Читать книгу Successful Drug Discovery, Volume 5 - Группа авторов - Страница 34

The associated cost of late‐stage clinical trials represents a major financial risk, even for large pharmaceutical companies. As a result, strong efforts are taken to increase the predictivity of development success and minimize risks associated with compound development. This leads to strict criteria applied to compounds before entering preclinical and clinical development and to a development process that is as standardized as possible. Certainly, minimizing risk may go along with minimizing chance. Often, difficult disease areas are abandoned, even if medical need is high. An example is the development of treatments for dementia, in particular Alzheimer's disease. The lack of suitable predictive models, combined with late‐stage clinical failure of several approaches addressing amyloid and tau associated pathologies and a lack of other promising pathways, encouraged many companies to leave this area. Development of novel antibiotics is another area big pharma left some time ago. Here, the very limited successes of target‐based screening campaigns and limited commercial prospects have turned into roadblocks. When powerful new antibiotics are identified, they are saved as last resort medications. This practice obviously contradicts the blockbuster model of big pharma, which is needed to finance the large headcount of the companies. In the case of antibiotics, the patents will likely expire before the drug sees broader use. Lastly, pharmacoeconomic considerations have led to big pharma leaving established disease areas like diabetes and cardiovascular diseases. Both diseases still represent major burdens to individuals and economy. The prevalence of diabetes is extremely high in Western countries (in 2018, 34.2 million Americans – or 10.5 % of the population – and 60 million people aged 25 years and over in Europe were suffering from diabetes), and even after more than 100 years of research, treatment still is only symptomatic. Cardiovascular diseases represent the most frequent cause of mortality [123] in Western countries. However, cost pressure by more restrictive reimbursement policies in many countries and availability of generic medications reduced the potential profit margin, rendering drug discovery in these disease areas less attractive.

These trends are even accelerated by company mergers, frequently resulting in erosion of the research infrastructure in the acquired company. Also, the number of different approaches addressing a specific target decreases since the number of companies pursing this target gets smaller. This leads to a significant reduction of available and clinically tested chemical matter, which will certainly have negative consequences on the availability of future medications.

The reduced internal research activity in several big pharma companies, however, opens up great opportunities for academic drug discovery. The motivation and primary goals of academic research are fundamentally different from industrial goals. In academia, research is mainly driven by scientific interest and curiosity. There is no need to create a business case and maximize potential revenue. To the contrary, medical need of neglected diseases or niche indications is an attractive field for research at universities. Novelty, scientific innovation, and increase of knowledge are key deliverables for academic researchers, and individual laboratories strive to prove their creativity and scientific aptitude. As a consequence, standard approaches following predefined routine protocols are disfavored, as they are regarded as scientifically less valuable. Unusual and challenging projects are encouraged. Driver of projects are the individual interests of the respective principal investigators (PIs), who have frequently been working a long time in a specific area and thus have developed strong expertise on the one side but may also be able to more easily spot room for opportunity and innovation. Also, funding criteria, as defined by the NIH and other research organizations, include innovation as one of the five key factors for grant evaluation [124], making it harder to obtain public funding when pursuing approaches of incremental improvement. Time is not a key criterion, while industrial approaches follow strictly defined timelines that are required to ensure resource and budget planning, academic scientists can pursue their projects as long as they individually feel it is advisable and their curiosity and excitement persists. Of course, financial constraints apply to academics as well, as their budget normally is far more limited compared to industrial scientists, but as long as funding can be secured, consumables can be purchased, and a talented and motivated student is available, new results can be obtained. Shortfall of resources and high rejection rates at funding agencies have significant impact on prolonged discovery and development times, but as the PI can select the followed research interests autonomously, the projects may be paused but not halted. The academic research environment frequently results in long‐term project relations. For example, the cooperation of Ron Breslow and Marks or Erik De Clercq and Antonin Móly lasted for more than 30 years.

A key success factor for drug discovery is smoothly connected interdisciplinary research. In academia, a large number of potential collaboration partners with complimentary experience are available. Hurdles for setting up a collaboration are low and frequently occur by meeting at scientific conferences, recommendation of colleagues or by spotting interesting publications and reaching out to the authors. In contrast to companies, where teams are assigned based on expertise, available resources, and budget constraints, in academic settings it is frequently observed that long‐term relationships and friendship result in projects. And after all, if a collaboration does not work out, it is relatively easy to end it and search for a new cooperation partner. However, perhaps the most important point to consider is the vast number of academic research groups. Every group thrives for an individual, recognizable profile. Thus, a tremendous variety of projects and approaches is pursued. The individual activities of the research groups are quickly disseminated to the public, and these results can then stimulate other researchers working in related fields. This leads to rapid increase of knowledge and quick progress.

However, academia can also be a difficult place for drug discovery. Successful drug discovery requires access to a multitude of disciplines, specifically medicinal chemistry, in vitro and in vivo pharmacology, structural biology, and ADME to name a few. Many academic centers will not be able to provide all of this infrastructure. Furthermore, albeit timelines may be less pressing, access to resources can be very limited. Also teaching obligations, peer reviewing and grant writing consume significant amounts of time of academicians. This may lead to a lack of focus and slow down drug discovery projects or even prevent them from being successful. Also the focus on high‐impact publications and the urge to publish results quickly in order to secure further funding may be detrimental to patenting efforts and to securing intellectual property rights during the – sometimes long – optimization phase. It can be difficult for PhD students to get engaged in such kind of optimization campaigns when their future career may depend on successful publication outcome of their thesis. Even for the PI it may be challenging to maintain resources and patience with an optimization program when the first high impact publication is out and the tedious fine‐tuning begins to optimize and eventually identify a preclinical candidate. The needed persistence requires access to a suitable infrastructure and required critical resources.

The in‐depth knowledge on how molecules are successfully optimized is not regularly taught at many universities. This expertise resides mainly in industrial research units. Lack of medicinal chemistry experience and key optimization parameters frequently leads to optimization campaigns solely focusing on inhibition potency and neglecting other important parameters like metabolic stability, permeability, or solubility.

These campaigns frequently deliver mediocre hits with micromolar potency and insufficient physicochemical properties, selectivity or ADME parameters. When pursuing licensing negotiations with business development units at universities and pharmaceutical ventures, different opinions on the maturity and valuation of the project may lead to significant disappointment on both sides. While the university side may be convinced that the identified micromolar asset is just ready to go into clinical development, the pharma side may consider the obtained structure as an advanced hit or early lead, at best. This will undoubtedly complicate definition of milestones and payment terms. Here both sides have to openly interact and educate each other.

However, the previously mentioned examples demonstrate the invaluable contributions of academic medicinal chemists to drug discovery. Many new approaches have already been brought to practice. A large number of academically developed drugs is listed in the WHO list of essential drugs. Also financially, it can pay off for a university to pursue drug discovery and try to convert ideas and concepts from fundamental science into clinical practice. The reduced internal research in big pharma calls for new models, and more scientists with experience in the pharmaceutical industry are starting groups in academic settings and importing the knowledge of the drug industry into universities. Specifically, the increased demand for translational research calls for professionalized drug research at academic centers and will make drug discovery a vital and indispensable discipline at academic institutions.