Business

Dis rupti ve approac hes to acce lerate drug disco very and develop ment

part 1: tools, tec hnolo gies and t he c ore model

Tesla intends to implement and practise an ‘open source’ philosophy to its large patent portfolio and claims it would not pursue any legal action against anyone using them in good faith. This is a hard pill to swallow for the industry at-large. But, the pharmaceutical industry ought to seriously consider such an inclusive strategy to enhance the pace of and development for the benefit of humanity’s welfare.

he staggering failure rate of experimental content; Alibaba, the world’s most valuable retail - By Ibis Sánchez- drugs in clinical trials indicates that er owns no inventory; and Airbnb, the world’s Serrano, T despite huge investments in novel tech - largest hotelier, owns no real estate. Most recently, Dr Tom Pfeifer nologies, productivity gains in the pharmaceutical three large US corporations, Amazon, Berkshire and Dr Rathnam industry remain elusive. The pharmaceutical Hathaway and JPMorgan Chase, have announced Chaguturu industry is facing a serious innovation deficit. The the formation of an independent healthcare com - current biopharma model is therefore unsustain - pany for their employees in the United States to able and disruptive approaches are needed to rem - deal with the soaring cost of health insurance pre - edy the status quo. It is incumbent upon the miums and pharmaceuticals. In ‘The Evolution of biomedical research community to harness the collective intelligence of pharma, biotech, academia, governmental agencies, non-profit research foundations and patient advocacy groups “Tesla Motors was created to accelerate the advent of to accelerate innovation. Disruption – the force sustainable transport. If we clear a path to the creation that both fuels and rises out of innovation – con - of compelling electric vehicles, but then lay intellectual tinues to affect every industry on the planet, from financial services to healthcare to telecommunica - property landmines behind us to inhibit others, we are tions. For example, consider the recent break - acting in a manner contrary to that goal.” through innovation models: Uber, the world’s largest taxi company owns no vehicles; Facebook, Elon Musk, CEO and Chief Architect of Tesla Motors the world’s most popular media owner creates no

Drug Discovery World Spring 2018 39 Business

Everything: How New Ideas Emerge’ (Harper, ‘Waze’-type shared-knowledge, openly-accessible 2016), Matt Ridley provides stunning perspective innovation model to harvest data and create a on innovation, it is as compelling as controversial, crowd-sourced path towards a safer and faster as authoritative as ambitious. road to the discovery and development of life-sav - So, the question we have to ask is who actually ing medicines. Pharma ought to give serious con - drives innovation: the public or private sector? For sideration to such a game-changing concept 1. more than a half century, it has been an article of faith that basic science would not get funded if the Breakthrough innovations government did not do it, and economic growth at the drug discovery front would not happen if science did not get funded by It may seem at times that we are losing the battle the taxpayer. It may be a bitter pill to swallow, but against many of the diseases that inflict humanity; the hard truth is that government funding of basic in reality, we have made great strides. We now live science was necessary because it is cheaper to copy longer, with a life expectancy that has almost dou - than to do original research. Then, there are those bled over the last 150 years. Improvements in who think there is less need for government to nutrition, sanitation and housing, combined with fund science because industry will eventually do advancements in public health, including the use of this itself, having made innovations, it will then prophylactic vaccines and antibiotics, have eradi - pay for further innovation. cated deadly diseases that claimed millions of lives In reality, intellectual property rights through across the globe. However, with changing issued patents dampen innovation. The original lifestyles, new diseases are emerging, age-associat - rationale for granting patents was to encourage ed co-morbidities are increasing and many old dis - inventors to share their inventions, not just to eases still remain incurable. There are ~36 million reward inventors with monopoly profits. A certain deaths worldwide attributable to non-communica - amount of intellectual property law is plainly nec - ble diseases 3. essary to achieve this. But it has gone too far. Most Our knowledge of disease modalities is expand - patents are now as much about defending ing. Over the last decade researchers, primarily monopoly and deterring rivals as about sharing academia and supported by public funds, have ideas. And that discourages innovation! However identified more than one thousand new biological hard and bitter it may be, the pharmaceutical changes that could translate to new targets or industry needs to consider following the example biomarkers of disease and its progression. set by Elon Musk… for society’s sake. Genome-wide association studies have uncovered a Science drives technology, often resulting in multitude of gene variants that may be contribut - patentable inventions. Invention leads to innova - ing to complex diseases, such as schizophrenia, tion. Both scenarios are inherently and fundamen - coronary artery disease and diabetes. tally intertwined. For the betterment of humanity, Unfortunately, the translation of many of these dis - it is imperative upon us, the guardians, to see that coveries into therapeutics has not been realised. science-driven inventions ultimately lead to tech - Limitations in capacity, funding and even culture nology-based innovations 1. in an industrial setting make the selection of the While biotechnological advances, genomics and best new therapeutic targets from the overwhelm - high-throughput screenings or combinatorial and ingly-large list unlikely 3. asymmetric syntheses have long promised new vis - tas in drug discovery, the pharmaceutical industry Altruistic role for pharma is facing a serious innovation deficit. The costs of The pharma industry can help stimulate break - drug development have escalated, the number of through on the discovery front. What if pharma’s drug withdrawals has increased to historic highs in-house facilities could become available for aca - and the transition from bench to bedside has been demic entrepreneurs, small biotechs or other spin- long and arduous 2. off’s looking for ‘ready set-up’ labs and just want - There are many reasons for this unsustainable ing access to equipment and bench space, at cost? business model. Most importantly, none of the Tax breaks to the company could allow for this. pharmaceutical companies openly share the rea - Perhaps the more significant benefit is if the insti - sons for the failure of their clinical candidates in tution’s programmes being shut-down, abandoned real time to effectively navigate the ‘industry’ from or placed on the shelf could be viewed by small committing the same mistakes. It is time for the biotech and academic labs for the potential of gain - pharmaceutical industry to embrace, metaphorical - ing access in order to complement programmes/ ly-speaking, a community-driven ‘Wikipedia’ or research already on-going in their not so cutting-

