Contemporary Accounts in Drug Discovery and Development E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 964

Veröffentlichungsjahr: 2022

Beschreibung

CONTEMPORARY ACCOUNTS IN DRUG DISCOVERY AND DEVELOPMENT A useful guide for medicinal chemists and pharmaceutical scientists Drug discovery is a lengthy and complex process that typically involves identifying an unmet medical need, determining a biological target, chemical library screening to identify a lead, chemical optimization, preclinical studies and clinical trials. This process often takes many years to complete, and relies on practitioners' knowledge of chemistry and biology, but also--and perhaps more importantly--on experience. Improving the success rate in discovery and development through a thorough knowledge of drug discovery principles and advances in technology is critical for advancement in the field. Contemporary Accounts in Drug Discovery and Development provides drug discovery scientists with the knowledge they need to quickly gain mastery of the drug discovery process. A thorough accounting is given for each drug covered within the book, as the authors provide pharmacology, drug metabolism, biology, drug development, and clinical studies for every case, with modern drug discovery principles and technologies incorporated throughout. Contemporary Accounts in Drug Discovery and Development readers will also find * Case histories used as an engaging way of learning about the drug discovery/development process * Detailed biological rational and background information, drug design principles, SAR development, ADMET considerations, and clinical studies * The full history of individual marketed small molecule drugs * Coverage of drug candidates that have passed Phase I clinical trials with different modalities, such as antibody drug conjugates (ADC), proteolysis-targeting chimera (PROTAC), and peptide drugs * The application of new technologies in drug discovery such as DNA-encoded libraries (DEL), positron emission tomography (PET), and physics-based computational modeling employing free energy perturbation (FEP) Contemporary Accounts in Drug Discovery and Development is a helpful tool for medicinal chemists, organic chemists, pharmacologists, and other scientists in drug research and process development. It may be considered essential reading for graduate courses in drug discovery, medicinal chemistry, drug synthesis, pharmaceutical science, and pharmacology. It is also a useful resource for pharmaceutical industry labs, as well as for libraries.

Leseprobe

Contemporary Accounts in Drug Discovery and Development

Edited by

Xianhai Huang

InventisBio Co., Ltd., Florham Park, USA

Robert G. Aslanian

New Jersey City University, Jersey City, USA

Wayne H. Tang

Schrödinger Inc., New York, USA

This edition first published 2022© 2022 John Wiley & Sons, Inc

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The right of Xianhai Huang, Robert G. Aslanian, and Wayne H. Tang to be identified as the authors of the editorial material in this work has been asserted in accordance with law.

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Library of Congress Cataloging‐in‐Publication Data

Names: Huang, Xianhai, editor. | Aslanian, Robert G., editor. | Tang, Wayne H. (Wayne Haifeng), editor.Title: Contemporary accounts in drug discovery and development / edited by Xianhai Huang, Robert G. Aslanian, Wayne H. Tang.Other titles: Case studies in modern drug discovery and development.Description: Second edition. | Hoboken, NJ : Wiley, 2022. | Preceded by  Case studies in modern drug discovery and development / edited by  Xianhai Huang, Robert G. Aslanian. 2012. | Includes bibliographical  references and index.Identifiers: LCCN 2021055890 (print) | LCCN 2021055891 (ebook) | ISBN  9781119627715 (cloth) | ISBN 9781119627852 (adobe pdf) | ISBN  9781119627814 (epub) | ISBN 9781119627784 (oBook)Subjects: MESH: Drug Discovery | Drug DevelopmentClassification: LCC RM301.25 (print) | LCC RM301.25 (ebook) | NLM QV 745  | DDC 615.1/9–dc23/eng/20211228LC record available at https://lccn.loc.gov/2021055890LC ebook record available at https://lccn.loc.gov/2021055891

