S. Mason Sosei Heptares Steinmetz Building Granta Park Cambridge UK
Lothar Roessig Research & Development, Pharmaceuticals Bayer AG Wuppertal Germany
Laurent Salphati Drug Metabolism and Pharmacokinetics Genentech, Inc. South San Francisco USA
Peter Sandner Research & Development, Pharmaceuticals Bayer AG Wuppertal Germany
Tomi Sawyer Maestro Therapeutics Southborough USA
Sarah K. Scott Encoded Library Technologies/NCE Molecular Discovery GSK Cambridge USA
Hong C. Shen Department of Medicinal Chemistry, Therapeutic Modalities Roche Innovation Center Shanghai Shanghai People’s Republic of China
Steven T. Staben Discovery Chemistry Genentech, Inc. South San Francisco USA
Johannes‐Peter Stasch Research & Development, Pharmaceuticals Bayer AG Wuppertal Germany
Wayne Haifeng Tang Drug Discovery Group Schrödinger Inc. New York USA
Ling Tong Discovery Chemistry Merck Research Laboratories Kenilworth USA
Song Yang Department of Medicinal Chemistry Therapeutic Modalities Roche Innovation Center Shanghai Shanghai People’s Republic of China
Hongying Yun Department of Medicinal Chemistry Therapeutic Modalities Roche Innovation Center Shanghai Shanghai People’s Republic of China
Wei Zhu Department of Medicinal Chemistry Therapeutic Modalities Roche Innovation Center Shanghai Shanghai People’s Republic of China
Ning Zou R&D Chemistry, Therapeutic Proteins Regeneron Pharmaceuticals, Inc. Tarrytown USA
1 Current 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
