Biotechnology Entrepreneurship

Leading, Managing and Commercializing Innovative Technologies

Craig Shimasaki, Craig Shimasaki

• Publisher: Academic Press
• Year: 2020
• ISBN:
  9780128155868
• Edition: 2
• Topic: Medicine
• Subtopic: Medical Theory, Practice & Reference

This second edition of Biotechnology Entrepreneurship: Leading, Managing, and Commercializing Innovative Technologies is an authoritative, easy-to-read guide covering biotechnology entrepreneurship and the process of commercializing innovative biotechnology products. This best practice resource is for professional training programs, individuals starting a biotech venture, and for managers and experienced practitioners leading biotech enterprises. It is a valuable resource for those working at any level in the biotech industry, and for professionals who support and provide essential resources and services to the biotech industry. This practical, "how-to" book is written by seasoned veterans experienced in each of the operational functions essential for starting, managing, and leading a successful biotech company. Biotechnology Entrepreneurship explains the biotech business components and underlying strategies, interspersed with practical lessons from successful biotech entrepreneurs, educators, and experienced practitioners. These veteran contributors share their insights on how to be successful in this challenging but exciting industry. Subjects range from technology licensing and translating an idea into a viable business, forming your legal company entity, securing angel and venture capital, navigating product development, FDA regulatory approval, and biomanufacturing.This book is a user-friendly guide to decision-making and overall strategy written as a hands-on management tool for leaders and managers of these dynamic biotechnology ventures. If you are contemplating starting a biotech company, are a manager at any level, a seasoned veteran, or service provider in the biotech industry, this book is a "must read."

This second edition includes several new chapters on topics such as:

• What you need to know about valuation and term sheets
• Investor presentations and what you need in a biotech investor pitch deck
• Mentorship and why you need mentors
• Artificial intelligence applications in biotech and pharma
• Common biotech entrepreneur mistakes and how to avoid them

Section VII

Biotechnology Product Development

Outline

• Chapter 24 Therapeutic Drug Development and Human Clinical Trials
• Chapter 25 Integrating Diagnostic Products Into the Drug Development Workflow: Applications for Companion Diagnostics*
• Chapter 26 The Development and Commercialization of Medical Devices
• Chapter 27 Commercialization and Applications of Agricultural Biotechnology
• Chapter 28 Artificial Intelligence: Emerging Applications in Biotechnology and Pharma
• Chapter 29 Artificial Intelligence in Biotechnology: A Framework for Commercialization¹
• Chapter 30 Regulatory Approval and Compliances for Biotechnology Products
• Chapter 31 The Biomanufacturing of Biotechnology Products
• Chapter 32 Biotechnology Products and Their Customers: Developing a Successful Market Strategy

Chapter 24

Therapeutic Drug Development and Human Clinical Trials

Donald R. Kirsch, PhD, Harvard Extension School, Cambridge, MA, United States

Abstract

Therapeutic products go through two distinct stages during their progress toward commercialization: drug discovery and drug development. The drug-discovery stage focuses on the identification of an optimized drug candidate which then, in drug development, is put into human testing to determine its value as a clinical therapeutic. There is no standardized method for drug discovery although modern drug-discovery operations have developed a series of consensus steps that can be used as a general guide for the drug-discovery process. These include target selection and validation, assay development, screening, chemical analog synthesis for lead optimization, and animal model testing. Clinical drug development, overseen by regulatory authorities (Food and Drug Administration in the United States), includes clinical transition (chemical, pharmacological, and toxicological studies designed to provide evidence for human safely), safety trials in healthy volunteers (Phase 1), safety and preliminary efficacy trials in patients (Phase 2), and clinical efficacy trials in patients (Phase 3).

Keywords

Drug discovery; drug development; target validation; chemical optimization; clinical trials; FDA; safety; efficacy

Chapter Outline

Outline

• Small Molecule Drugs 339
  • Small Molecule Target Identification and Validation 340
  • Target Identification and Validation—Areas of Uncertainty 342
  • Assay Development and High-Throughput Screening 342
  • Assay Development and High-Throughput Screening—Screen Implementation 343
  • Lead Discovery 344
  • Lead Optimization 345
  • Drug Absorption and Distribution 346
  • Drug Metabolism 346
  • Clinical Candidate Compound Selection and Characterization in Animal Disease Models 347
• Large Molecule Drugs 348
  • Target Identification and Validation 348
  • Hormones 348
  • Cytokines 348
  • Vaccines 348
  • Therapeutic Antibodies 349
  • Structure Optimization and Identification of a Clinical Candidate 350
• Clinical Transition Studies—Investigational New Drug Approval 351
• Clinical Trials 352
  • Phase 1 352
  • Phase 2 353
  • Phase 3 354
  • New Drug Application Approval and Postlaunch Surveillance 355
  • Areas of Uncertainty 355
• The Human Dimension 356
• Conclusion 357
• Summary 358
• References 358

