Novel drugs are not hiding in corners,waiting to be discovered. They areinvented by scientists trained to identify

which molecules are most likely to be potent andefficacious using medicinal chemistry and a rangeof in vitro and in vivo assays.

These early drug discovery efforts used to begenerally confined to the early stage research divi-sions of Big Pharma, hallowed grounds whereteams of in-house scientists identified promisingdrug targets and then determined if modulatingthem would have a therapeutic effect. A goodexample of this conventional approach can befound in the field of HIV/AIDS, where the discov-ery of protease inhibitors more than two decadesago ushered in the era of highly-effective antiretro-viral therapy.

But today, pharmaceutical companies are moreapt to share the reins of this high-risk, high-rewards ride. Most pharmaceutical companieshave set up a network of collaborations with aca-demic labs and small companies, but also with con-tract research organisations (CROs), an industrythat historically has operated in the well-choreo-

graphed arenas of clinical and pre-clinical testingusually on a contract-by-contract basis, to supple-ment in house capabilities. Biopharmaceuticalcompanies have been strategically using CROs fortargeted segments of their discovery work to com-plement and augment internal capabilities, withsome collaborations, including the one formed byGenentech and Argenta (acquired by Charles RiverLabs last year and now part of its DiscoveryServices Division), stretching back 10 years ormore. Outsourced discovery services run the gamut– from medicinal chemistry, in vitro and in vivobiology, structural biology and computer-aideddrug design that can identify a promising candidate– to process chemistry for scale up of promisingcandidates. If successful, the outcome is the identi-fication of a compound that is druggable enough toadvance to preclinical development, including pre-clinical toxicology studies – another activity that isfrequently outsourced by biopharmaceutical com-panies to CROs.

This work is, technologically speaking, lessempirical than the bench science that brought usdrugs decades ago. Indeed, most drug discovery

By Dr John Montanaand Cornelis E.C.A. Hop

Reprinted from Drug Discovery World Summer 2015

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BROTHERS IN ARMS:BioPharma and CROscollaborating in earlydrug discoveryBioPharma and CROs are riding the latest wave – discovery research –together with a vigour and gusto that might have seemed implausible five yearsago. How these collaborations are structured, and how well they function, canvary widely, though.

efforts begin with a list of desirable attributes – atarget candidate profile – and a range of in vitroassays, arranged in an efficient screening cascade,to help identify leads. Yet the odds of finding ablockbuster is as steep as ever, in part because thetargets developers are seeking are harder to crack,and once cracked, the likelihood of target modula-tion resulting in the desired clinical efficacy issmall.

So some CROs have taken a soup-to-nutsapproach, creating integrated teams of industry-experienced scientists in all aspects of drug discov-ery that work synergistically to solve multi-factori-al scientific issues for its partners in the pharma-ceutical and biotechnology industry. The integrat-ed services range from target identification and val-idation and the design and characterisation of mol-ecules that interact with such targets, through scaleup and preclinical toxicology testing. The chem-istry services, in particular, can include everythingfrom the synthesis of reference compounds andlibraries, through the design of compounds that arespecific for the target of interest and on throughlead optimisation to deliver quality developmentcandidates.

The key reasons behind these collaborations arewell-documented. Everyone is familiar with howlong it takes to get a drug to market (10-15 years),and how risky the stakes are. Figures cited by thePharmaceutical Research and Manufacturers of

America (PhRMA) suggest that for every 5,000 to10,000 compounds that enter the pipeline, onlyone receives approval1. Even medicines that reachclinical trials have only a 7-15% chance of beingapproved2,3, in large part because it has been sohard to translate promising preclinical findings toefficacy in patients4.

Frequently, drugs fail in preclinical toxicologytests or are unsuccessful in clinical trials due tolack of efficacy or unforeseen adverse events. So ifa CRO is able to demonstrate even minor improve-ments in the lead optimisation process, it couldsave time and money and help improve future busi-ness opportunities for its partners. These days, anadditional and equally important reason for bio-pharmaceutical companies to engage CROs is tosupplement limited in-house resources and thedesire to keep their infrastructure lean.

