Thought leaders in the world of biotherapeutics development converged on Carlsbad, California this September for the 25th Annual Charles River Biotech Symposium. Aptly titled, “Biotechnology-Derived Therapeutics Perspectives on Nonclinical Development,” this forum gave Sponsors developing novel biologic-based therapies (e.g. therapeutic vaccines, mAbs, Bs/TsAbs, oligos, peptides, RNAs, CGTs, etc) an opportunity to present perspectives and share challenges as their products and technologies navigate IND-enabling studies on their way to the clinic. Participants from small biotech to large pharma brought diverse perspectives and insights. Here are three key takeaways from the meeting:

1. While Agency guidance is key to establish a basic framework, nonclinical development for biotherapeutics requires a customized approach

The symposium kicked off strong Sunday with a workshop dedicated to late stage development and the nuances associated as they prism through the biotherapeutics lens. Perspectives from large pharma and CROs on the bench and consultants in the field provided insights on the key challenges encountered and practical strategies to address these challenges.

Exemplary discussions including “DART Strategies for Biotherapeutics” and “Carcinogenicity Assessments” explored the key elements of species employment for reliable and credible data as programs move from nonclinical models (in vitro, ex vivo and in vivo) to the clinic. All speakers made direct reference to Agency guidance, with emphasis on the ICH S6(R1); most recently updated and revised in 2011. This guidance is intended specifically for biotechnology-derived therapeutics and focuses on a number of key development parameters including safety evaluation for species selection, target identification, specificity, pharmacologic activity, MOA, immunogenicity, PK/PD, developmental toxicity, and carcinogenicity.

The second half of the day highlighted the criticality of interplay between scientific and regulatory components for a successful Biologics License Application (BLA) program. Presentations including “Roundabouts, Forks, and Roads Less Traveled: How to Navigate the BLA” and “Mind the Gap! How to Identify and Rectify Program Gaps Before Registration,” made it quite apparent that although guidelines can be utilized as a barometer for BLA program milestones, each program presents unique challenges which require diverse skillsets to overcome.

2. Clinical translation of safety and efficacy is often elusive, yet the right nonclinical models can minimize risk as you approach the clinic

A series of case studies sparked open dialogue between speakers and attendees. Fellow therapeutic vaccine and bispecific antibody developers had the opportunity to learn much about nonclinical safety and strategy for these novel modalities. From evaluating the differential immune response in non-human primate models (NHPs) after administration of novel antigen expressing adenovirus’ contrasted, to traditional check point inhibitors, to the impact of high molecular weight species in formulations for bispecifics, conversations centered around applicable and translatable nonclinical models and markers of safety and efficacy.

3. Nonclinical species selection is critical and there are tradeoffs between rodent and NHP models

As one attendee observed, “species selection during the nonclinical development of biotherapeutics is a serious matter that can have dramatic clinical implications.”

With a wide variety of models available, how do you choose which is right for your program? Pharmacology? Pharmacokinetics? Speakers on days three and four drove home the impact nonclinical species selection has on clinical translatability and patient safety, including:

• understanding the various biological interactions of multicomponent therapeutics like antibody-drug conjugates (ADCs) and probody-drug conjugates (PDCs),
• determining applicable models for therapeutic vaccine development and novel gene therapies, and
• overcoming immunogenicity, like anti-drug antibodies (ADAs), which can alter key drug efficacy and pharmacokinetics.

Rodent models have had significant scientific impact on understanding immune response, largely due to ease of genetic manipulation. However, they come with important caveats, most notably, the disconnect in translatability to human disease and lack of human homology. With rodents deficient in these critical attributes, NHPs have almost exclusively been utilized for biotherapeutics development post rodent proof of concept. Although NHPs have a high degree of genetic homology, are susceptible to human pathogens, and have been tremendously successful in understanding mechanisms of immune response, they are far from perfect representations of human biology. Thus, NHPs should be vigorously understood in context to the specific therapy before deployment in humans.

Contact Premier Consulting to learn how we can support your nonclinical program.