The 1950s can be considered to be the start of the modern drug-discovery era. Although a number of effective medicines were available for clinical use at the end of World War II, most of these were traditional medicines that had been discovered long ago and the vast majority of the medicines that had been discovered in the 19th and the first half of the 20th centuries were basically found by pure chance. Only two medicines discovered during the late 19th and first half of the 20th centuries could be said to have resulted from a pure directed effort to find a new therapy: the discoveries of arsphenamine (Salvarsan) by Ehrlich, the first effective treatment for syphilis [1], and streptomycin by Waksman, the first effective treatment for tuberculosis [2]. In both of these cases the inventors set out with the specific goal to find a new treatment for a specific disease and were successful.

Each of these directed discoveries provided invaluable discovery strategies that were adopted by the drug development industry. The lesson from streptomycin was that although substances with medicinal properties are very rare, medicines, or chemical compounds that could be modified and then turned into medicines, could be found through methodical screening approaches. The lesson from Salvarsan was that a drug could be created through the application of biological assays to guide chemical analog synthesis efforts to identify compounds with therapeutic value.

Small Molecule Drugs

Small molecule drugs are either synthetic chemicals or chemical metabolites produced by plants or microorganisms. (In some cases, these metabolites need to be chemically modified to produce a clinically effective therapeutic.) Synthetic chemicals are custom designed to be drugs, or in rare cases, chemicals that turn out to have drug properties by accident. The clinical utility of naturally occurring small molecule drugs is probably almost certainly due to chance since these compounds are not made by the plant or microorganism with the intended purpose of being drugs. In other words the foxglove plant does not synthesize digitalis in order to treat heart failure. Rather, these naturally occurring metabolites are exploited by humans and repurposed for therapeutic use.

The contemporary approach to small molecule drug discovery was born out of, and is an amalgam of, the abovementioned century-old research strategies. There is now a strong general consensus regarding the standard steps and phases of the drug-discovery process (Fig. 24.1) [3,4]. However, there is no standardized method for drug discovery and every novel drug is discovered in its own unique way. The consensus steps presented later should be taken simply as a broad experience-based, general guide to the drug-discovery process.

Figure 24.1 Drug discovery (therapeutic discovery and preclinical testing) and development (human clinical testing). Standard phases of drug discovery and development. Development processes encompass the preclinical and clinical studies whose results will be used in regulatory submissions (to the FDA in the United States).

Small Molecule Target Identification and Validation

The ultimate success or failure of any drug-discovery project is fundamentally dependent upon the correct selection of the drug target for the chosen disease. As will be discussed in greater detail later, the drug-discovery project will fail if the selected target is not in a pathway driving the underlying basis of the disease, or if the selected target affects other metabolic processes in the body that negatively affects the viability (side effects). The methods currently available to identify and validate effective drug targets are limited and imprecise as is the knowledge of the underlying molecular etiology of many important diseases. These shortcomings are a major factor driving the high failure rate in drug discovery. However, patients need medicines, and biopharmaceutical companies need new products, and therefore the drug-discovery enterprise carries on.

Perhaps the single most important guiding concept in contemporary pharmacology is Paul Ehrlich’s receptor theory which states that all drugs work by binding to a specific chemical component or receptor within the cell and that drugs act by modifying the activity of the receptor. Receptors are most commonly (1) enzymes which are proteins that speed up reactions within the organism, (2) cellular switches that are actually called receptors because in many cases they were identified as drug targets before their biological cellular functions became known, and (3) signaling pathway elements that act downstream from receptors (see Fig. 24.2). While traditional drugs were discovered through serendipity, the field has changed so that instead of finding a drug by good fortune and then determining how it acts, receptor targets are now selected based on fundamental scientific principles and drugs are then sought that will act on the chosen receptor target.

Figure 24.2 Drug targeting example. Growth factors are produced by specialized cells to induce the growth and division of target cells, acting through growth factor receptors present on the surface of the cell and spanning the cell membrane. These growth factor receptors, in response to the presence of growth factors, transfer the growth signal into the interior of the cell. The interior of the cell has a variety of components mediating cell growth and division including, in this example, a number of classic enzymes—tyrosine kinases, serine/threonine kinases, and small GTPases. When activated by signaling cascades, transcription factors enter the cell nucleus where they bind to specific DNA sequences and regulate genes that control cell growth and cell division.

All diseases have an underlying cause or molecular mechanism that produces the disease called the disease molecular etiology. This idea can probably be most easily understood for infectious diseases; for instance, the molecular etiology for tuberculosis is infection by the pathogenic bacterium Mycobacterium tuberculosis. The bacterium produces damage to the body and leads to the symptoms of the disease. Eliminate the bacterial pathogen and you cure the disease (of course you still need to identify a molecular target within the bacterium that will kill the bacteria without harming the patient)....