The costs of drug development are also astro-nomical. One widely-cited figure last year from theTufts Center for the Study of Drug Development inCambridge suggests that it will cost as much as$2.6 billion to develop and win marketingapproval for a single new prescription drug5. Eventhe more conservative figures that have been citedhover around $1 billion.

Between the steep costs, long development time-lines and competitive environment, it is under-standable why pharmaceutical and biotech compa-nies desire more innovative and flexible models to

Reprinted from Drug Discovery World Summer 2015

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Reprinted from Drug Discovery World Summer 2015

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make the discovery process faster and more effi-cient, and they have turned to CROs to meet thesegoals. For their part, CROs that specialise in earlydrug discovery are eager to gain a strongerfoothold in this decidedly less staccato section ofdrug development. The ranks of CROs are filledwith scientists that began their careers at BigPharma and, in the area of chemistry at least,employ more researchers today than many bio-pharmaceutical companies. A recent study by thebusiness analyst Visiongain predicts that drug dis-covery outsourcing will reach $16.6 billion thisyear, with an increasing trend for pharmaceuticaland biotech companies to form alliances and col-laborations with CROs during the early drug dis-covery phase6.

Integrating the scienceSo how are these collaborations structured andhow do they, well, collaborate?

The partnership between Genentech andArgenta began in 2005 with a single project tryingto identify suitable inhibitors of the kinase targetMEK, an important link in a chain of proteins thatdial up tumour cell proliferation and survival.Around six to eight Argenta medicinal chemistsspent three years working with its Genentech col-leagues to progress early hits all the way throughto a development candidate.

From those relatively small beginnings the col-laboration expanded, adding multiple projects –largely in the realm of oncology and immunology– and drawing on the extensive expertise of dozensof chemists and biologists as well as scientists rep-resenting drug metabolism and pharmacokinetics,pharmaceutical sciences and structural biology.These partners now provide a lot of the innovationwithin projects while more mundane activities areoutsourced to other CROs. The collaboration hasworked on nearly a dozen targets, including JAK,a driver in autoimmunity, and EGFR, which isresponsible for the growth and progression oftumour cells and is the target of Genentech’s lungcancer therapy Tarceva.

How the collaboration is structured and how itfunctions can be illustrated by the retinoic acidreceptor-related orphan receptor or ROR project.The science behind this endeavour hinged onRORs, in particular RORc, which helps drive thedifferentiation and function of certain pathogenicimmune cells and tumour cells produced by theprotein IL-17.

The RORs are relatively new members of thenuclear hormone receptor family (others includethe hormone estradiol) that help regulate gene

expression. RORs are somewhat of a mystery, andtheir biology has not yet been fully elucidated. Butdiscoveries made by other groups linking mono-clonal antibodies that target IL-17 with effectivetreatments for autoimmune disorders, mostnotably Novartis’ recently-approved psoriasisdrug secukinumab, created a buzz in the field.There is now considerable interest among a num-ber of different biopharmaceutical companies inadvancing RORc modulation to the next level,with a new piece in the biology of the RORc jig-saw being the identification of small moleculeinhibitors of RORc against autoimmune diseasesthat was the focus of a collaboration betweenGenentech and Argenta7.

To study RORc, Genentech generated crystalstructures of the receptors and then transferred thetechnology and all the structural biology toArgenta, which enabled structure-based design.Argenta provided substantial drug design input,medicinal chemistry, in vitro biology and structur-al biology support, and took the lead in optimisingone of the two chemical series that had promisingactivity against the biological target. Genentechtook the lead with the other chemical series, withsome input from Argenta and help from their invitro and structural biology resources. Thisapproach led to the generation of a number ofpatent applications surrounding these novelinhibitors and co-authored publications focusingon the drug discovery science that has evolvedfrom this collaborative project.

