The Core Model

A Collaborative Paradigm for the Pharmaceutical Industry and Global Health Care

Ibis Sanchez Serrano, Ibis Sanchez-Serrano

• Publisher: Academic Press
• Year: 2019
• Print ISBN:
  9780128142936
• eBook ISBN:
  9780128142943
• Topic: Medicine
• Subtopic: Pharmaceutical, Biotechnology & Healthcare Industry

The Core Model: A Collaborative Paradigm for the Pharmaceutical Industry and Global Health Care develops the innovative core model, an organizational research and design paradigm and economic theory that proposes a collaborative approach to resolving global health issues and improving the productivity of drug development. The model proposes that scientific collaboration does not occur in an unstructured manner, but actually takes place within a highly structured order where knowledge is transferred, integrated and finally translated into commercial products. An understanding of this model will help solve the global pharmaceutical industry´s productivity problems and address important global health care and economic issues. This book is useful to researchers, advanced students, regulators, and management in pharmaceutical industries, as well as healthcare professionals, those working in health economics, and those interested in scientific innovation processes. - Explores the current state-of-the-art in the pharmaceutical industry and the global healthcare sector - Includes insights from world-leading figures in the pharmaceutical industry, healthcare sector, federal funding agencies, regulatory bodies, investment sector, entrepreneurship, intellectual property law, philanthropic organizations, and advocacy groups - Develops in-depth, original concepts, which have important implications in the understanding of, and search for, potential solutions to the world´s health care crisis

Part

Part I

Outline

Chapter 1. Introduction: the remarkable success story of the development of bortezomib

Chapter 2. Lessons from the development of bortezomib: the Core Model

Chapter 1

Introduction

The remarkable success story of the development of bortezomib ^∗

Abstract

In this chapter, the development of the cancer drug bortezomib (Velcade; Millennium Pharmaceuticals) by a biotechnology company—Myogenics/ProScript—started by academics from Harvard University, is discussed to dissect the key academia–industry/public sector–private sector interactions that made the development of this drug a success despite many barriers. Here, the subject matter of this book, the Core Model, which is an organizational paradigm for drug discovery and development that explains how and why bortezomib was approved in record time, is presented. The academia–industry/public sector–private sector interface is analyzed within the Core Model framework.

Keywords

Academia–industry; Biotechnology; Bortezomib; Core Model; Drug discovery and development; Health care; R&D; R&D models; Ubiquitin–proteasome pathway; Velcade

On May 13, 2003, the US Food and Drug Administration (FDA) approved Velcade (bortezomib), a proteasome inhibitor (Fig. 1.1), under “Fast-Track” Application for the treatment of multiple myeloma, an incurable cancer of the blood that affects approximately 32,110 patients in the United States annually ¹ (Box 1.1, Note 1). The story behind the development of this drug is quite unique and remarkable for many reasons, including:

1. • the initially fragile funding base of the original company that discovered and developed it (Myogenics/ProScript);
2. • the risks involved in pursuing a new molecular target (the proteasome) with a new, and allegedly ill-reputed, class of inhibitors (boronates);
3. • internal struggles and disagreements in the firm between the academic founders and the management regarding the indication for which the drug was to be developed;
4. • change of the original company's business model (from cachexia to inflammation to cancer) and subsequent change of the firm's name—from Myogenics to ProScript;
5. • enormously disruptive drop by Hoechst Marion Roussel, Inc., of proteasome inhibitors for inflammation and cancer and its return of its license rights on the drug to ProScript;
6. • change in leadership;
7. • depletion of initial funding and inability to secure further funding for clinical trials;
8. • the general lack of interest and total disbelief of the biopharmaceutical industry on bortezomib; and

   

   Figure 1.1 The proteasome, nuclear factor-κB, and bortezomib.The proteasome is a barrel-shaped multiprotein particle that destroys proteins that have been marked for degradation by conjugation to ubiquitin. Binding of the transcription factor nuclear factor-κB (NF-κB) to the inhibitor protein IκB in the cytoplasm renders NF-κB inactive. Cellular stimuli, such as cytokines, antigens, oxidants, viruses, and other agents, trigger a cascade of signal transduction events that phosphorylate and ubiquitinate IκB, leading to its degradation by the proteasome, which in turn liberates NF-κB for translocation into the nucleus. Once in the nucleus, NF-κB binds to the promoter regions of genes coding for proteins that are involved in the activation of transcription, growth, angiogenesis, anti-apoptotic factors, and cell-adhesion molecules. By inhibiting the proteasome, bortezomib inhibits the activation of NF-κB (orange crosses) and subsequent events that can promote tumor cell survival and proliferation.
   Source: Sánchez-Serrano, I, 2006. Success in translational research: lessons from the development of bortezomib. Nature Reviews Drug Discovery 5, 107–114.

