3/4/2019 DRUG DISCOVERY - Zebrafish in Preclinical Drug Development - A Small Fish With Big Returns

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Issue:Issue: April 2019April 2019

DRUG DISCOVERY – Zebra�sh in Preclinical Drug Development – ADRUG DISCOVERY – Zebra�sh in Preclinical Drug Development – ASmall Fish With Big ReturnsSmall Fish With Big Returns INTRODUCTIONINTRODUCTION

Recently the University of California, San Francisco (UCSF) joined forces with Barcelona,Recently the University of California, San Francisco (UCSF) joined forces with Barcelona,Spain-based CRO ZeClinics to commercialize a zebra�sh model for childhood epilepsy thatSpain-based CRO ZeClinics to commercialize a zebra�sh model for childhood epilepsy thatmimics the convulsive behavior and seizures associated with epilepsy. The model has amimics the convulsive behavior and seizures associated with epilepsy. The model has aproven track record in successfully identifying new treatments against epileptic disordersproven track record in successfully identifying new treatments against epileptic disordersand already has three compounds in Phases 1 and 2 clinical trials.and already has three compounds in Phases 1 and 2 clinical trials.

Like the researchers at UCSF, numerous others from academia and the pharmaceuticalLike the researchers at UCSF, numerous others from academia and the pharmaceuticalindustry across the globe are using zebra�sh industry across the globe are using zebra�sh (Danio rerio) (Danio rerio) to develop new drugs. Treatmentsto develop new drugs. Treatmentsare being developed more quickly to treat a broad array of therapeutic areas, includingare being developed more quickly to treat a broad array of therapeutic areas, includinginfectious diseases, Alzheimer’s disease, cardiovascular diseases, neural disorders, cancers,infectious diseases, Alzheimer’s disease, cardiovascular diseases, neural disorders, cancers,hearing loss, and rare diseases, to name just a few. The researchers are realizing a majorhearing loss, and rare diseases, to name just a few. The researchers are realizing a majorbene�t of drug development made possible with the use of zebra�sh: high-throughputbene�t of drug development made possible with the use of zebra�sh: high-throughputscreening of small molecules. These preclinical studies quickly assess toxicity and e�cacyscreening of small molecules. These preclinical studies quickly assess toxicity and e�cacyof new drugs, saving both time and money, necessities in this age of great pressure to doof new drugs, saving both time and money, necessities in this age of great pressure to doboth.both.

Indeed, more than 25,000 papers have been published indicating just how important a drugIndeed, more than 25,000 papers have been published indicating just how important a drugdiscovery tool zebra�sh have become – and why.discovery tool zebra�sh have become – and why.

CHANGING TIMES CALL FOR A NEW WAY OF THINKINGCHANGING TIMES CALL FOR A NEW WAY OF THINKING

The pharmaceutical sector has certainly undergone numerous changes in recent years, andThe pharmaceutical sector has certainly undergone numerous changes in recent years, andchanging times call for new ways of thinking. The development process of any drug, fromchanging times call for new ways of thinking. The development process of any drug, fromearly target identi�cation to clinical testing, registration, and market approval takes at least aearly target identi�cation to clinical testing, registration, and market approval takes at least adecade and is extremely costly. It was only a few years ago that drug manufacturers did alldecade and is extremely costly. It was only a few years ago that drug manufacturers did allof their compound discovery and development in-house. Now the industry is buffeted notof their compound discovery and development in-house. Now the industry is buffeted notonly by pressure to reduce development costs but is also being maligned for the high cost ofonly by pressure to reduce development costs but is also being maligned for the high cost ofprescription drugs.prescription drugs.

Moreover, the industry faces increasing pressure from global regulatory agencies. That too,Moreover, the industry faces increasing pressure from global regulatory agencies. That too,coupled with the need for speed to market, has intensi�ed pressure on the industry. As acoupled with the need for speed to market, has intensi�ed pressure on the industry. As aresult, the downsizing trend took hold, leading to an unprecedented outsourcing of researchresult, the downsizing trend took hold, leading to an unprecedented outsourcing of researchto specialty contract research organizations (CROs).to specialty contract research organizations (CROs).

The need to balance innovation �exibility with cost e�ciency has never been more evident.The need to balance innovation �exibility with cost e�ciency has never been more evident.The classic drug development model is no longer sustainable.The classic drug development model is no longer sustainable.

Recently,Recently, Nature Nature published an article about the current trend toward pharma outsourcing as published an article about the current trend toward pharma outsourcing asheadcounts are decreasing despite the fact that more and more drugs are entering theheadcounts are decreasing despite the fact that more and more drugs are entering themarket. Particularly for the many small drug makers but also big pharma, it is di�cult tomarket. Particularly for the many small drug makers but also big pharma, it is di�cult tohave internal know-how at every step of the drug development process. By specializing inhave internal know-how at every step of the drug development process. By specializing inparticular therapeutic areas and stages of compound development, CROs are able to provideparticular therapeutic areas and stages of compound development, CROs are able to providequality services and operational �exibility at more competitive prices.quality services and operational �exibility at more competitive prices.