The collaboration worked as follows. AGenentech scientist headed up the ROR projectand was the final decision maker. Argenta had aproject leader acting as the medicinal chemistrylead to make sure all the activities undertaken byArgenta were in line with the project’s overallexpectations. Senior scientists from differentGenentech and Argenta disciplines met biweekly(by webex) to discuss the latest data and nextsteps. Infrastructure was set up for seamless datatransfer and both parties had access to all relevantin vitro and in vivo data using shared databases.The latter, while technically complicated, is essen-tial to enhance design and decision making by bothparties. Another essential component was a com-prehensive screening cascade which described thevarious assays in place at Genentech and Argentaand their sequence as well as success criteria for acompound to progress down the cascade. All ofthis created a very transparent and collaborativeenvironment, further illustrated by Argenta’s nameon patents and as a co-author on publications andpresentations at scientific meetings.

Good communication was essential throughoutthe process. Senior team members provided quar-terly face-to-face updates to a management com-mittee comprised of three high-level managersfrom both companies who were responsible forproviding strategic input and making sure thework was moving forward, and identifying andaddressing resource bottlenecks while staying onbudget. The senior management committee alsoresolved occasional scientific disagreements amongthe scientists.

Different strokes Not every project is as integrated as this one was,nor do perfect collaborative models exist. Virtualcompanies outsource all discovery activities whilemaintaining a level of management oversight.Other companies are more hesitant and only out-source specific activities on a less exclusive fee-for-service basis after extensive qualification of theCRO in question. Indeed, the type of interactionbetween the partner and the CRO reflects the inter-nal resources at the partner, but also its culture.

Multiple factors influence how a particular part-nership is structured, how it functions and howlong it lasts. The level of scientific expertise has tomeet, if not exceed, expectations and the projectshave to add value to the sponsor’s portfolio. Whileit is easy to make compounds, synthesising theright compound is another matter entirely; perhaps

the ultimate proof of success being the number ofdevelopment candidates that are delivered and theamount of time it takes to deliver them. The aver-age industry success rate for delivering a develop-ment candidate for a drug discovery project isaround 45% right now according to a NatureDrug Discovery study8, but is more likely around35%. To date, the Genentech-Argenta collabora-tion has generated seven quality development can-didates out of 11 projects.

Even more importantly, perhaps, are the per-centage of development candidates that progress toclinical proof-of-concept or beyond, which is nowbetween 12 and 24%9. Extensive experience pro-vides greater innovation and problem-solving,reducing delivery times for candidates. And theability to run integrated projects within a singleCRO significantly reduces client management time.This is one reason why Charles River Discoveryhas been able to deliver 61 development candidatesin the last 15 years, with 28% reaching clinicalproof of concept studies.

Another important factor that affects the utili-ty of these collaborative arrangements is the abil-ity to remain flexible. Today’s ultra competitivelandscape requires both parties to be able torespond quickly to developments in the preclini-cal and clinical pipeline. This can be somewhattricky in the world of bench science, where scien-tists loathe giving up on a good idea. But the fact

In the early discovery space,collaborations come in many

shapes and forms

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joint teams

client ‘hands-off’

single function

multiple interactions

integrated project

is that throughout industry developers are optingout of otherwise promising projects because acompetitor turns out to be too far ahead in thegame to make the investment worthwhile. Whilethis situation is not unique to these collaborationswith CROs, it does mean that partners must beable to adapt quickly to the changing environ-ment. Indeed, the Genentech/Argenta collabora-tion has encountered this situation, but there issufficient scientific depth and flexibility to quick-ly swap out targets as needed.

The costs of CRO services can also vary widelywithin the collaboration due to their level ofexpertise and the range of services provided. Forinstance, Western providers tend to be two to threetimes more expensive than Eastern providers butthey also generate two to four times more com-pounds per scientist than Eastern CROs and theirimpact on drug design is much greater.