40 Drug Discovery World Spring 2018 Business

edge labs. When business decisions often force cant amount of pre-clinical and often clinical pharma to shut down a mature programme, it assessment may no longer be appealing to pharma; potentially allows interested academic researchers academia, foundations and non-profits may still and small biotechs to utilise the knowledge to find value and reposition or repurpose these fallen accelerate other related programmes and could angels through their in-house programmes starved provide future benefit to pharma. One can consid - of promising candidates. This, of course, requires er this much like having an independent research that pharma does not attach strings that are ardu - group working on increasing the value of an asset ous for the development path. We propose and that was deemed to be of little value, with no cost. seek an obligatory mandate by the FDA and other Surely the possibilities exist that if 20 such project drug approval organisations for the promoting accesses were granted, perhaps one would provide company to provide the unformulated drug for returns and possibly a later stage programme of non-profit and academic uses. significant value. A simple framework for this could be as simple as non-confidential summaries Open science and data sharing that could be put in a web-based storefront. Deals The open science mantra has initiated some excite - would have to be relatively simple so as to not ment of the possibilities of gaining a better grasp on impede development of the technology or possible science/data often hidden away behind locked future business deals – perhaps with the pharma doors, or just merely left on the lab bench to decay having a time-limited first rights for negotiation and rot. The concept behind open science is not down the way. new – openly share results of pre-clinical discovery While the business case for the development of in hopes that the information will enable new ideas certain drug leads which have undergone a signifi - and concepts to emerge and push drug development

Top co nferences and work valu shops o3 e rd able insi r ghts into o 33 International Exhibition for Fine and Speciality Chemicals R&D ngoing projects! Agro chemical L ecture The Chemspe atre c Careers Pharm Clinic a Lecture Regulato Theatre ry Services Lecture Th RSC Lectu eatre re Theatre Innovative Start-ups

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Drug Discovery World Spring 2018 41 Business

forward. As it operates mostly in the pre-clinical can alleviate a syndrome. Previously we have relied space, it does not hamper drug development, but as on si/shRNA knockdown to investigate which proponents say, it will enhance it. The Montreal genes are necessary from an expression point of Neuroscience Institute (a working hospital and view with the hopes of uncovering potential targets research institute) and partners have spearheaded for our compounds. Miniaturisation of the tech - such an endeavour in neuroscience, an area which nology, utilising reverse transfection technology has seen few new drug approvals and a drastic fail - has been able to provide the interrogation of thou - ure rate, but all areas of science could benefit from sands of genes, via siRNA or CRISPR (clustered such an approach (Montreal institute going ‘open’ regularly interspaced short palindromic repeats) to accelerate science doi:10.1126/science. aae0265). technologies on a glass slide that can easily be Talking the talk is easy in this case, as everyone can viewed by high content instruments. Persomics, Inc say “we publish our results so we are open sci - (http://www.persomics.com/ ) has pursued this ence”. However, walking the walk is a bit more technology and, once it becomes validated in the challenging and will require new thoughts on how community, one could envision larger arrays cover - one really creates an open environment. Publication ing the entire genome. If the phenotypic assay is of results in a timely manner is one facet, but in run on one slide, one could quickly determine the reality, it happens only with ‘failed’ research pro - effects of RNA expression on assay readouts and jects, or when the impact has fallen off the cliff. this would perhaps lead one to be able to identify One of the biggest and perhaps most valuable pathways which would be appropriate to drug. aspects is also the inclusion and/or publication of With the advance of CRISPR technologies, this has negative results. Think about it. Each year, billions become simpler and perhaps more practical in that of dollars are provided to academic labs to pursue genes are knocked out providing a clearer picture ideas, and each year a large number of research of protein involvement in a disease. papers are published. It is, however, rare to see the research that did not work. Yet, the same experi - CRISPR ments are often carried out by other researchers, CRISPR has revolutionised the way we do discov - who would have not travelled the path and wasted ery biology. This exquisite technology comes from significant resources had they known. Negative a bacterial defence mechanism used to destroy data is good data to have, particularly as we move invading DNA. The small DNA repeats in the bac - towards an era of employing artificial intelligence terial genome producing short RNAs which recog - to enhance discovery and development. But how nise and bind to the invading DNA while bringing does one employ this in a world which only the DNA cleavage enzyme Cas9 to its location to rewards positive results through publications and cut the DNA so it becomes ineffective, while ensur - grants? One potential way would be to utilise a self- ing a copy of the short piece of invading DNA is curated Wikipedia-like contribution which has reproduced and inserted into the bacterial genome some data entry standards employed to make the to ensure ‘memory’ of this invading species. Since data easily searchable with respect to field, technol - 2013 CRISPR technology has generally replaced ogy used and results portrayed. other gene-editing/modifying systems due to its precise and efficient abilities. Examples include Outsourcing knocking out specific genes in cells and in animals, To harness the best avenues possible in the most cost- gene editing of human embryos to correct muta - effective way, pharmaceutical industry now actively tions, as well as extraction of HIV from a living pursues and outsources many of its activities, and organism thus preventing the progression of a academic partnerships have become a key element of latent . early pipeline strategies 3. When we outsource As we delve more and more into the disruption research, we risk losing serendipity and chance obser - of protein-protein complexes to create a newer vations/findings that quite often fuel innovation and generation of drugs, we need to be aware that a pave the path towards unchartered territories. For knock out (KO) of that protein may not provide this not to happen, outsourced research projects compelling proof of target validation. Quite often, must be managed actively, with an eye towards ‘neg - a KO is lethal, causing drug developers to drop the ative’ results and unexpected findings. target – unless your field is oncology. But in other fields, it is not a KO that is required but more of Phenotypic and cell-based screening an inhibition of an interaction with a neighbouring Along with comes the chal - protein that is critical to prevent the disease or out - lenge of identifying genes/proteins/compounds that come. By modulating that interaction, one could