Cover Design: WileyCover Image: © Sergey Nivens/Shutterstock

Preface

It has been almost nine years now since the publication of the first edition of Case Studies in Modern Drug Discovery and Development in 2012. The book has been well received, in part for its breadth of topics including accounts of the discovery of life‐saving drugs. The purpose of the first edition of the book was to preserve knowledge of drug discovery and development at a time that small‐molecule drug discovery was seemingly at a crossroad and looking for direction. In the years since the publication of the first edition, we have been fortunate to witness the approval of many new drug products. In fact, 2018 witnessed a historic number of novel drug approvals by the FDA (a total of 59). Technology has advanced at an amazing pace in the past few years, which has enabled many formally untenable modalities, such as peptides, drug conjugates, antibodies, RNA, and vaccines, to provide new options for drug discovery. In addition, advances in basic science have also helped to accelerate the drug discovery process. In particular, structure‐based drug design has had a profound impact on modern drug discovery. For example, physics‐based free‐energy perturbation could finally be used to realistically predict relative ligand‐binding potency after almost 30 years of effort. CryoEM technology, which was the subject of the 2017 Nobel Prize in Chemistry, has also shown an increasing impact on structure‐based drug design and enabled access to previously unobtainable protein structures. Artificial intelligence has also started to play an important role in drug discovery, although more time is needed to realize its full impact. These are very encouraging results; however, it still takes a long time to transform the initial basic discoveries from academic labs into a drug product. For example, a number of studies have shown that on average, it still takes more than 10 years and several billion dollars to develop and bring a new drug to market from the hit‐finding stage. Furthermore, the failure rate for clinical compounds remains unacceptably high at about 90% with some therapy areas suffering even higher rates. With these important advances and challenges in the drug discovery field, we feel that it is the right time to have a new edition of the book to showcase these new developments in driving the drug discovery process. In the first edition of the case study book, we mainly focused on marketed small molecule drugs and covered their discovery and development stories from initial biological rational to products on the market. In the new edition of the book, we not only cover the full stories of several marketed small molecule drugs but also include drug candidates with different modalities such as antibody drug conjugates, proteolysis targeting chimeras, and peptide drugs. The application of new technology such as DNA‐encoded library and positron emission tomography in drug discovery will also be covered in the book. Improving the drug discovery success rate continues to be a key factor that will weigh heavily on the success, and perhaps even the survival, of the pharmaceutical industry. How to more efficiently apply drug discovery principles and technologies to improve the success rate becomes a critical question. Knowledge gained from the successful discovery and launch of marketed drugs, and lessons learned from failed drug discovery stories can provide a very useful and important template for future drug design and discovery. We hope that the new edition of Case Studies in Modern Drug Discovery and Development (newly named as Contemporary Accounts in Drug Discovery and Development) can serve this purpose in addition to bringing educational value to the readers. Like the first edition, each chapter will have a detailed biological rational and background information, drug design principles, SAR development, ADMET considerations, and clinical studies, with modern drug discovery principles and technologies incorporated.

Like the first edition, this edition of Case Studies in Modern Drug Discovery and Development covers almost all aspects of the drug discovery process with detailed examples to showcase the science and technology; thus, it essentially will be suitable for all levels of scientists who are involved in drug discovery. The main targeted readers are medicinal chemists, and undergraduate and graduate students who are interested in drug discovery. Since it not only traces the drug discovery process from idea to marketed drug with a detailed explanation of the application of modern drug design principles and discovery technologies, but also showcases the importance of cross‐disciplinary applications of knowledge from different fields such as computer science and statistics, Contemporary Accounts in Drug Discovery and Development essentially will be beneficial to any scientist involved in the drug discovery process. It is also designed to be used as a textbook in a medicinal chemistry class. The book has 15 chapters and fits one full semester. With the comprehensive information included in each independent chapter, it is also suitable for professional seminars or courses that relate to drug design. Some of the drug discovery stories collected in this book are popular and life‐saving medications, so it will be of interest to the public who want to learn more about how these drugs are discovered.

Editing a scientific book is not an easy process; it took more than three years from the conception of the book, author recruiting, and chapter editing to the publication of the book. During this long process, there are many friends and colleagues who helped to make it possible. We would like to thank our editor, Jonathan Rose, for initiating the process, giving us the opportunity, and trusting us in editing Contemporary Accounts in Drug Discovery and Development. We also want to thank Wiley Managing Editor Dr. Andreas Sendtko for his role as a consistent point of contact both during the writing phase and right through to publication. His support has made the book‐editing process run very smoothly. We would also like to thank all the authors who dedicated their time to contribute the chapters and their respective companies for permission to publish their work. Without their unselfish contributions, especially during an unprecedentedly difficult period of the COVID‐19 pandemic, it is almost impossible to accomplish such a daunting job. We salute them for their time, effort, persistence, and dedication. We continue to believe that all the chapters will have a very important impact on future drug discovery programs and benefit future scientists of this field for generations to come. We would like to thank the reviewers of our book proposal for their valuable suggestions and critiques. We would like to thank Dr. Wen‐Lian Wu for his inputs/comments on the Alzheimer's disease chapter and Dr. Shuangping Shi for her expert comments on Appendix A. Xianhai is indebted to his wife Dr. Hongmei Li and his children Alexander and Angelina for their support and understanding. Bob would like to thank his wife Antoinette and his family for their encouragement and support over the years. Wayne is also grateful to the infinite support from his family.