9. • the resulting merging of ProScript into Cambridge-based LeukoSite and, six months later, the purchase of LeukoSite by Millennium Pharmaceuticals.

Despite all these major obstacles that could have quickly destroyed any company or drug development program, bortezomib managed not only to make it to the market but to do so in record time and at a significantly lower cost than biopharmaceutical industry average.

BOX 1.1 Additional notes

1. • Note 1: Multiple myeloma is predominantly a disease of the bone marrow and is the second-most common cancer of the blood (representing 1% of all cancers and 2% of all cancer deaths). It is estimated that, in the United States alone, approximately 120,000 people have multiple myeloma, and 32,110 patients develop the disease annually (18,130 in men and 13,980 in women). The average life expectancy of these patients is ∼4.3 years, though some individuals can live up to 10–20 years with the disease (see the Multiple Myeloma Research Foundation website for further information: https://themmrf.org/).
2. • Note 2: The history of boronates as pharmaceutical agents is interesting. They were initially developed as serine–protease inhibitors by Dupont/Merck. However, the original compound failed in Phase II clinical trials as a treatment for emphysema, and so boronates acquired a poor reputation among medicinal chemists. Adams's team linked a boronate group to Myogenics lead compounds, which showed considerably increased efficacy against the proteasome, and so created a novel chemotype.
3. • Note 3: Agreement reached for up to US$38 million from Hoechst Marion Roussel, Inc. (HMR), plus royalties paid to ProScript on sales of products deriving from this partnership; https://www.thepharmaletter.com/article/hmr-and-proscript-sign-r-d-pact; accessed 2/28/2019.
4. • Note 4: US$20 million in equity investment from Roche Group to ProScript, plus royalties on sales of products resulting from this collaboration; https://www.thepharmaletter.com/article/hmr-and-proscript-sign-r-d-pact; accessed 4/8/2019.
5. • Note 5: From a business point of view, it must be stressed that although the conclusion to focus on cancer was influenced by these results, bortezomib was first developed as an antiinflammatory agent and was licensed to HMR for that purpose (arthritis). The decision to pursue cancer as a business model was a fallback position because HMR chose to focus upstream of the proteasome in inflammation. Ultimately, HMR dropped proteasome inhibitors for inflammation and cancer, and returned its license rights on the drug to ProScript.

Why did bortezomib—which was considered doomed to failure from the beginning (Box 1.1, Note 2)—become a success story unlike countless other well-funded examples in the industry? How did it manage to reach the market in record time? What can we learn from this story and what relevance does it have in other related areas, such as the way in which the pharmaceutical industry develops novel drugs and the form in which governments craft and implement their innovation policies? What implications does this learning have for the academia–industry/public–private relationship in biopharma? What impact on global health care? Before answering these questions, I will narrate the remarkable story of the discovery and the development of this breakthrough drug.

Brief story of the discovery and development of bortezomib

In 1992, Alfred Goldberg, a cell biology professor at Harvard Medical School, decided to use the growing basic knowledge on the proteasome to create a biotechnology company focused on one goal: using inhibitors to block the proteasome. The proteasome is a hollow and cylindrical enzymatic complex that is present in both the cytoplasm and the nucleus of all eukaryotic cells and is necessary for the degradation of >80% of the cell's proteins. ² This blockage was aimed at investigating the physiological roles of the proteasome and translating basic proteasome research into a therapeutic application. The company, Myogenics, was founded in 1993, and its objective was to target the ubiquitin–...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Professional profile: Ibis Sánchez-Serrano
• Preface
• Acknowledgments
• Part. Part I
• Part. Part II
• Part. Part III
• Part. Part IV
• References
• Index