42 Drug Discovery World Spring 2018 Business

have created a therapy. But once again the chal - doomed – hence being synthetic lethal. Finding lenge is very often protein-protein interactions and compounds that cause this effect are a potential often these surfaces do not have big pockets or source of new drugs and a new mechanism of clefts for a small molecule to bind into. The ques - action for treating cancers. If two mutations can tion is still out as to how to do this. CRISPR may work together to provide lethality, could the provide a potential answer. Recently Salk scientists reverse not also be true – synthetic health. This have adapted the CRISPR mechanism to modulate approach would seek non-related mutations which expression of genes – rather than knock them out cure the phenotypic disease or at least slow it (DOI: https://doi.org/10.1016/j.cell.2018.02.033). down. This strategy could also be used in drug They have done this by utilising a defective Cas9 combination types of approaches and creation of which cannot cleave but can still target the gene chimeric compounds. specificity by the appropriate guide RNA. Thus, there is the ability to turn genes off and on at the Death of a dogma: CDS and ORFs transcriptional level, which enables a number of In the world of big data, it is often useful to remind key experiments that drug developers have been ourselves as to how data is being analysed and ask wishing for – the ability to modulate components ourselves to go back and visit the bioinformatics’ of a protein complex without having to clone all algorithms applied and the curated data generated. the genes involved. This next round of CRISPR What was relevant and cutting edge then, may not reagents will have a profound effect on how we be so now with our ever-expanding knowledge look at altering with the abilities base. Years ago, this fault was demonstrated in the for turning genes on or off or to potentially disrupt RNA world as we became aware of siRNA’s being a translation of a portion of a protein (DOI: important in both gene regulation and mRNA sta - https://doi.org/10.1016/j.cell.2017.10.025). By bility/translation and more recently with exosomal removing specific domains of proteins, we can bet - RNA, RNA transported via exosomes to other ter learn the full potential of drugging them and cells and snoRNAs. hopefully zero in on the regions or interactions Now we see the same with proteins. In the early that are critical. days of genomics and bioinformatics, one mRNA coding sequence (CDS) was considered to be asso - Genetic modalities ciated with only one protein-coding gene. But now is often the route chosen for target identi - we know that eukaryotic mRNAs contain not a fication and validation, a result of Genome-Wide single refCDS but usually several ORFs. The single Association Studies (GWAS) linking certain genetic CDS dogma has artificially limited our view of the variants or mutations to a disease condition or coding capacity of mRNAs and has prevented the having a direct biomarker in the gene causing the discovery of alternative proteins despite some disease. While we utilise the results of genome- clues in the literature over the years. Functional wide sequencing data and incorporate gene expres - relationships between reference and alternative sion data within the rationale for pursuing drug proteins expressed from the same gene may help discovery efforts of specific pathways and proteins, identify a new layer of regulation of protein activ - the use of genetics to aid in finding a cure is often ity. Previously, the definition of a protein was clas - left behind. Compensatory mutations that can res - sically defined as a stretch of 100+ amino acids cue the original mutation is an area of genetics that with a start and stop codon, with some minor has been the focus in model organisms for quite variations. The algorithm has broadly been used some time. Its possible application to drug devel - to ‘identify’ the number of proteins in the genome opment adds another avenue to consider when of just about every organism sequenced. Of searching for a disease modifying drug. Can a drug course, variations of these parameters have been against a protein in another pathway solve/prevent made but back in the 80s, with the limited knowl - the condition caused by the original mutation? A edge available, it made sense. However, today it is similar approach has been harnessed in drug devel - becoming increasingly apparent that one has to opment for cancers – synthetic lethality, or in the closely look at our definition of a protein. dug development world, chemical lethality – as a Spearheaded out of the University of Sherbrooke means of selectively destroying cancer cells. In this by the Roucou lab ( www.roucoulab.com ), the case the cancer cells have a mutation which in part Alt-Prot analysis of the genome has lowered the is responsible for their phenotype. When this muta - requirement of a protein to 30 amino acids. tion is combined with another mutation (which The protein coding potential of eukaryotic also by itself has no effect on the cell) the cell is mRNAs has surely been underestimated (see