The road to the discovery and development of life‐saving drugs is not and will never be easy and straightforward. With scientific advancements, technological innovations, close collaborations and knowledge sharing, and the lifetime dedication of pharmaceutical scientists and academic medical researchers, it is possible to improve the efficiency of drug discovery and development to deliver the therapies that will alleviate suffering and extend lives. We hope that this book can serve as a small stepping stone in this complex process and help the readers to contribute to the improvement of the health of humanity.

New Jersey, February 2022

Xianhai HuangRobert G. AslanianWayne H. Tang

List of Contributors

Robert AbelDrug Discovery GroupSchrödinger Inc.New YorkUSA

Robert AslanianDepartment of ChemistryNew Jersey City UniversityJersey CityUSA

Corina BeckerResearch & Development, PharmaceuticalsBayer AGWuppertalGermany

Andrea BortolatoResearch and Development, Computer‐Assisted Drug Design, Molecular Discovery TechnologiesBristol Myers SquibbPrincetonUSA

David Yu‐Kai ChenDepartment of ChemistrySeoul National UniversitySeoulSouth Korea

Yun DingEncoded Library Technologies/NCE Molecular DiscoveryGSKCambridgeUSA

Wu DuHinova Pharmaceuticals Inc.ChengduPeople’s Republic of China

Markus FollmannResearch & Development, PharmaceuticalsBayer AGWuppertalGermany

Jeffrey J. HaleAssociate Vice PresidentDiscovery ChemistryMerck & Co., Inc.West PointUSA

Amy HanR&D Chemistry, Therapeutic ProteinsRegeneron Pharmaceuticals, Inc.TarrytownUSA

Junliang HaoDiscovery Chemistry Research and TechnologiesLilly Research LaboratoryEli Lilly and CompanyLilly Corporate CenterIndianapolisUSA

Timothy P. HeffronDiscovery ChemistryGenentech, Inc.South San FranciscoUSA

Xianhai HuangDiscovery ChemistryInventisBio Co., Ltd.Florham ParkUSAWenping LiTranslational ImagingMerck Research LaboratoriesWest PointUSA

Jonathan S. MasonSosei HeptaresSteinmetz BuildingGranta ParkCambridgeUK

Lothar RoessigResearch & Development, PharmaceuticalsBayer AGWuppertalGermany

Laurent SalphatiDrug Metabolism and PharmacokineticsGenentech, Inc.South San FranciscoUSA

Peter SandnerResearch & Development, PharmaceuticalsBayer AGWuppertalGermany

Tomi SawyerMaestro TherapeuticsSouthboroughUSA

Sarah K. ScottEncoded Library Technologies/NCE Molecular DiscoveryGSKCambridgeUSA

Hong C. ShenDepartment of Medicinal Chemistry, Therapeutic ModalitiesRoche Innovation Center ShanghaiShanghaiPeople’s Republic of China

Steven T. StabenDiscovery ChemistryGenentech, Inc.South San FranciscoUSA

Johannes‐Peter StaschResearch & Development, PharmaceuticalsBayer AGWuppertalGermany

Wayne Haifeng TangDrug Discovery GroupSchrödinger Inc.New YorkUSA

Ling TongDiscovery ChemistryMerck Research LaboratoriesKenilworthUSA

Song YangDepartment of Medicinal Chemistry Therapeutic ModalitiesRoche Innovation Center ShanghaiShanghaiPeople’s Republic of China

Hongying YunDepartment of Medicinal Chemistry Therapeutic ModalitiesRoche Innovation Center ShanghaiShanghaiPeople’s Republic of China

