Industry perspective on the nonclinical safety assessment of heterobifunctional degraders.

Targeted protein degraders (TPDs), which act through the ubiquitin proteasome system (UPS), are one of the newest small-molecule drug modalities. Since the initiation of the first clinical trial in 2019, investigating the use of ARV-110 in patients with cancer, the field has rapidly expanded. Recently, some theoretical absorption, distribution, metabolism, and excretion (ADME) and safety challenges have been posed for the modality.

Characterization and Potential Mitigation of Corneal Effects in Nonclinical Toxicology Studies in Animals Administered Depatuxizumab Mafodotin.

To characterize the ocular toxicity of an antibody-drug conjugate (ADC), depatuxizumab mafodotin (Depatux-m), in nonclinical species and to evaluate the effects of drug-antibody ratios (DARs), variations of the ADC construct, and potential methods for mitigation of the corneal toxicity. Depatux-m contains the potent cytotoxic agent monomethyl auristatin F as the ADC payload. Depatux-m was administered intravenously to cynomolgus monkeys at doses up to 30 mg/kg and to mice up to 100 mg/kg.

Off-target binding of an anti-amyloid beta monoclonal antibody to platelet factor 4 causes acute and chronic toxicity in cynomolgus monkeys.

ABT-736 is a humanized monoclonal antibody generated to target a specific conformation of the amyloid-beta (Aβ) protein oligomer. Development of ABT-736 for Alzheimer's disease was discontinued due to severe adverse effects (AEs) observed in cynomolgus monkey toxicity studies. The acute nature of AEs observed only at the highest doses suggested potential binding of ABT-736 to an abundant plasma protein.

Strategies and Recommendations for Using a Data-Driven and Risk-Based Approach in the Selection of First-in-Human Starting Dose: An International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Assessment.

Various approaches to first-in-human (FIH) starting dose selection for new molecular entities (NMEs) are designed to minimize risk to trial subjects. One approach uses the minimum anticipated biological effect level (MABEL), which is a conservative method intended to maximize subject safety and designed primarily for NMEs having high perceived safety risks. However, there is concern that the MABEL approach is being inappropriately used for lower risk molecules with negative impacts on drug development and time to patient access.