Abstract
Writing and editing a book can be a mammoth undertaking. When a book is finally published and released, there is often information that is outdated. This is no fault of the authors or editors but an issue with the time involved in writing and working with the publisher to have the book finally published. Drs Cavagnaro and Cosenza have been working on this book for at least 1 year.
Despite the normal publication delay and any concerns for outdated information, there was a good discussion in the book about the COVID vaccine EUAs that were put into place in late 2020 and early 2021 with the subsequent approvals. The normal publication delay did not impact the value and information included in the chapter by Drs Novicki and Klas on translating nonclinical data to the clinic for vaccines. Overall, the data and information contained in this book, despite rapid advances and the normal publication delay, successfully conveys the important message of clinical translation.
The book is divided into 4 logical sections – Principles, Practices, Product Attributes and Practical Applications. Each chapter is rather short but concisely conveys key information and perspective for biotherapeutic development. The presentation of the information in most of the chapters assumes the reader has more than a basic understanding the drug development pathway for biotherapeutics as well as the potential toxicity associated with these modalities.
Principles
This section is composed 5 chapters and serves as the foundation of biotherapeutic development for the clinic. The initial chapter by Dr Cavagnaro stresses an important consideration that drug development for biotherapeutics is case-by-case leading toxicologists into scientific judgement for study design and interpretation rather than relying on a “cook-book” approach. These initial chapters lay out the field of biotherapeutic development by describing the selection of animal models, a critical consideration for these modalities that includes not only the typical models, eg, monkeys, but also describes the need to utilize diseased animal models for safety assessment. In this particular chapter, Dr Blanset and co-authors make the right point about demonstrating pharmacological relevance of the selected species, and that sequence homology alone may be insufficient for such demonstration. In subsequent chapters, Dr Sullivan discusses the fundamental purpose of this book, ie, translating the results from the work we do as toxicologists to the clinical evaluation of the drug. The drug development process is a logical flow of science but is always done in the context of a developmental strategy. Dr Williams’ chapter is uniquely titled but drives the point home of the need to strategically plan that process in a way that engages not only the nonclinical scientist but also the clinician, CMC subject matter expert(s) and the regulatory scientist. It is this latter point that serves as a basis for other chapters in the book, including the chapter by the co-editor, Dr Cosenza, that clearly outlines the regulatory expectations at all steps in the drug development process, as well as the expectations from regulatory authorities.
Practices
This section of the book is composed of 13 chapters and represents the core features of biotherapeutic development that often plague toxicologists engaged in this area, including immunogenicity, cytokine expression and off-target binding. The key considerations for CMC by Drs McKenzie and Branson describe the need for a toxicologist to understand to some degree the manufacturing process of the biotherapeutic to ensure safety evaluation for the clinic. This is an important consideration that is at times overlooked.
There are several chapters on the practical aspects (aka Practices!) of biotherapeutics including inhalation toxicology, DART, general toxicology and study designs. Much has already been written in the literature on these topics, but the editors have done a service to the toxicology community by pulling these diverse subjects into a single source and by authors well-recognized for their experience.
The chapters on comparability, biosimilars and combinations present a detailed discussion of these ever-changing topics. In particular the chapter on comparability by Drs Ellis and Hartsough describes the considerations for moving into biosimilars with issues of product quality and the need for nonclinical testing. These needs are further highlighted in the chapter of biosimilars by Dr Kimzey and co-authors, and then the process for evaluating the safety of combination products. This latter topic has come to the forefront of the toxicology community as sponsors look for means to extend patent life (exclusivity) as well as tackle diseases that have been difficult to treat. This chapter is written from the perspective of biotherapeutics but also has applicability for small molecules.
Other chapters in this section round out the practical aspects of biotherapeutic development including due diligence, early regulatory interactions and selecting and monitoring the CRO to examine these molecules. The chapter by Dr Lansita and co-authors was particularly noteworthy as the authors presented real-world case studies that provides a learning for managing nonclinical data in a regulatory context. FDA case studies are always useful in the field of drug development, whether biotherapeutics, peptides or small molecules.
