Contemporary Accounts in Drug Discovery and Development. Группа авторов

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 abroad that encourages growth and protects its competitiveness is critical. Policymakers will need to surmount large political and economic challenges in order to foster continued robust biopharma research and development worldwide. Any solution that aspires to lower drug prices should also expand access to affordable insurance, streamline regulation, and spread cost and risks across all of the players in the biopharma ecosystem. While the reactive ramp up of world‐wide efforts in reaction to the SARS‐CoV‐2 pandemic was not ideal, it may contain elements (e.g. aggressive repurposing of existing therapeutics; parallel, collaborative efforts interrogating new potential therapeutics and preventatives; rapid publishing of preclinical and clinical data on open‐source platforms) that could inform on reforming drug discovery and development models [19].

      Despite the somewhat dire picture painted by the challenges above, drug discoverers and developers worldwide have made some remarkable contributions to the pharmacopeia over the last decade. Advances in immuno‐oncology that unleash a patient's own anti‐tumor immunity to treat certain cancers have been revolutionary [20, 21]. The potential to couple new drugs with programmed cell death protein‐1 (PD‐1) inhibitors like Opdivo^® (nivolumab) and Keytruda^® (pembrolizumab) has led a veritable renaissance of research into novel immunomodulators and cellular metabolism regulators, all with the hope that they could be exploited as combination agents in cancer therapy, as well as provide insights into or be exploited for the treatment of cardiovascular and neurologic disorders. Dysfunctions in the humoral immune system that manifest as aggressive B‐cell non‐Hodgkin lymphomas are now treatable with inhibitors of Bruton's tyrosine kinase (Btk) inhibitors such as Imbruvica^® (ibrutinib); Btk inhibitors with enhanced tolerability and resistance profiles are under active clinical investigation [22]. New anti‐diabetic drugs like Jardiance^® (empagliflozin), a selective inhibitor of sodium glucose co‐transporter‐2 (SGLT2), have been clinically demonstrated to provide significant cardiovascular benefit [23]. The discovery and development of the hepatitis C (HCV) NS5B protein RNA polymerase inhibitor Sovaldi^® (sofosbuvir) and HCV NS5A inhibitor Harvoni^® (ledipasvir) led the charge to identify cross‐genotype HCV drugs that can cure infected patients in three months or less. Recent breakthroughs that have produced drugs effective against multi‐drug resistant tuberculosis demonstrate that progress can be made against decades old problems [24]. These and other groundbreaking therapies have benefited from the innovations and insights of drug discovery and development chemists. I am confident that medical researchers and drug hunters have the potential to maintain this trajectory as we move into the 2020s.

      While AstraZeneca's widely cited five‐dimensional framework on research and development productivity [25] does not explicitly call out “the right chemistry” among its factors for long‐term research success, many recent advances in chemical biology and medicinal chemistry have the potential to impact those factors as we move forward. Barriers to drugging “the right target” and establishing “the right safety” are on their way to being toppled by advanced tools and technologies that allow for deliberate exploitation of allostery, the modulation of RNA biology with small molecules [26], the therapeutically beneficial manipulation of transcription factors [27], the resetting of the autophagy “rheostat” [28] and the targeted degradation of disease‐relevant proteins [29]. The last – which can be thought of conceptually as the post‐translational knockdown of proteins – is particularly intriguing today, as the first “molecular glues” and proteolysis targeting chimeras (PROTACs) have reached the clinic [30] and the field of targeted degraders promises to produce more molecules