Wei ZhuDepartment of Medicinal Chemistry Therapeutic ModalitiesRoche Innovation Center ShanghaiShanghaiPeople’s Republic of China

Ning ZouR&D Chemistry, Therapeutic ProteinsRegeneron Pharmaceuticals, Inc.TarrytownUSA

1Current Drug Discovery: Great Challenges and Great Opportunity (an Introduction to Contemporary Accounts in Drug Discovery and Development )

Jeffrey J. Hale

Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, PA 19486‐004, West Point, PA, USA

As we approach the end of the second decade of the twenty‐first century, global human health faces significant challenges. In May 2018, the World Health Organization (WHO) reported that more than half of recent deaths worldwide were attributable to 10 major causes [1]. Mortality following from cardiovascular disorders, such as ischemic heart disease and stroke, figured prominently on that list, while conditions such as chronic obstructive pulmonary disease, dementias, and diabetes were noted to have increased in frequency since 2000. While the prevalence of deaths from non‐communicable diseases may be perceived to be of greater concern in high‐income countries, the WHO noted that “diseases of aging” are significant globally. In September 2018, the International Agency for Research on Cancer noted the increasing prevalence of cancers worldwide, with an expectation at current rates that one in five men and one in six women will develop cancer during their lifetime, and one in eight men and one in 11 women die from it. Outbreaks of infectious diseases (e.g. dengue, Ebola, influenza, Zika) exacerbated by behavioral and social factors, as well as the associated issue of growing antimicrobial resistance, highlights another acute threat to human health [2]. The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in late 2019/early 2020 and the subsequent world‐wide pandemic that ensued was an extremely sobering reminder of this latter point [3]. A 2017 report from the United States Bureau of Vital Statistics indicated that life expectancy (all source mortality) may be leveling off or even decreasing, after close to a century of increase in this metric [4]. All told, a significant opportunity is before us to identify new methods to prevent, modify and treat disease and reverse the course of these human health trends.

In the first edition of Case Studies in Modern Drug Discovery and Development, my mentor and industry colleague Dr. Malcolm MacCoss posited that the pharmaceutical industry was facing a “perfect storm” of pressures that presented large challenges. These included patent expiries, the continued rising costs of research and development, the long discovery and development time cycles of the industry and the over‐reliance on a “blockbuster business model”. All of these are relevant at the present time with the addition of the current complexities of acute societal, political and economic pressures on healthcare allocation and delivery [5]. Since the middle of this decade, multiple analyses of industry‐wide productivity have been published [6–9]. While the data sets and methodologies used by the respective authors differ somewhat, pipeline productivity (as measured by transition rates through development phases or overall success rates to registration) has not manifestly improved. Questions about how best to model and organizationally scale basic biomedical research, the effectiveness of clinical trial design and execution practices, and how to navigate complex regulatory landscapes seem to regularly recur in an attempt to discern the root cause(s) of our inability to change productivity. A response in part to these challenges has been the continued activity within the biopharma industry in mergers, acquisitions and partnerships, driven by the desire to mitigate the effect of loss of exclusivity of key products, identify new portfolio synergies and hedge against the continued rise in operational costs [10]. “Mega‐mergers” are still quite prevalent, as evidenced by 2019s numerous multi‐billion‐dollar deals (e.g. Takeda/Shire, Bristol‐Myers Squibb/Celgene, AbbVie/Allergan, Pfizer's merger of Upjohn/Mylan). For the biopharmaceutical industry today, this is on the background of additional questions regarding the nature of its interactions with partners and stakeholders (e.g. What should be the respective contributions and desired impact of biomedical research funded by governments vs. private industry? What is the value to patients and payors of “new” drugs that are or perceived to be “me too” products?) [11]. There is anticipation of enhanced pricing pressures on prescriptions drugs in the United States that will likely require creative solutions as that country moves into the new decade [12]. Isaac Stoner (COO, Octagon Therapeutics) recently commented on challenges specific to new antibiotics, but the call to have market reform drive research productivity and downstream patient access extends well beyond that arena:

If our industry truly believes we have a responsibility to put patients ahead of profits, we need to work to fix this broken market rather than ignoring the problem in favor of more profitable disease areas. There are major externalities driven by access to new effective antibiotics. Without the ability to treat infections, simple procedures such as Caesarian‐sections or hip replacements will present enormous risk, and cancer mortality rates will skyrocket. Saving lives should be good business but, in this case, it's not. Without real market reform, antibiotic development will continue to be un‐investable, and these medicines will not be available to patients who desperately need them.