Drug Discovery World Spring 2018 43 Business

Figure 1 The proteasome, nuclear factor- KB 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- KB (NF- KB) to the inhibitor protein IKB in the cytoplasm renders NF- KB inactive. Cellular stimuli, such as cytokines, antigens, oxidants, viruses and other agents, trigger a cascade of signal transduction events that phosphorylate and ubiquitinate I KB, leading to its degradation by the proteasome, which in turn liberates NF- KB for translocation into the nucleus. Once in the nucleus, NF- KB 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- KB (orange www.Openprot.org ). It has already demonstrated screening for the right potency, selectivity and crosses) and subsequent events that can promote that another body of knowledge around possible ‘humanised’ lead. In the past few years, the idea tumour cell survival and targets for drug discovery is becoming relevant has emerged to begin with fully human, not mouse, proliferation. and will provide a treasure trove of knowledge for antibodies as the starting point to alleviate some of Source: Sánchez-Serrano, I. future drug discovery scientists to think about and the challenges of developing drug candidates. Success in Translational Research: perhaps revisit fallen programmes where ‘knock - Much like the chemists have defined useful back - Lessons from the Development of Bortezomib. Nature Reviews out’ data confirmed an interaction but drugging bones for compound drug development, biologists Drug Discovery, 5 (2):107-14 the ‘protein’ never provided the anticipated have now defined a number of scaffolds based on (2006) results. Lots of rationale of why the drug may not those that have been in Phase I and combined that have worked, but perhaps the wrong protein was with V-regions and alleles that are shared by all drugged. What if it was an alt-protein responsible human populations. Along with selecting specific for the effect? CDR regions and creating a diversity of 76 billion Abs allows for quick selection of mAbs with high Biologicals specificity and good clinical perspective. This ‘Bio Monoclonal antibodies are the hot topic of pharma Superhuman library 2.0’ – a synthetic monoclonal industry as these drug approvals are picking up Ab library – claims to reduce monoclonal lead dis - and the ability to utilise them in CAR-T and other covery and development to about two months technologies is gaining momentum. The roots of (https://www.distributedbio.com ). creating and selecting these monoclonals has diverse streams, however; the common one from The phoenix: core model approach to academia is the creation of a mouse mAb utilising drug discovery and development hybridoma methodology as a starting point. While Given the crucial importance of the pharmaceuti - this has produced great tools for biology and cal industry in the world’s healthcare systems 4-6 , it sometimes is the starting point for development of is very surprising that little attention has been paid a humanised version for drug development, we to the understanding of the ways in which the now realise that this is a tricky and complicated pharmaceutical industry has succeeded in bringing development path involving time-consuming remarkable novel drugs to the market in its

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approximately 150 years of history and to whether (iv) Change of the original company’s business there is a paradigm that could explain how the model (from cachexia to inflammation to cancer) public-private sector interaction has both driven and subsequent change of the firm’s name – from the growth of this industry and brought economic, Myogenics to ProScript. social and healthcare benefits for society. (v) Enormously-disruptive drop by Hoechst Back in 2004, one of the authors (Ibis Sanchez- Marion Roussel of proteasome inhibitors for Serrano) was investigating the multiple factors inflammation and cancer and its return of its that could account for the success and failure of license rights on the drug to ProScript. biotechnology firms in the United States and (vi) Change in leadership. Europe. Some of the variables involved in this (vii) Depletion of initial funding and inability to analysis – -eventually published in 2006 in secure further funding for clinical trials. Nature Reviews Drug Discovery 7 – were the rela - (viii) The general lack of interest and total disbelief tionship between early-stage biotechnology firms of the biopharmaceutical industry on bortezomib. and their parental academic organisations and (ix) The resulting merging of ProScript into other academic institutions; the collaborations Cambridge-based LeukoSite and, six months later, that these firms established with pharmaceutical purchase of LeukoSite by Millennium Pharmaceu- companies and private investors; the role of fed - ticals. eral-funding agencies in the translational process In spite of all these major obstacles, that would between academia-industry/private-public sector; have quickly destroyed any company or drug the support that early stage firms received from development programme, bortezomib managed philanthropic organisations and advocacy not only to make it to the market, but to do so in groups; and considerations of the impact of secre - record time and at a significantly lower cost than cy and intellectual property (IP), as described by the biopharmaceutical industry’s average. the ‘Tragedy of the Anticommons’, a type of para - Why did bortezomib – which was doomed to doxical setting, in which too many separate failure from the beginning – became a success story rights-holders of a single resource can block each unlike other countless well-funded examples in the other’s use of that resource 8. industry? How did it manage to reach the market In studying the story-case of many successful in record time? and failed biotechnology companies throughout the world, the story-case of the development of The Core Model bortezomib for the treatment of multiple myeolo - Without knowing or planning it, ma by the Cambridge (US)-based biotechnology Myogenics/ProScript used an organisational company Myogenics/ProScript (later acquired by model, coined ‘The Core Model’ ( Figure 2 ), Millennium Pharmaceuticals), seemed both highly grounded on the ‘trade of assets’ (exchange of per - unusual and a quintessential example of what it sonal connections, knowledge, materials, animal takes to develop a drug in the biotechnological models, etc) between academia and industry, field. between the public and private sectors, in a very On May 13, 2003, the FDA-approved Velcade systematic and effective way to advance scientific (bortezomib), a proteasome inhibitor ( Figure 1 ), research. According to this model, the company’s under ‘Fast-Track’ Application for the treatment of ‘Core’, formed by the founders, internal people multiple myeloma, an incurable cancer of the and resources and the drug ‘champions’, were very blood that affects approximately 14,000 patients focused on demonstrating the revolutionary thera - in the US annually. The story behind the develop - peutic application of using proteasome inhibitors – ment of this drug is quite unique and remarkable and in this specific case, of boronates – based for many reasons, including: exclusively on the scientific data available and fol - (i) The initial fragile funding base of the original lowing the biology at every turn. From the begin - company that discovered and developed it ning, the ‘Core’ realised that, given its extremely (Myogenics/ProScript). low economic and technological resources, they (ii) The risks involved in pursuing a new molecular needed to acquire more knowledge about the target (the proteasome) with a new and ill-reputed effects of inhibiting the proteasome in vivo , and class of inhibitor (boronates). this could only be accomplished via collaboration (iii) Internal struggles and disagreements in the and bi-directional interaction with academia and firm between the academic founders and the man - with external, non-competing scientists interested agement regarding the indication for which the in similar mechanisms or problems. These external drug was to be developed. collaborators were crucial in securing, in many