With regard to staffing levels, the critical mass ofscientists employed by Asian CROs are generallyquite capable of replicating well-established mod-els and have a good track record of delivering onhigh volume routine projects, but they lack theresearch depth and experience to handle the morechallenging upstream work10. As an example, halfthe scientists on Argenta projects have a PhD com-pared to around 10% at Asian CROs. Moreover,high turnover of staff at Asian CROs is of concernwith rates on the order of 20% to 30% a year. Onthe other hand, Western CROs are more stable andhave the innovation, industrial experience andexpertise, and the scientific management to deliveron challenging projects, but they are also moreexpensive11. Thus, the ideal collaboration includesboth a Western CRO and an Asian CRO – eachfocusing on their respective strengths.

The non-regulated research space of early dis-covery is also, paradoxically, more challenging tonavigate for collaborations. By necessity, the rela-tionships must be more fluid and flexible due tothe different kinds of technology and models thatare employed to collect the data used in makingcrucial go/no go decisions which are frequentlysomewhat subjective and associated with a levelof uncertainty.

It also takes time to build partnerships aroundmutual interests, expertise and trust. Finding thescientific equivalent of that perfect eHarmonymatch – one that lasts a long time and is mutuallysatisfying – often hinges on chemistry, both on andoff the bench. Frequent communication and honestfeedback is essential to make the collaborationwork and last – especially in light of the non-linearand non-precedented nature of drug discovery.

Some sponsors want their CRO partners at thetable, others prefer to call the shots and keep theirdistance. On the other hand, some CROs are notshy about offering their opinions and activelypursue a bigger role in how the projects are man-aged. Others are less forceful. Finding the rightbalance of personalities takes time and somematch-ups – like any relationship – inevitablylack the right ingredients to make the collabora-tion work. Recognising and adapting to the cul-tural differences within each organisation canhelp relationships thrive, though, and learningfrom each project is one reason why some collab-orations are so durable.

In short, much of this early discovery work iscomplex and difficult to execute. It sounds obvi-ous, but cross-communication and regular conver-sations between the two entities matter, whateverthe collaboration’s structure or scope. When con-structive dialogue is lacking, stuff happens andprojects become difficult to manage.

It is better to be ‘brothers in arms’ in the pursuitof innovation to allow valuable drugs to reachpatients quicker. DDW

Dr John Montana is Executive Director, ScientificAlliances, of Charles River Discovery Services’Division where he has been instrumental in the sci-entific and commercial growth of the company. Amedicinal chemist by training, he has carried outresearch across a range of therapeutic areas andworked for a number of large multinational com-panies including GlaxoSmithKline and Cell Tech.

Cornelis E.C.A. Hop leads the Drug Metabolismand Pharmacokinetics department at Genentechand, as a member of the Small MoleculeLeadership Team, chairs the Genentech-Argentacollaboration. He has close to 20 years of pharma-ceutical industry experience at Merck, Pfizer andnow Genentech.

References1 Pharmaceutical Research andManufacturers of America:2013 Pharmaceutical ResearchIndustry Profile. PublishedApril 2013, Page 32.http://www.phrma.org/sites/default/files/pdf/PhRMA%20Profile%202013.pdf.2 Hay, Michael et al. NatureBiotechnology, ClinicalDevelopment Success Ratesfor Investigational Drugs, Vol.32, 40-51, 2014.3 Bunnage, Mark E. NatureChemical Biology, GettingPharmaceutical R&D Back onTarget, Vol. 7, 335-339, May2011.4 Molho, Davide. Partneringwith the right CRO is awinning strategy forcompanies big and small. DrugDiscovery World, Fall 2013.http://www.ddw-online.com/business/p216817-partnering-with-the-right-cro-is-a-winning-strategy-for-companies-big-and-small-fall-13.html.5 Tufts Center for the Study ofDrug Development, PublishedNov. 2014, http://csdd.tufts.edu/files/uploads/cost_study_backgrounder.pdf.6 visiongain, Drug DiscoveryOutsourcing: World Market2013-2023, PublishedNovember, 2012.https://www.visiongain.com/Report/945/Drug-Discovery-Outsourcing-World-Market-2013-2023.7 Van Niel, Monique B et al.Bioorganic and MedicinalChemistry Letters, Vol. 24,Issue 24, Dec. 15, 2014., 5769-5776. http://www.sciencedirect.com/science/article/pii/S0960894X1401097X.8 Paul, Steven et al. NatureReviews Drug Discovery, Vol.9, Pages 203-214, March 2010.http://www.nature.com/nrd/journal/v9/n3/full/nrd3078.html.9 Paul, Steven et al. NatureReviews Drug Discovery, Vol.9, Pages 203-214, March 2010.http://www.nature.com/nrd/journal/v9/n3/full/nrd3078.html.10 Baxter InternationalIndependent Survey, 2014.11 Baxter InternationalIndependent Survey, 2014.