[13]

None of this is helped by the public's low regard for the pharmaceutical industry, which in one recent analysis by Gallup lagged significantly behind perennial poor performers like the legal profession and the United States government [14]. While some of this may be attributed to decreasing science literacy [15], it is also undoubtedly driven by things like the poor handling by industry players of specific commercialization strategies (e.g. insulin pricing [16]) and the high‐profile debacles involving extreme bad actors (e.g. the price gouging scandal involving the anti‐toxoplasmosis drug Daraprim® by Martin Shkreli and Turing Pharmaceuticals [17]; the unethical and fraudulent promotion of its blood sample analysis technology by Elizabeth Holmes and Theranos [18]). A broad, holistic approach is likely needed to address the structural challenges that the pharmaceutical industry faces, and I would argue that broad reform of healthcare systems in the United States and abroad that encourages growth and protects its competitiveness is critical. Policymakers will need to surmount large political and economic challenges in order to foster continued robust biopharma research and development worldwide. Any solution that aspires to lower drug prices should also expand access to affordable insurance, streamline regulation, and spread cost and risks across all of the players in the biopharma ecosystem. While the reactive ramp up of world‐wide efforts in reaction to the SARS‐CoV‐2 pandemic was not ideal, it may contain elements (e.g. aggressive repurposing of existing therapeutics; parallel, collaborative efforts interrogating new potential therapeutics and preventatives; rapid publishing of preclinical and clinical data on open‐source platforms) that could inform on reforming drug discovery and development models [19].

Despite the somewhat dire picture painted by the challenges above, drug discoverers and developers worldwide have made some remarkable contributions to the pharmacopeia over the last decade. Advances in immuno‐oncology that unleash a patient's own anti‐tumor immunity to treat certain cancers have been revolutionary [20, 21]. The potential to couple new drugs with programmed cell death protein‐1 (PD‐1) inhibitors like Opdivo® (nivolumab) and Keytruda® (pembrolizumab) has led a veritable renaissance of research into novel immunomodulators and cellular metabolism regulators, all with the hope that they could be exploited as combination agents in cancer therapy, as well as provide insights into or be exploited for the treatment of cardiovascular and neurologic disorders. Dysfunctions in the humoral immune system that manifest as aggressive B‐cell non‐Hodgkin lymphomas are now treatable with inhibitors of Bruton's tyrosine kinase (Btk) inhibitors such as Imbruvica® (ibrutinib); Btk inhibitors with enhanced tolerability and resistance profiles are under active clinical investigation [22]. New anti‐diabetic drugs like Jardiance® (empagliflozin), a selective inhibitor of sodium glucose co‐transporter‐2 (SGLT2), have been clinically demonstrated to provide significant cardiovascular benefit [23]. The discovery and development of the hepatitis C (HCV) NS5B protein RNA polymerase inhibitor Sovaldi® (sofosbuvir) and HCV NS5A inhibitor Harvoni® (ledipasvir) led the charge to identify cross‐genotype HCV drugs that can cure infected patients in three months or less. Recent breakthroughs that have produced drugs effective against multi‐drug resistant tuberculosis demonstrate that progress can be made against decades old problems [24]. These and other groundbreaking therapies have benefited from the innovations and insights of drug discovery and development chemists. I am confident that medical researchers and drug hunters have the potential to maintain this trajectory as we move into the 2020s.

While AstraZeneca's widely cited five‐dimensional framework on research and development productivity [25] does not explicitly call out “the right chemistry” among its factors for long‐term research success, many recent advances in chemical biology and medicinal chemistry have the potential to impact those factors as we move forward. Barriers to drugging “the right target” and establishing “the right safety” are on their way to being toppled by advanced tools and technologies that allow for deliberate exploitation of allostery, the modulation of RNA biology with small molecules [26], the therapeutically beneficial manipulation of transcription factors [27], the resetting of the autophagy “rheostat” [28] and the targeted degradation of disease‐relevant proteins [29]. The last – which can be thought of conceptually as the post‐translational knockdown of proteins – is particularly intriguing today, as the first “molecular glues” and proteolysis targeting chimeras (PROTACs) have reached the clinic [30] and the field of targeted degraders promises to produce more molecules that can be put in the context of “rule‐of‐five” chemical space [31]. Our rapidly developing understanding of the complexities of human microbiome and its connection to cardiovascular, immunologic, and neurologic “health” will likely expand target space and point to new approaches for therapeutic intervention. This is tied to the re‐emergence of phenotypic drug discovery in general and all of this could be accelerated via the application of present‐day genomics tools coupled with the state‐of‐the‐art informatics capabilities.

