, necessitating assessment of immunomodulation. Assessment of the test article’s impact on immune cells via flow cytometry is important, and only limited data is available in Sinclair miniature swine. This study aims to develop and validate a method to assess immune cell populations using a flow cytometric assay and to increase swine whole blood stability for analysis.

Stabilized blood samples with 1:1 Streck Cell preservative to increase stability were processed by established protocols. Total, Helper, Cytotoxic, γδ T-cells, B, and NK-cells were evaluated using a BD Fortessa Flowcytometer and analyzed using FCS Express. Validation focused on sensitivity, inter-/intra-assay precision, and pre- and post-stain sample stability, reporting absolute counts via a dual-platform method and relative percentages of lymphocytes and/or total T cells.

Results demonstrate immunophenotyping of T, B, and NK cells as important baseline data in Sinclair miniature swine. In addition, results demonstrated that Streck cell preservative mixed with whole blood enhanced pre-stain stability to 71 hours at 4 °C. Intra-assay precision was validated across two runs (< 25%) and inter-assay precision by two analysts (< 20%), meeting acceptance criteria. Post-stain stability was validated for 24 hours for all cell populations passed.

This study provides a reliable immunophenotyping method for toxicological testing in Sinclair miniature swine models and validates the extended stability of samples. This ultimately facilitates batch processing of samples, optimizes resource utilization, and reduces costs for both GLP and non-GLP studies.

In the last few years, many gene therapy products have advanced in development from preclinical to clinical. Currently, gene therapy delivery in animals or humans falls into two main categories, including viral vectors (modified viruses carry the genetic material) and nonviral vectors (lipids, metal, or polymers). In-vivo gene therapy (GT) utilizing Adeno-Associated Virus (AAV) vectors or Lipid Nanoparticles (LNPs) present immunological challenges in the commonly used nonhuman primate (NHP) animal model, including activation of both the innate and adaptive immune systems. This presents a critical obstacle often necessitating premedication with immunomodulation or suppressive agents to mitigate adverse responses. A review of data from 30 preclinical studies in NHPs conducted in the last few years showed that ~50% utilized a pretreatment regimen prior to dosing with AAV/LNPs, sometimes in combination with other supportive medications. Another essential aspect of GT is to determine that the gene product will not be transmitted to the offspring of treated patients. Thus, new approaches have been developed to investigate the potential for germline integration, with the main objective being to prove a negative regarding DNA integration and a risk for germline modification. Preclinical studies investigating germline integration have been conducted on sexually mature NHPs. Genomic analysis was performed on semen collected at several time points during the study or in oocytes collected at termination. This presentation will discuss several case studies, including challenges and potential opportunities moving forward.

After a short discussion of why nonclinical studies are required and some basics of study design, study outlines with errors will be given to the tables for the participants to review, identify the errors, and develop clarifying questions they would need answered to develop a protocol.

Development of drugs for rare diseases and genetic conditions is challenging but crucial because of significant unmet medical needs. Preclinical testing currently requires animal models, including juveniles. This presentation will discuss advances in nonhuman juvenile toxicology and new approaches to increasing the ease of obtaining appropriately aged juveniles. 

This session is a commercially supported Exhibitor-Hosted Program. Although not an official part of the ACT Annual Meeting scientific program, its presentation is permitted by the College.