Reprinted from Drug Discovery World Summer 2015

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Reprinted from Drug Discovery World Summer 2015

Corporate Profile

Discovering and characterisingdrug candidates for preclinicaldevelopment relies upon innova-

tive and reliable science. Charles Riverdelivers just that, adopting a strategic, col-laborative approach to our partners’ dis-covery programs, enabling them to delivertherapeutics to patients in a timely andcost-effective manner.

Charles River offers the most compre-hensive preclinical CRO drug discoveryservice portfolio in the industry, supportedby scientific excellence across major thera-peutic areas and target classes. Clients andstrategic partners can engage with us at theearliest point in the drug discovery processand benefit from our capacity to partnerwith them throughout the drug develop-ment lifecycle.

Delivering innovation Charles River provides significant value toour partners. In the past 15 years, we haveestablished the enviable record of delivering61 preclinical candidates through our inte-grated drug discovery collaborations, 27%of which have progressed to clinical proof-of-concept or beyond, compared with theindustry standard of 12-24%1. In addition,partnering with Charles River allows ourclients to bring their ideas to fruition whileprotecting their intellectual property. Ourimpact is exemplified by inventorship onmore than 280 client patents.

Through a comprehensiveofferingAs your scientific partner and preclinicalCRO, Charles River provides innovation,flexibility and efficiency from target dis-covery through in vivo pharmacology mod-els and safety assessment. Our unique com-bination of multidisciplinary drug discov-ery expertise and an unparalleled scope ofplatform capabilities allows us to deliverdepth and breadth in science with insightand data you can trust to progress yourdrug discovery programs.

With an eye on the future At Charles River, we are passionate aboutour role in improving the quality of peo-ple’s lives. We approach each day with theknowledge that supporting our clients’ dis-covery programmes contributes to thehealth and well-being of our families,friends and colleagues across the globe. Weare committed to providing the highestquality service, science, technology andregulatory support. This commitment,along with a strong sense of purpose,guides us in all that we do and enables ourclients to focus on the important businessof advancing novel therapeutics to thepatients who need them. We are proud tohave supported our clients at some point inthe discovery and development lifecycle ofmore than half (55%) of the new drugsapproved by the FDA in 2014.

With more than 60 sites around theglobe, we are strategically positioned to co-ordinate worldwide resources and applymultidisciplinary perspectives in resolvingyour unique challenges. Our focus on time-liness and accuracy in every stage of devel-opment means you can count on reliable,reproducible results, every step of the way.

For more information visit www.criver.com.

Reference1 Nature Drug Discovery, 2010, 9, 203; DDT,2003, 8(23), 1067; DDT, 2013, 19(3), 341.

Charles River — the partner of choice forthe discovery of tomorrow’s therapeutics

Disease area No. of candidatesMost advances in compound

PCC Ph I Ph IIa Ph IIb Ph III Registration

12

23

6

4

11

1

1

2

1

Toxicology

Pharmaceutical development

In vivo pharmacology

Biomarkers and imaging

In vitro ADMET, In vivo PK/PD

In vitro pharmacology

Structural biology and biophysics

Synthetic, medicinal and process chemistry

Every Step of the Way.

Hit ID (small molecule, fragment and natural product)

Target discovery and validation