Oliver Plettenburg (University of Hannover and Helmholtz Centre Munich) affords an overview on drug discoveries originating from academic research. The chapter covers both small‐molecule drugs and biologics as well as some natural product‐derived drugs. The chapter testifies to how drug discovery has become vital and indispensable discipline at many academic institutions.
Ynonne Alice Nagel, Adrian Britschgi, and Antonio Ricci (Roche) summarize new ways of breaking down disease‐associated proteins. Targeted protein degradation via so‐called PROTACS and other approaches now allows researchers to modulate previously undruggable target proteins.
Part II: Drug Class Studies
Lars Linderoth, Jacob Kofoed, János T. Kodra, Steffen Reedtz‐Runge, and Thomas Kruse (Novo‐Nordisk) review the very important drug class of GLP‐1R agonists for the treatment of diabetes type 2. Since the discovery of GLP‐1 in the 1980s and the launch of the first GLP‐1R agonist‐based therapeutics, multiple development paths have arisen for this successful class of drugs.
Ana Marta de Matos, Patr
Whitney Gladney, Julie Jadlowsky, Megan M. Davis, and Andrew Fesnak (University of Pennsylvania) review the field of cell‐based therapy in a chapter on “CAR T Cells: A Novel Biological Drug Class.” Their chapter describes the first cell‐based gene therapy treatment used for the treatment of relapsed acute lymphoblastic leukemia.
Sarah Walter and Marcelo E. Bigal (Antiva Biosciences and Ventus Therapeutics) describe CGRP (calcitonin gene‐related peptide) inhibitors for the treatment of migraine, which represent a new class of drugs consisting of both small‐molecule drugs and biologics.
Part III: Case Studies
Takehisa Kitazawa, Koichiro Yoneyama, and Tomoyuki Igawa (Chugai Pharmaceuticals) provide a case study of emicizumab, a humanized bispecific antibody to coagulation factors IXa and X that also possesses factor VIII cofactor activity. Emicizumab (HEMLIBRA™) was approved by US FDA in 2017 for treatment of hemophilia A.
Zenon D. Konteatis and Zhihua Sui (Agios Pharmaceuticals) describe the discovery and development of ivosidenib (Tibsovo™), which was approved by US FDA in 2019 for newly diagnosed acute myeloid leukemia with a susceptible IDH1 mutation.
Christopher T. Brain, Rajiv Chopra, Sunkyu Kim, Steven Howard, and Moo Je Sung (Novartis) recount the discovery of ribociclib (Kisqali™), a CDK4/6 inhibitor for the treatment of HR positive/HER2 negative advanced brain cancer. Ribociclib was approved by the US FDA in 2017 for use in combination with an aromatase inhibitor.
The editors and authors thank Wiley‐VCH and personally Dr. Frank Weinreich and Katherine Wong for the excellent collaboration.
János Fischer
Budapest
Wayne E. Childers
Philadelphia
Christian Klein
Zürich
June 2020
1 Drug Discovery in Academia
Oliver Plettenburg1
1Helmholtz Zentrum München (GmbH), German Research Center for Environmental Health, Institute of Medicinal Chemistry, Ingolstädter Landstr. 1, D‐85764, Neuherberg, Germany
2Leibniz Universität Hannover, Center for Biomolecular Research, Institute of Organic Chemistry, Schneiderberg 1b, D‐30167, Hannover, Germany
1.1 Introduction
It is estimated that the global pharmaceutical industry invested more than US$ 1.36 trillion in the decade from 2007 to 2017, and predicted annual spending is assumed to totally sum up to 181 billion for the period to 2020 [1]. At the end of 2019, the 10 largest pharmaceutical companies represented a market capitalization of approximately US$ 1.68 trillion [2].
The tremendous advances in science starting in the 1990s stipulated hopes that the discovery of new medicines would soon turn into an engineerable process. The decryption of the human genome provided a plethora of new target opportunities for exploitation, and the availability of large screening collections, efficient miniaturized high‐throughput screening technologies, and computer‐assisted methods for hit generation suggested that generation of reasonable lead structures should be feasible for many of these targets. Furthermore, cellular models for early prediction of metabolic liabilities and toxicological risks enhanced the optimization of drug‐like properties. However, after 30 years, these hopes did not turn into reality; the number of approved drugs remained approximately constant, at least for the period from 1989 to 2013. In 2019, the Food and Drug Administration (FDA) approved 47 new drugs, 9 of which are biologics (Figure 1.1) [3]. It is an interesting observation that despite the trend to focus research on biologics and small‐molecule drug business was said to be dead for several years, the fraction of annual new biological drug approvals is still stagnating at about 25 %.
In an article published in 2011, Stevens [4] analyzed the contributions of publicly funded organizations to current approval rates over a period of 40 years. It is remarkable to note that about 9 % of all approvals (143/1541) were enabled or at least facilitated by public funding. If one compares the contributions for new molecular entities, the rate rises to 13.3 % (64 out of 483). For new molecular entities that have been granted priority review, the report cites an impressive 21.1 % (44 out of 209). In a recent study, Nayak et al. [5] confirmed the significance of pharmaceutical research driven by universities and clinical centers. They thoroughly analyzed FDA drug approvals between 2008 and 2019, considering also patent information. Among the 248 approvals of new molecular entities, they identified significant contributions by publicly funded organizations for 62 (25 %) of them. It is puzzling that pharmaceutical ventures with their highly skilled scientists and an infrastructure that is capable of accessing virtually unlimited funds dedicated solely to the purpose of drug discovery did not perform better than these figures tell us. This is even more surprising in light of the fact that provision of new drugs to the pipeline is obviously a vital task in order to maintain the company going in the future and patent lifetime of approved therapies is clearly very limited.
Figure 1.1 FDA drug approvals from 1990 to 2019.
Source: Data from Mullard [3].
Independent development of a drug to a marketed product is clearly out of scope for any academic. It