Drug Discovery World Spring 2018 45 Business

A B

Figure 2: The Core Model A This model has three major elements: the ‘core’, the ‘bridge’ and the ‘periphery’. In a biotechnology start-up company, the core represents the company’s internal resources and people who are hired because they have assets that are directly related to the core’s objective – making drugs. The core needs a strong leader who is capable of keeping the enterprise focused and is able to secure collaboration with external people. The ideas of the core are protected by patenting and secrecy. The bridge represents the immediate collaborators of the core and the private institutions to which the core has indirect access through the external collaborators. The bridge contains external scientists interested in similar problems or whose research would be enriched as a result of the collaboration. It also includes consultants and Scientific Advisory Board (SAB) members (non-founders) working in exclusive and non-exclusive ways. The periphery contains the institutions/agencies interested in what the core has to offer for the benefit of society, as well as the funding and regulatory structures that support the core and the bridge. The periphery is an open, public and co-operative system. The goal of the core is to absorb efficiently and legally as much relevant knowledge and information as possible from its surroundings in three ways: via the leverage of the assets, professional backgrounds and connections of the people within the core; via the assets, connections and expertise of the external collaborators within the bridge; and via the support, relevant public knowledge and know-how within the periphery. B Illustration of the roles of selected people involved in the development of bortezomib using the core model. Source: Sánchez-Serrano, I. Success in Translational Research: Lessons from the Development of Bortezomib. Nature Reviews Drug Discovery, 5 (2):107-14 (2006)

different ways, further knowledge relevant to a oration established with external people to better understanding of the biological mechanisms exchange assets), knowledge integration (incorpo - associated to the proteasome and its inhibitors ration and assimilation of external assets) and while providing animal models and validation. knowledge translation (the conversion of all, inter - They actually allowed the company to save an nal and external, assets into a commercial thera - enormous amount of time, human capital, infras - peutic product). tructure and money, and fundamentally acted as a Myogenics/ProScript carried out collaboration ‘Bridge’ or ‘catalyst’ between the ‘Core’ and the with outside groups exceptionally well, as ‘Periphery’ – that is, all those public resources explained by the Core Model, and so particularly available in society to sponsor and foster innova - benefited from these collaborations at crucial tion with the objective of creating economic and points, both when the company needed scientific healthcare benefits for its members. The knowledge to move forward and when it lacked ‘Periphery’ includes federally-funded agencies, the necessary economic resources. Even though advocacy groups, philanthropic organisations, today some companies form collaborations in their consortia, regulators and all those organisations programmes, these collaborations are more oppor - interested in the well-being of society. In summary, tunistic than planned. More importantly, there is ProScript developed bortezomib through a ‘Core’ little understanding, in all the collaborative sides, modus operandi using knowledge transfer (collab - of the dynamics and benefits of such collaborations

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within a major, logical framework or paradigm ‘Core’” (in this case academic inventors and rooted in basic economic principles. As a result, Hoechst), the ‘Bridge’ (other academic scientists collaborations are underexploited and the entire working in related problems), and the ‘Periphery’ process of drug discovery and development, the (public hospitals, the German government and business of science, and the public policies that reg - other not-for profit organisations). Other German ulate and fund basic, applied and translational sci - firms (such as Merck & Co, Afga and Bayer), the ence remain sub-optimal or deficient, bringing major Swiss firms (Ciba, Hoffmann-La Roche, severe penalties on the economy and the global sys - Sandoz) and European and American firms fol - tems of healthcare. lowed a similar pattern in the second half of the Furthermore, in spite of the realisation that col - 19th century, cementing the great success of the laboration is essential for the progress of science, pharmaceutical industry ever since. In the 20th there is still a great deal of secrecy, misunderstand - century, medicines such as penicillin (first pro - ing, and misuse of intellectual property, hindering duced in a mass-scale by Merck & Co in the collaborative efforts. Of course, secrecy and pro - United States), insulin (commercially released by tection of intellectual property are necessary in the Eli Lilly), the first sulphonamide, Prontosil (Bayer) business of science (or are they?), but the attitude and antibiotics, in general, were also developed in toward it has become obsessive and paranoiac the same fashion. Late in the 20th century, the resulting in many useless patents that do nothing birth of the biotechnology industry and the devel - but block scientific progress in related areas. All of opment of the first biotechnology drugs can be this adds to the economic burden of developing explained by the Core Model, with a close and new drugs. systematic collaboration between academia, industry, investors, government agencies and phi - ‘Old-school pharma’ lanthropic organisations/advocacy groups, via and the Core Model knowledge transfer, integration and translation. In examining the Core Model further and the his - tory of the biopharmaceutical industry, it becomes The bio-pharmaceutical clear that this model is not only a paradigm for the industry challenges today development of present-day biotechnology drugs One of the greatest challenges that the bio-pharma - (it also solves the ‘Paradox of the Anticommons’), ceutical industry has to face today is the high cost but actually a universal model that has been in use of research and development (R&D) 1. According to great effect in the development of drugs since to recent estimates by the Tufts Center for the the beginning of the pharmaceutical industry. Study of Drug Discovery and Development Though it is impossible to discuss here in detail (TCSDD), it takes, on average, more than $2.558 the abundant specific cases of drugs that were suc - billion (pre-tax, 2013 dollars) and 10-15 years to cessfully-developed in this fashion (see references develop a new drug 9. Although these exact figures 1-3 for the history of drug discovery and develop - are controversial – and we should bear in mind ment), several examples of drugs and companies that the actual expenditure depends on the drug that benefited from this approach need to be and whether it is developed by a pharmaceutical or noted. For instance, the success of the German a biotech company – it is a fact that drug discovery chemical and pharmaceutical company Hoechst and development is a very complex, difficult, lay in its ability to secure strong ties with unpredictable, risky and capital/labour-intensive academia and academic scientists, such as Robert endeavour. Furthermore, over the last years the Koch (and later with Clemens von Pirquet and amount of money invested in this field has dramat - Koch’s student Arnold von Libbertz) for the devel - ically increased while the number of new chemical opment of tuberculin as a testing agent for tuber - entities (NCEs) brought to the market has lagged culosis; with Emil von Behring, who discovered behind. This situation calls for a careful examina - the diphtheria antitoxin and developed a serum tion of the reasons accounting for the increase of therapy against diphtheria (together with Emile overall R&D cost as well as for novel ways to opti - Roux) and tetanus; and, among many others, with mise the process. Paul Ehrlich, who postulated the theory of recep - Pharmaceutical drugs form an essential compo - tors, coined the term chemotherapy, found a cure nent of the global healthcare system. They are for syphilis (Salvarsan), and carried out impressive needed even for preventive-prophylactic pro - studies on autoimmunity. The development of grammes. But the high price of innovative drugs these agents in a commercial manner was the and the lack of drugs in some important and spe - direct result of close collaboration between the cific disease areas is perhaps the greatest challenge