A group of my MSD Chemistry colleagues recently rejected the position that the act of designing and synthesizing molecules is a commoditized aspect of pharmaceutical research, but rather “that excellence and innovation in synthetic chemistry continues to be critical to success in all phases of drug discovery and development [32].” This sentiment echoes the recent views of other chemists from both academic and industrial circles [33–36] and I can point to multiple times over my 35 year career where organic synthesis has indeed been a significant inspiration of my ideas (both good ones and bad ones). Looking forward, the capability exists for most industrial medicinal chemists to rapidly work through the more empirical aspects of their drug discovery projects using powerful automation tools [37] enabled by machine learning and artificial intelligence and this will likely become part of the standard academic training regimen for the next generation of drug discovery and development chemists [38]. The horizons of organic synthesis continue to expand via the continued innovation in areas of chemo‐ and biocatalysis [39], electrochemistry [40], flow chemistry [41], methods to productively disconnect carbon–carbon bonds [42], and photochemically induced oxidation/reduction chemistry [43]. These will not only afford access to new biologically interesting chemical space for medicinal chemists, but also pave future paths to design concepts. Synthesis is not (nor should it be) the only driver of molecular design and it is presently complemented by current capabilities of machine learning to understand and optimize molecular interactions as well as finely balance the molecular properties critical to bioperformance (absorption, distribution, metabolism, excretion, and toxicity) [44]. While there are currently growing pains with machine learning in drug research [45], it has the potential to positively impact future drug research efforts.

In the era when we see public figures staking claim to “alternative facts” and regularly hear claims that inconvenient or uncomfortable (but objectively verifiable) information is “fake news”, broad societal pressures and the “human element” may pose the biggest threat to continued new discoveries in drug research. In his ground‐breaking 2005 book The World Is Flat: A Brief History of the Twenty‐first Century, Thomas Friedman lays out how the digitization of information and the broad reach of the internet has led to the rapid democratization of capabilities and knowledge [46]. Anyone connected to or embedded in drug research now regularly grapples with the resulting positive and negative impacts of Friedman's flat world. While we can marvel at the power and convenience of conducting broad literature searches in seconds by simply clicking a mouse, this comes at a cost to researchers of having to discern increasingly faint signals in an exponentially expanding sea of noise. As we enhance our ability to leverage artificial intelligence [47] and exploit big data we may be able to eventually corral large quantities of disparate sets of information that is relevant to drug discovery and development, but pitfalls that can be traced to the humans behind the computers have already come to the fore [48].

I also believe that there are significant risks to future innovations posed by the fracturing of the complex research environments into discrete units and continued efforts to optimize their individual parts. This has manifested itself in a pharmaceutical “gig economy” that can reinforce a short‐term, transactional mindset and poses significant challenges to individuals who may be more accustomed to or who would thrive in more traditional research environments [49]. In order to ensure we are on the path to discovering future medicines, we must realize that the rigorous application of the scientific method coupled with savvy decision‐making is critical. The disciplined fostering of individual and group behaviors that promote innovation should be a priority. Making sure that we tolerate failure, allow for experimentation, ensure psychological safety, promote collaboration and demand that we have leaders who support all of this is crucial to have if we seek to avoid having promising research undercut by non‐productive human intervention [50].

While we in the field of medicinal chemistry and drug research and development find ourselves in an era of great challenges, I am optimistic about the future of the discipline. The chapters in this volume that detail efforts that resulted in new drugs to treat bacterial and viral infections, numerous metabolic disorders and various cancers serves as a testament to the creativity, persistence, technical skill and innovative insights of the many individuals and large teams required to make these therapeutics a reality. Beyond that, none of this would have been possible if not for the dedication and effort of those researchers who happen to have direct connections to the specific biologic targets