Industry Immersion Learning

2

Integration of Pharmaceutical and Diagnostic Co-Development and Commercialization: Adding Value to Therapeutics by Applying Biomarkers

Michael Stocum

Contents

2.1 Mission

2.2 Goals

2.3 Predicted Learning Outcomes

2.4 Introduction

2.4.1 Current Environment for Pharmaceutical and Diagnostic Product Development

2.4.2 Potential Solutions to the Challenges Confronting Pharma

2.4.2.1 Genomics and Proteomics, Metabolomics, and "Other -omics"

2.4.2.2 Translational Research

2.4.2.3 Biomarkers

2.4.3 Drug Development for Targeted Cancer Therapies

2.4.3.1 Tamoxifen in Estrogen-Receptor-Positive Breast Cancer

2.4.3.2 Trastuzumab (Herceptin) in Breast Cancers Overexpressing Her2

2.4.3.3 Imatinib (Gleevec) in Chronic Myelogenous Leukemia and Gastrointestinal Stromal Tumors

2.4.3.4 Other Targeted Therapies

2.4.4 Specific Example of Lapatinib (Tykerb)

2.4.4.1 Leveraging Biomarkers and Diagnostics to Accelerate Drug Development

2.4.4.2 Potential to Enhance Commercial Success with Companion Diagnostics

2.4.5 Personalized Medicine

2.5 Case Scenario

2.6 Timeline

2.7 Study Plan and Assignments

2.7.1 Session 1

2.7.1.1 Presentations

Drug and Diagnostic Product Development (Presentation #1)

2.7.1.2 Assignment #1

2.7.2 Session 2

2.7.2.1 Presentations

2.7.2.2 Assignment #2

2.7.3 Session 3

2.7.3.1 Presentations

2.7.3.2 Assignment

2.7.4 Session 4

2.7.4.1 Presentations

2.7.4.2 Assignment #4

2.7.5 Session 5

2.7.5.1 Assignment #5

2.7.6 Session 6

2.7.6.1 Presentations

Acknowledgment

Resources

2.1 Mission

This case will explore the current state of pharmaceutical and diagnostic development and identify opportunities to optimize product development and commercialization for each industry through co-development of products. Specifically, students will develop a project plan that offers solutions to technical, scientific, and business challenges for the integration of diagnostics in example drug discovery programs.

2.2 Goals

This case will

• provide examples of therapeutic development projects that integrate diagnostics;
• enable students to understand the complexity of developing therapeutics as well as diagnostics;
• offer an opportunity to apply students' existing science and business knowledge to the field of personalized medicine.

2.3 Predicted Learning Outcomes

Students will learn the complexity of developing therapeutics, as well diagnostics. They will be offered the opportunity to apply their learning by designing both technical and business solutions to the issues within co-development of these areas. At the end of the case, students will

• be able to choose a drug target and a molecule (existing small molecule or biopharmaceutical);
• develop a hypothesis-driven targeted drug development program that could result in a personalized medicine product.

2.4 Introduction

In the latter half of the twentieth century and into the beginning of the twenty-first century, tremendous growth occurred in the global pharmaceutical industry (inclusive of biotechnology companies developing and commercializing therapeutics). Accompanying this growth was a dramatic increase in the availability of reliable and generally safe medicines throughout most of the developed world and portions of the developing world. As the mantra of one pharmaceutical company states, these medicines are "helping people do more, feel better and live longer"1). Such advancements have resulted in vaccines that have almost eradicated childhood diseases such as polio and measles, replacing extreme fear with an expectation that children will be healthy throughout their early development.