Drug Discovery World Spring 2018 47 Business

Table 1: The most expensive specialty drugs (2017)

Source: Drugs.com; https://www.drugs.com/slideshow/top-10-most-expensive-drugs-1274; October, 2017

DRUG NAME COMPANY INDICATION PRICE/Year Glybera (alipogene uniQure Lipoprotein lipase $1.2 million tiparvovec) deficiency Ravicti (glycerol Horizon Pharma Cycle Disorder $793,000 phenylbutyrate) Brineura (cerliponase BioMarin Late infantile neuronal alfa) Pharmaceutical ceroid lipofuscinosis type $700,000 2 (CLN2) disease, a form of Batten disease Carbaglu (carglumic Orphan Europe N-acetylglutamate $419,000 - acid) synthase deficiency $790,000 Lumizyme Genzyme Pompe disease. $524,000 - (alglucosidase alfa) $626,000 Actimmune Horizon Life-threatening $244,000 - (interferon gamma- osteopetrosis $572,000 1b) Soliris (eculizumab) Alexion Hemolytic uremic $432,000 - syndrome (aHUS)/ $542,000 paroxysmal nocturnal

hemoglobinuria (PNH) Folotyn (pralatrexate) Allos Therapeutics Relapsed or refractory $96,000 - peripheral T-cell $472,000 lymphoma (PTCL) Demser, (metyrosine) Valeant Pheochromocytoma $96,000 - Pharmaceuticals $472,000 Ilaris (canakinumab) Novartis Periodic Fever $379,000 - Syndromes; Active $462,000 Systemic Juvenile Idiopathic Arthritis

for these systems 4. As our understanding of dis - ways to develop drugs. Unfortunately, achieving eases has become more sophisticated and as dis - this goal is becoming more challenging every day eases have, in some cases, become more complex given the increasing complexity of the process, the and difficult to treat due to the combined influ - higher regulatory hurdles for drug approval, and ences of unhealthy lifestyles, changing global envi - the larger amount of information that needs to be ronmental conditions and demographics, and con - taken into consideration and evaluated during the stant exposure to harmful chemicals and infectious entire undertaking. agents; and as important variables among the In our consumerist and pharmaco-dependent human population which affect both the nature society, it is expected and demanded to have access and the experience of disease, such as gender-speci - to the best possible drugs with the lowest number ficity, ethnicity, age, among others, are taken into of side-effects. However, like consumer goods, peo - consideration for drug discovery and development, ple get what they pay for. So, it is not surprising there is an ever greater need to find more effective that access to the best drugs (for which more

48 Drug Discovery World Spring 2018 Business

investment, capital and otherwise, have been need - metabolomics, Big data, etc, have all represented a ed) will require the payment of a premium. This, in mine of information that will facilitate a better fact, is becoming a novel trend in the industry (see understanding of how the cell and living organisms Table 1 for a list of recently-developed drugs with work. This will eventually have a great positive staggering prices). Since the actual cost of specific impact in finding better treatments and cures for drugs is not disclosed by biopharmaceutical com - disease. However, handling all this information all panies, nowadays it is difficult for the consumer to at once today has made the biopharmaceutical know which drugs required more investment than industry situation even more complicated. So, others, as drugs are being priced according to there is not really clarity about which models, both whatever the market can bear. Unfortunately, this at the R&D and business levels, the biopharmaceu - strategy and all the marketing expenses involved in tical industry will pursue in the years to come. selling new drugs are unsustainable both for the Thus, we are at a very crucial point in which, pharmaceutical industry as well as for the health - more than ever, it is necessary to align pharmaceu - care systems. Therefore, it is no wonder that we tical innovation with global healthcare policies for are facing a world’s healthcare crisis 4. the benefit of patients and the survival of the To compound the problem over the last few world’s healthcare systems. But how do we deal years the bio-pharmaceutical industry has needed with these challenges? to deal with several important issues such as the massive patent expiration of some of its best-sell - Benefits of the Core Model and its ing drugs, lower productivity output, deficient approaches today pipelines, pressure from investors, litigation issues Understanding the Core Model – which brings to a regarding the safety of drugs or related to intellec - convergence point all the elements necessary for tual property, more stringent regulatory require - successful drug discovery and development – and ments, etc. Given this situation, the pharmaceutical understanding the nature and contribution of each industry has implemented a wide range of strate - one of its constituents (see Table 2 ) could be of gies to contain costs and maximise profits, such as great assistance to the biopharmaceutical industry massive layoffs, R&D cuts, divestitures, mergers in the creation of better strategies to improve drug and acquisitions (M&A), patent ever-greening, discovery development and serve as a guide to gov - increment in the number of clinical trials, expan - ernments to formulate and implement better phar - sion of indications, pursue of niche markets, price maceutical, innovation and healthcare policies. It increase, reorganisation, etc. Even biotech compa - could help governments, investors and philan - nies have followed a similar pattern in order to sur - thropic organisations/advocacy groups on how to vive, as recently demonstrated by Celgene and its allocate and deploy funding and economic acquisition of Impact Biomedicines 12 . In fact, the resources in an optimal way. sale of early stage biotech firms to big pharma At present, the Periphery of the Core Model is right after proof-of-concept in humans or at the becoming more dynamic than ever. For instance, end of Phase II clinical trials has become both fash - patient groups as well as health systems, which are ionable and profitable. In most of these cases partners of the pharmaceutical industry in clinical biotech companies have become the R&D arm of trials, are now playing an active role beyond advo - big pharma, while big pharma have become pow - cacy, including actual financing of drug develop - erhouses for clinical trials and marketing. The ment, especially in rare diseases. This was the case, large size of most pharma companies, which has for instance, with the Cystic Fibrosis Foundation come as a result of the heavy M&A activity that financing Kalydeco with Vertex, and thus bypass - we have experienced in the last decade, has created ing big pharma. Patient opinion leaders and online additional layers of management and dramatic communities are now collaborating in clinical tri - changes in the dynamic of these organisations, als and conducting their own observational stud - which have made it more difficult for them to be ies, as in the case of PatientsLikeMe and its managed, to be efficient and to be focused on pro - 600,000 members. The importance of patient- ductive R&D. reported outcomes in collecting real-world evi - From a scientific perspective, the information dence is covered in several policy journals, such as provided by the sequencing of the human genome, Health Affairs and Value in Health. These initia - higher sophistication of experimental models in tives are becoming a novel and important model animals and in humans, new genetic engineering for improving drug development. techniques (such as CRISPR, among others), the Frustration with the biopharmaceutical compa - advent of proteomics, systems biology, nies’ high pricing of drugs, sudden increase in

