Amgen Research (Munich) GmbH

Pharmaceutical companies, which are IQ DruSafe/3R-TPS members, explored novel ways to reduce reliance on non-human primate (NHP) use in nonclinical drug development. These companies conducted a survey on NHP use in toxicology studies during discovery and development of CD3-bispecific antibodies (BsAbs) for the treatment of cancer. The objectives of the survey were to collect data on and case study examples of both first-in-human (FIH)-enabling (≤1-month) and Phase II/III-enabling (3-month) NHP studies conducted with CD3-BsAbs. The survey addressed study design elements, e.g. number of dose groups, number of animals/dose group, recovery arms, etc. when a study is deemed warranted. Survey questions also focused on whether data from Phase II/III-enabling studies addressed patient risk that was not identified in FIH-enabling studies, and whether Phase II/III-enabling studies impacted regulatory decisions pertaining to clinical development. The survey findings enabled the development of a Weight of Evidence (WoE) approach to assess the utility of Phase II/III-enabling toxicity studies in understanding potential safety risks with CD3-BsAbs and informing later-stage molecule development. Both study design optimization and WoE approaches offer a path for reduced NHP use without compromising nonclinical safety assessment of CD3-BsAbs for oncology indications, as illustrated by several case examples.

Development of monoclonal antibodies (mAbs) for oncology is increasing. An IQ DruSafe Working Group conducted an industry survey to evaluate non-human primate (NHP) use in nonclinical toxicity testing of oncology mAbs for well-characterized targets (WchT) with the aim to identify opportunities to reduce NHP use. The survey addressed sources of information used to justify WchT, weight of evidence (WoE) approaches to reduce NHP use, and design of nonclinical toxicology programs. All respondents used literature to define WchT. WoE approaches helped reduce the number and size of general toxicology studies. Most companies conducted non-Good Laboratory Practice (non-GLP) dose-range finding studies prior to GLP toxicology studies, often non-terminally, allowing for potential reuse of NHPs. For GLP studies, most companies maintained a standard design for 1-month studies (when conducted) but were more flexible with 3-month studies, often excluding recovery groups. Case studies illustrate successful regulatory acceptance of streamlined nonclinical safety packages. Engaging drug regulatory authorities (DRA) to discuss the need for additional and/or specialized studies would be beneficial to reduce NHP use. In conclusion, NHP use can be reduced in developing oncology therapeutics against WchT by optimizing nonclinical toxicology approaches with appropriate strategic planning, fit-for-purpose toxicology study designs, and discussion with DRA.

Development of T cell engagers (TCEs) for oncology indications is regulated mainly by ICH S6 and S9. Investigational new drug applications are usually supported by a 1-month toxicology study in a relevant animal species. Before the start of registrational clinical trials, a longer-duration toxicology study, typically 3 months, is performed in the same species to support marketing. As longer-term studies with human-specific biologics in animal species can be hampered by development of anti-drug antibodies and TCEs are quick-acting molecules, we analyzed the value of 3-month toxicology studies for some of our TCEs. We present data from 1- and, where applicable, 3-month toxicology studies for 4 TCE programs and describe our interactions with regulatory agencies. In none of the cases did the 3-month studies reveal new information to influence further the respective clinical development plans. Considering 3Rs (Replacement, Reduction and Refinement) in pharmaceutical development, we highlight that 3-month studies with TCEs don't always offer additional safety insights. Therefore, alternative strategies should be evaluated and conduct of 3-month studies carefully considered in the light of 3Rs and discussed case-by-case with health authorities.