Preface

Fibrosis is a disease that culminates from aberrant tissue remodeling processes in a variety of organs. Fibrosis itself is not a discrete pathological node for intervention. Instead, it is the downstream outcome of earlier detrimental stress, damage repair or inflammatory states. Thus, targeting fibrotic disease has historically been a reactive, rather than proactive process. Fibrotic disease remains an area of high unmet medical need. In reality, it will only become more of a challenge for doctors, clinicians and health care systems as more of the world adopts lifestyles that promote fibrotic disease progression. Notably, despite the immense body of research focused on developing viable anti-fibrotic therapies, to date, there have been very few examples of success clinically. The vast majority of therapies targeting the fibrotic disease axes, have met with failure, often during late-phase clinical evaluation. This may be, in part, due to the complexity of fibrotic disease progression biology, limitations with the current translation capacity of in vitro and in vivo disease models, or a lack of robust disease-relevant biomarkers. In reality, it is likely to be due to a combination of all these factors and more. Recent progress in understanding the complex interplay of disease and tissue remodeling pathways via systems biology, as well as the implementation of more physiologically relevant tissue culture and 3-D printed organ models, may help bridge the gap in translating pre-clinical efficacy to clinical application.

This book was conceived as a means of highlighting some of the new therapeutic modalities that are emerging for fibrotic disease treatment. By no means exhaustive, we have chosen to focus on several key targets and pathways that are currently relevant. As a disclaimer, we have purposefully excluded the vast body of work relating to cystic fibrosis (CF) research. The decision to do so was in part due to the large body of work in this field, and the currently well represented clinical landscape in CF research. Additionally, in CF, tissue remodeling and fibrosis is largely due to inflammatory damage resulting from repeated bacterial infections that are not cleared due to misfolded or ineffective cystic fibrosis transmembrane region (CFTR) proteins. Thus, the majority of current therapies target the CFTR (or are anti-bacterial) rather than specific tissue remodeling processes. Hence, we have not chosen to include this area of research here. In the same vein, other promising targets and therapies were not included because the stories of their discovery and progression are not ready for publication yet [for instance the Gilead/Nimbus acetyl-CoA carboxylase (ACC) program for non-alcoholic steatohepatitis (NASH), the Goldfinch canonical transient receptor potential 6 (TRPC5) inhibitors for chronic kidney disease (CKD), or the Boehringer-Ingelheim soluble guanylate cyclase (sGC) activators for diabetic nephropathy (DN)]. Additionally, some topics were omitted as a result of data that emerged during the compilation of this book, which, in turn, warranted a re-evaluation of their therapeutic potential. As a complex chronic disorder, fibrotic diseases may need polypharmacy of polypharmacological interventions. We envision that subsequent editions of this book would be poised to capture these and the latest emerging concepts and stories in anti-fibrotic drug discovery in due course.

Currently, 998 clinical trials for “fibrosis” are listed on ClinicalTrials.gov. These span a large number of targets for multiple fibrotic indications and involve various study designs. If one looks more closely at the distribution of clinical trials for which a pharmaceutical or biological intervention is under evaluation, it is clear that considerable effort is underway to tackle fibrotic disease (Figure 1).

These interventions include cell therapies, antibodies, human proteins, small molecules, natural products/traditional Chinese medicines, and repurposed drugs. As is evident from Figure 1, the majority of clinical activity can be found in treating liver fibrosis. It is however important to point out that this includes a number of anti-viral therapies targeting hepatitis C. The next largest area of clinical activity is in the space of idiopathic pulmonary fibrosis (IPF). This is in large part due to the clinical successes of the only two approved anti-fibrotic drugs (pirfenidone and nintedanib, discussed further in Chapter 1). This book seeks to be agnostic to target tissue and therapeutic modality, but our chapters have, in essence, naturally mirrored the distributions shown above. In future editions, we would hope to see an expansion of clinical trials and hence drug discovery programs with robust drug discovery in the cardiorenal space, which is currently lacking. Targeted therapies for systemic sclerosis, ocular fibrosis and rare fibrotic disorders like the Hermansky–Pudlak Syndrome are also currently underway. From a modality perspective, we have captured fibrosis research concepts related to small molecules, carbohydrates, targeted degraders, antibodies and nanotherapeutics. We have also sought to provide insights into the interplay between fibrosis and cancer and the opportunities to capitalize on the research synergies between the two in the future. Our hope is that this book will serve as useful reference tool for anyone working in the field of anti-fibrotic drug discovery, and will encourage and excite the community at large to continue their search for the next generation of therapies.

We wish to thank all of the contributing authors for their hard work and dedication to fibrotic drug discovery and to the compilation of this book. Their tireless dedication and commitment to sharing their work and the work of others in their respective areas of expertise, made this book a reality. We also want to thank all of the reviewers that edited and contributed to the refinement of the chapter content. Their guidance and helpful commentary allowed the chapters to emerge stronger and more insightful as a result. We also wish to thank Dave Rotella of Montclair State University for encouraging the development of this book and Katie Morrey and Drew Gwilliams of the Royal Society of Chemistry for their constant support and guidance during the entire process.

Jehrod Brenneman and Malliga Iyer