Other infectious diseases viewed as conditions with high mortality rates and rapid progression, such as the acquired immune deficiency syndrome (AIDS), and its causative agent the human immunodeficiency virus (HIV), are now routinely managed to extend infected patients' lives by 10, 15, even 20 years or more. The advancements have also led to medicines that reduce the incidence and spread of diseases such as typhoid fever, leishmaniasis, and malaria in developing countries. In addition, therapies exist today that treat a wide variety of diseases from chronic conditions such as cardiovascular disease and diabetes to acute disease episodes such as sepsis, myocardial infarction, and stroke. Even one of the most challenging human diseases, cancer, is increasingly manageable, resulting in longer life expectancy and improved quality of life.2)

http://progressreport.cancer.gov/index.asp Similarly, the medical diagnostics industry experienced tremendous growth in the last quarter of the twentieth century and is poised to experience further growth in the early twenty-first century. While both the pharmaceutical and diagnostics industries are expected to gain from the increased knowledge of the human genome, proteome, and other research within the areas of human biology and disease etiology, the diagnostics industry has the ability to directly "productize" such findings.

An example is the recent finding that the individual level of expression (messenger RNA, or mRNA) from 16 genes predicts whether a woman with breast cancer needs chemotherapy for her cancer or whether she can avoid it while having a relatively high confidence that her chances of survival will be similar or identical to if she had received the chemotherapy.3) Genomic Health (Redwood City , CA), a company that offers clinical diagnostic laboratory testing services, has commercialized a test, OncoType Dx, based on these findings.

Other examples exist where an improved understanding of the interindividual genetic variation in drug-metabolizing enzymes and vitamin K receptor allows physicians to select the appropriate dosage of the anticoagulant drug S-warfarin.4) This drug is difficult to dose, and this difficulty results in thousands of patients every year being at risk of adverse events due to the drug.5)

Approximately 30 years have elapsed since the utility of cholesterol testing was recognized, and today it is assessed during routine medical examinations. Perhaps the biggest utility of cholesterol testing has been to predict risks of cardiovascular disease, particularly atherosclerosis and associated heart attacks and strokes. Medicines have been developed to treat elevated levels of cholesterol, and a corresponding reduction in the incidence of cardiovascular disease has been observed.6) Additional innovative products have been commercialized by the diagnostics industry enabling tracking of patient's general lipid profile, including triglycerides, high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol (LDL), resulting in further refinements to the treatment and management of cardiovascular disease.7),8)

In the post-World-War-II era of healthcare in most of the developed countries, therapeutics and diagnostics have been used in tandem by caregivers to diagnose, treat, and manage disease. People are beneficiaries of this synergy, enjoying improved health and greater productivity throughout increasing life spans. The advances, however, are coming with increasing cost and broader healthcare, societal, and ethical dilemmas.

2.4.1 Current Environment for Pharmaceutical and Diagnostic Product Development

Pharmaceutical and diagnostic product development consists of many complicated steps; an overview of them is provided in Figure 2.1. Commonly referred to as the "product development cycle", the continuum of drug research, discovery, development, and commercialization begins when an organization selects a disease condition to pursue. The selection of biological targets is a critical first step, as the targets must be relevant in the disease area of interest and must be "addressable", meaning that the target may be altered by a pharmacological agent (a biological or chemical molecule). Once a target is identified, validation is achieved by altering the target and demonstrating through in vitro experiments and some animal models (frequently mice) that the alteration in the target somehow changes the biology of the disease. Following target validation, large libraries of molecules are screened against a validated target to look for molecules that alter the target and the disease in the disease models. A small number or series of molecules demonstrating the best profiles are then optimized to create several molecules that have drug-like properties and address the target. The organization will then select from these one or more candidates to run through safety and toxicology testing in animals and standard laboratory safety tests as required by regulatory agencies. When these tests are completed, an Investigational New Drug (IND) application is filed with the Food and Drug Administration (in the United States) or similar regulatory body in other countries or regions of the world.

Fig. 2.1 Drug product development cycle.

Following this submission, and in the absence of regulatory holds on further research, the organization is free to pursue the first studies in humans. The molecule is studied at low doses as established from safety and toxicology studies in animals, then given repeatedly at larger doses so that clinical scientists may assess the properties of the molecule in humans. Assuming the drug is found to be safe and...