Juvenile Bone Toxicity: Study Considerations, Regulations, and Techniques for Assessment.

Recommendations on study designs that adequately evaluate the in-life effects leading to juvenile bone toxicity, the various imaging modalities that can aid interpretation of the bone effects, biomarkers that may be useful, and regulatory issues were presented in this 2020 ACT symposium. The pathologies encountered in past studies were briefly mentioned. The first speaker covered study design and the numbers of juveniles that may be necessary to power the evaluation. Changes in the International Council for Harmonisation (IHC) guidelines were reviewed. The second speaker launched the rest of the symposium by describing the tools that may help assess juvenile bone toxicity, specifically those used to monitor bone toxicity, healing, and remodeling as they relate or drive the study design including model, species selection, and age. The third speaker addressed in more depth the micro-Computed Tomography (CT) applications in juvenile toxicology for evaluation of skeletal elements and bone growth in both embryo-fetal development (EFD) and pre and postnatal development (PPND) studies. Lastly, a regulatory perspective on strategies to assess juvenile bone toxicity and the concerns of the regulatory agency with respect to these potential changes in the juvenile population was addressed.

PDGFRα monoclonal antibody: Assessment of toxicity in juvenile mice administered a murine surrogate antibody of olaratumab.

BACKGROUND: Olaratumab (Lartruvo™) is a recombinant human IgG1 monoclonal antibody that specifically binds PDGFRα. In order to support use of Lartruvo in pediatric patients, a definitive juvenile animal study in neonatal mice was conducted with a human anti-mouse PDGFRα antibody analog of olaratumab (LSN3338786). METHODS: A pilot study was used to set doses for the definitive juvenile mouse study. In the definitive study, juvenile mice were administered vehicle, 50, 100, or 150 mg/kg LSN3338786 by subcutaneous (SC) injection every 3 days between postnatal days (PND) 1 and 49, for a total of 17 doses. Blood samples were collected on PND 49 for antibody analysis and toxicokinetic evaluation. Tissues were collected on PND 52 for histopathologic examination. RESULTS: Results of the pilot study indicated that dosing neonatal mice starting on PND 1 via SC administration every 3 days was logistically feasible, produced exposures consistent with prior animal studies, and the selected dose levels were well tolerated by juvenile mice. In the definitive juvenile study, there were no LSN3338786-related deaths, clinical findings, and no effects on mean body weights, body weight gains, or food consumption. Additionally, there were no adverse LSN3338786-related hematology findings, and no macroscopic, organ weight, or microscopic findings of note. The highest dose evaluated, 150 mg/kg, was considered the NOAEL for juvenile toxicity. CONCLUSIONS: In conclusion, the juvenile animal studies did not identify any new toxicities or increased sensitivities for the intended pediatric patient population. The use of the surrogate antibody approach in a standard rodent model enabled the de-risking of theoretical concerns for toxicity in pediatric patients due to disruption of the PDGFRα pathway during early human development, such as pulmonary development.