Drug Discovery World Spring 2018 49 Business

Table 2: Selected summary of assets of the constituents of the Core Model References 1 Roy, A, Patwardhan, B, Chaguturu, R. Reigniting ATTRIBUTE ASSET pharmaceutical innovation through holistic drug targeting. Highly sophisticated ideas, narrow and focused objectives, Drug Discovery World. 45-55 revolutionary technologies, enthusiastic and highly qualified (2016, Summer). 2 staff, connections with colleagues and outside institutions, Chorgade, M, Liebman, M, Core Lushington, G, Naylor, S and effective leadership, economic incentives, concentration on Chaguturu, R. Translational chemical biology: Gap productivity, dynamism, flexibility, etc. assessment for advancing drug discovery, development and Personal connections (academia, biotech, pharma, hospitals, precision medicine. Drug regulators, investors, philanthropic organizations, etc.), tests

Discovery World. 72-90 and animal models, clinical trials and funding for clinical (2016/2017, Winter). 3 Palmer, M and Chaguturu, R. trials, tissue banks, new/complementary technologies, Expert Opin Drug Discov. reagents, new approaches and paths to drug discovery and 12(6):537-540 (2017). development, new perspectives to improvement, “free” or low 4 Sánchez-Serrano, I. The World’s Health Care Crisis: Bridge cost labor force (via collaboration), scientific knowledge, From the Laboratory Bench to problem solving, technological facilities (e.g. mice facilities), the Patient’s Bedside. Elsevier. special software, cell lines, advice, translational studies. All of ISBN 978-0123918758 (2016). this leads to savings time, money, and effort. It increases 5 Weatherall, M. In Search of a Cure: A History of knowledge and data that most of the time lead to important Pharmaceutical Discovery. publications. Oxford University Press. ISBN 978-0192617477 (1991). Funding, infrastructure, promotion, lobbying, recruitment of 6 Chandler, AD. Shaping the patients for clinical trials , “free” labor , equipment, positive Industrial Century: The Periphery Remarkable Story of the public image, knowledge, data, know -how, technology, tips Evolution of the Modern by regulators to correct wrong paths, guidance on how to be Chemical and Pharmaceutical efficient, translational science, saving time and money while Industries (Harvard Studies in Business History). Harvard guiding the Core on how to succe ed. University Press. ISBN 978- 0674017207 (2004). 7 Sánchez-Serrano, I. Nature Reviews Drug Discovery, 5 pricing of old, off-patent drugs such as the heart Partnerships Initiative (launched in 2012) to foster (2):107-14 (2006). 8 Heller, MA. Harvard Law medicine Nitropress, and shortages of essential collaboration between pharmaceutical companies Review, 111 (3): 621-88 (1998). medicines, such as morphine, as well as by the and the biomedical research community to 9 DiMasi, JA, Grabowski, HG, manipulation of the market by investors, has led advance therapeutics development as part of the Hansen, RW. Journal of Health a group of large hospital systems in the US 10 , NIH New Therapeutics Use Program. The objec - Economics, 47 (5):20-33 (2016). spearheaded by Intermountain Healthcare, and tive of this initiative is to match researchers with a 10 Abelson, R and Thomas, K. Fed Up With Drug Companies, involving Ascension – a Catholic system that is selection of ‘pharmaceutical assets’ to help the sci - Hospitals Decide to Start the nation’s largest non-profit hospital group – entists test ideas for new therapeutic uses 12 . The Their Own. The New York and very possibly the Department of Veteran second is Partnership for Accelerating Cancer Times, 18 January, 2018. Affairs, to the bold decision of creating a not-for- Therapies (PACT), a $215 million public-private https://www.nytimes.com/2018 profit organisation to create generic drugs to bat - partnership with 11 pharmaceutical companies /01/18/health/drug-prices- hospitals.html. tle shortages and high-prices in hospitals. In over a five-year agreement to advance research in 11 Wingfield, N, Thomas, K another bold movement, three large US corpora - new immunotherapy treatments that equip the and Abelson, R. Amazon, tions, Amazon, Berkshire Hathaway and immune system to attack cancer via the identifica - Berkshire Hathaway and JPMorgan Chase, have announced the formation tion, development and validation of biomarkers. JPMorgan Team Up to Try to of an independent health care company for their This initiative not only involves the partners just Disrupt Health Care. The New York Times, 30 January, 2018. employees in the United States to deal with the mentioned, but also the NIH Foundation, impor - https://www.nytimes.com/2018 soaring cost of health insurance premiums and tant academic research centres in the US, the Food /01/30/technology/amazon- pharmaceuticals 11 . and Drug Administration (FDA), Pharmaceutical berkshire-hathaway-jpmorgan- Two other important initiatives adopting the Research and Manufacturers Association health-care.html. Core Model are, firstly, the NIH-National Center (PhRMA) and the Department of Health and Continued on page 52 for Advancing Translational Sciences’ Industry Human Services, among others 13 .