The only criticism of this section of the book is the ordering of the chapters. From this reviewer’s perspective, the biological consequences of biotherapeutics, eg, immunogenicity, cytokine expression, should have been at the beginning of the section followed by topics of toxicological testing, combinations/biosimilars/comparability and then the other topics included in this section. However, there is no “right” or “wrong” way to present these topics, and the editors have accomplished the objective of presenting these topics in a reasonable chronology.
Product Attributes
This section of the book is particularly interesting….and useful. The authors of the 9 chapters cover topics that require certain toxicological experience to assist sponsors through the development process and highlight the need to consider the “case-by-case” approach for these therapeutics.
The complexity of these therapeutics can be noted as one reads through the chapters listed in the table of contents. Without minimizing the importance of any modality, this section begins with peptides by Dr Hartsough and subsequently ends with GCTs and genomic editing termed Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR). Whether intentional or not, the logic of presentation appears inescapable.
In the last number of years, there has been a large increase in the number of therapeutics targeting rare diseases, as described by Drs McKeever and MacLachlin, with a greater number of GCTs as described by Drs Feigal and Cosenza, and in a separate chapter by Dr Cavagnaro. The progress of gene editing is progressing at a rapid pace and is becoming recognized as the therapeutic area in the not-too-distant future. As shown by Dr Meyer-Tamaki, the listing of on-going clinical trials is extensive (Table 27-1). Although most clinical studies are in Phase 1 or 2, this listing highlights the progress in development of CAR-Ts, nucleases, etc. That CRISPR may play a prominent role into the future also is highlight by the author, and the recognition of the importance of this technology as shown by the 2020 Nobel Prize in chemistry given to Drs Emmanuelle Charpentier and Jennifer Doudna. 1
As it is applicable to this book, the authors of each chapter highlight the challenges and solutions for nonclinical safety testing and that at times, in vitro testing is the only recourse for those evaluations. This is a novel approach as the field of toxicology continues to face pressure to reduce animal usage.
Practical Applications
The last section of the book contains 4 chapters that specifically describes the nonclinical evaluation of biotherapeutics for oncology, immune-mediated diseases, neurodegenerative diseases and infectious diseases. Readers of this section, after walking through the other portions of the book, would immediately recognize how this is organized to provide an outcome of the learnings from the first 3 sections. Essentially, the last 4 chapters tie everything together from the sections that preceded those chapters.
The rapid advances in immune therapies for oncology is highlighted well in the chapter by Dr Todd and co-authors. Similarly, the chapters on immune therapies and biotherapeutics for infectious diseases highlight the importance of these modalities, and the authors of these chapter clearly outline the nonclinical testing strategies and issues that arise with these molecules. Importantly, the authors not only discuss the challenges of testing but provide a roadmap for overcoming those challenges. The chapter on the development of biotherapeutics for neurodegenerative diseases is particularly noteworthy since treatment generally requires penetration through the blood-brain barrier, a significant challenge for large molecules. Dr Hovland and co-authors acknowledge this challenge and describe how these have been overcome in nonclinical testing. In all, this section does describe “best practices” for nonclinical testing as noted by the editors in the Preface.
Summary
This reviewer knows that the editors have been working on this book for some time, and the effort by the editors and all authors has paid dividends to the toxicology community. This book has compiled a large body of data and information into an easy to read and generally concise description of the nonclinical development of biotherapeutics and application of those data to initiate or progress clinical trials. Hence, the title of the book is most appropriate. In many of the chapters, the authors provide a listing of on-going clinical trials for selected therapeutics. These listings are particularly useful not only as a guide to examine progress of clinical trials, but also to provide data that can be mined by toxicologists and others to examine the pitfalls and, importantly, possible solutions of drug development for these complex drugs. There is quite a bit to be learned from this book that cannot be completely described in this review. Therefore, toxicologists that practice in pharmaceutical drug development would benefit from reading through this book and having it on the shelf for ease of reference.