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Continued from page 50 All these examples attest to the flexibility of the Acknowledgements Core Model and its universality. Today, when the We thank our many colleagues who have influenced 12 National Center for bio-pharmaceutical industry does not know where us in innumerable ways over the years and for being Advancing Translational it is going, and with the extraordinary necessity of the beneficiary of their collective wisdom. DDW Science. About New Therapeutic Uses. coming up with more efficient ways to produce https://ncats.nih.gov/ntu/about. new drugs – given the extraordinarily big impact 13 National Institutes of that the high price of novel drugs has in the global Health (NIH). NIH partners healthcare systems and in some countries’ econo - with 11 leading my – it is extremely important to review the Core biopharmaceutical companies to accelerate the development Model paradigm and adapt it according to specific of new cancer immunotherapy circumstances. strategies for more patients. Press Release, 12 October, Concluding remarks 2017. https://www.nih.gov/ Despite considerable technological advances, the news-events/news- releases/nih-partners-11- pharmaceutical industry is experiencing a severe Ibis Sánchez-Serrano is the President of the Core leading-biopharmaceutical- innovation deficit, especially in the discovery of Model Corporation (CMC), focused on global companies-accelerate- new drugs. We have tried here to initiate discussion healthcare and biopharmaceutical innovation and development-new-cancer- about the complexities that face drug discovery translational science policy. He holds a Masters in immunotherapy-strategies- and development beyond their current horizons. International Business Relations and Technology more-patients. Indeed, older methodologies that have for years Management from the Tufts Fletcher School of been the basis of scientific discovery need to be Law and Diplomacy in collaboration with Suggested reading reviewed to determine if all the hypotheses they Harvard University and MIT’s Sloan School of Ridley, M. The Evolution of were built on are still valid. We propose innovative Management. He is based in Boston, Everything: how new ideas network science that addresses the general need for Massachusetts, USA and Panama City, Panamá, emerge. Harper, New York, 2016. improved applications in the discovery and devel - where he is very much involved in community Chaguturu, R. Ed. Collaborative opment of drugs. development and educational activities. Innovation in Drug Discovery: The ‘Core Model’, an economic and organisa - strategies for public and tional paradigm for drug discovery and develop - Dr Tom Pfeifer is the head of screening at the private partnerships. Wiley, ment, is elucidated through the story-case of the Centre for Drug Research and Development New York, 2014. Patwardhan, B and Chaguturu, development of the anticancer drug bortezomib. (CDRD, Canada’s national drug development and R. Eds. Innovative Approaches Some of the remarkable progress that has taken commercialisation engine). He is also the lead of in Drug Discovery: place is illustrated in the ‘Periphery’ (a constituent CDRD’s Neuroscience Task Force. He is currently Ethnopharmacology, systems of the model) and its ever-increasing active role in a member of the Board of Directors, International biology and holistic targeting. the financing of drug discovery and development Chemical Biology Society. He received his PhD Academic Press, New York, 2017. efforts to treat important diseases and in the col - from the University of Saskatchewan in molecular Sánchez-Serrano, I. The World’s lecting of crucial real-world data for clinical devel - biology. Health Care Crisis: from the opment. In the current pharmaceutical and health - laboratory bench to the care scenarios, drug leads that may otherwise lan - Dr Rathnam Chaguturu is the Innovation Czar, patient’s bedside. Elsevier, New guish in the laboratory could fully capitalise on the Founder & CEO of iDDPartners (Princeton York, 2016. Gassmann, O and use of ‘Core Model’ approaches to make it to the Junction, NJ, USA), a non-profit think-tank Schuhmacher, S. Leading patient, saving time, labour and capital. focused on pharmaceutical innovation. Most Pharmaceutical Innovation: In summary, the survival of the pharmaceutical recently, Deputy Site Head, Center for Advanced how to win the life science industry and of the world’s healthcare systems will Drug Research, SRI International, he is the race, Wiley, New York, 2018. ultimately depend on innovation, on a better Founding President of the International Chemical Gulfo, J. Innovation Breakdown: How the FDA and understanding of disease, on the efficient develop - Biology Society, a Founding Member of the Society Wall Street Cripple Medical ment of novel drugs and on preventive measures for Biomolecular Sciences and Editor-in-Chief- Advances, Post Hill Press, New coupled to an efficient use of our limited societal Emeritus of the journal, Combinatorial Chemistry York, 2017. resources. and High Throughput Screening . Rathnam pas - Moos, W and Miller, S. Imagine a world free of diseases. What a won - sionately advocates the need for innovation and Managing the Drug Discovery Process: how to make it more derful thought and sight. A pinnacle of unimagin - the virtues of collaborative partnerships in address - efficient and cost effective. able human achievement, a defining hallmark of ing pharmaceutical innovation crisis, and aggres - Woodhead Publishing, excellence in human endeavour and a lofty goal sively warns the threat of scientific misconduct in Cambridge, 2016. from times immemorial, but NOT yet achieved. biomedical sciences. He received his PhD with an The utopian thought is nowhere near our distant award-winning thesis from Sri Venkateswara sight. Or, is it ever achievable? That’s the question. University, Tirupati, India.

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