EARLIER PREDICTABILITY STEMS LOSSESEARLIER PREDICTABILITY STEMS LOSSES

The bene�ts of outsourcing preclinical research are not limited to cost and workforceThe bene�ts of outsourcing preclinical research are not limited to cost and workforcesavings. Hiring a CRO is not a simple replacement for in-house development with externalsavings. Hiring a CRO is not a simple replacement for in-house development with externalexpertise. Rather, it is about risk management and early predictability. Withdrawal ofexpertise. Rather, it is about risk management and early predictability. Withdrawal ofpotential drug candidates due to toxicity or e�cacy issues after months or even years ofpotential drug candidates due to toxicity or e�cacy issues after months or even years ofdevelopment remains a major source of losses for the pharma industry, particularly late-development remains a major source of losses for the pharma industry, particularly late-phase attrition at clinical and post-market stages.phase attrition at clinical and post-market stages.

To stem these losses, researchers are �nding that preclinical assays using zebra�sh funnelTo stem these losses, researchers are �nding that preclinical assays using zebra�sh funneldown large compound libraries by scrapping unsuitable candidates well before reachingdown large compound libraries by scrapping unsuitable candidates well before reachingmore costly regulatory more costly regulatory in vivo in vivo studies and clinical phases.studies and clinical phases.

The trick is to generate enough biologically relevant data early on in order to improveThe trick is to generate enough biologically relevant data early on in order to improvepredictability of drug targets and decrease the risk of late-phase attrition, bringing much-predictability of drug targets and decrease the risk of late-phase attrition, bringing much-needed certainty for making go or no-go decisions, ultimately contributing to theneeded certainty for making go or no-go decisions, ultimately contributing to thesustainability of projects. Zebra�sh allow pharmas to do precisely that.sustainability of projects. Zebra�sh allow pharmas to do precisely that.

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3/4/2019 DRUG DISCOVERY - Zebrafish in Preclinical Drug Development - A Small Fish With Big Returns

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The value of zebra�sh research has been stymied by the general lack of awareness in theThe value of zebra�sh research has been stymied by the general lack of awareness in thescienti�c community of an alternative vertebrate model. However, in the past 5 years, usingscienti�c community of an alternative vertebrate model. However, in the past 5 years, usingzebra�sh has become an increasingly prominent model for the early development of newzebra�sh has become an increasingly prominent model for the early development of newdrugs across diverse disciplines: toxicology, cancer research, human genomics,drugs across diverse disciplines: toxicology, cancer research, human genomics,developmental biology, and many more. Zebra�sh and humans share 71% of the samedevelopmental biology, and many more. Zebra�sh and humans share 71% of the samegenes, and 82% of genes associated with human diseases.genes, and 82% of genes associated with human diseases.

REGULATORS ARE CATCHING UPREGULATORS ARE CATCHING UP

While research conducted with zebra�sh has not yet enjoyed the same level of regulatoryWhile research conducted with zebra�sh has not yet enjoyed the same level of regulatoryrecognition as other widespread models, regulatory bodies are catching up with recentrecognition as other widespread models, regulatory bodies are catching up with recentscienti�c developments. Zebra�sh CROs, such as ZeClinics, are collaborating with the USscienti�c developments. Zebra�sh CROs, such as ZeClinics, are collaborating with the USNational Institutes of Health (NIH), the Environmental Protection Agency (EPA), the NationalNational Institutes of Health (NIH), the Environmental Protection Agency (EPA), the NationalToxicology Program (NTP), corporations, and academic groups in the SEAZIT global project,Toxicology Program (NTP), corporations, and academic groups in the SEAZIT global project,aimed at broadening the adoption of the zebra�sh model and harmonizing protocols foraimed at broadening the adoption of the zebra�sh model and harmonizing protocols forpreclinical toxicological screenings.preclinical toxicological screenings.

To date, the groups have jointly validated a library of nearly 100 marketed products as havingTo date, the groups have jointly validated a library of nearly 100 marketed products as havingperfect matches with the zebra�sh model. These sorts of ongoing initiatives are rapidlyperfect matches with the zebra�sh model. These sorts of ongoing initiatives are rapidlyspeeding awareness among regulators of the value of faster, cheaper zebra�sh models.speeding awareness among regulators of the value of faster, cheaper zebra�sh models.

WHAT ZEBRAFISH LARVAE & HEN’S EGGS HAVE IN COMMONWHAT ZEBRAFISH LARVAE & HEN’S EGGS HAVE IN COMMON

The regulatory arena for animal models is anything but static these days. In the cosmeticsThe regulatory arena for animal models is anything but static these days. In the cosmetics�eld, for example, there is a European Union (EU) ban on the sale of animal-tested�eld, for example, there is a European Union (EU) ban on the sale of animal-testedcosmetics, in force since 2013, which reduces testing options to in vitro models. This is notcosmetics, in force since 2013, which reduces testing options to in vitro models. This is notan isolated legislation with a scope limited to the cosmetics sector. Rather, it is part of aan isolated legislation with a scope limited to the cosmetics sector. Rather, it is part of abroader effort to reduce, re�ne, and replace the use of animals in toxicity assays (otherwisebroader effort to reduce, re�ne, and replace the use of animals in toxicity assays (otherwiseknown as the 3Rs initiative). Late last year European Commissioner for Internal Market andknown as the 3Rs initiative). Late last year European Commissioner for Internal Market andServices, Elżbieta Bieńkowska, claimed the European Union remains “fully committed” toServices, Elżbieta Bieńkowska, claimed the European Union remains “fully committed” toending animal testing.ending animal testing.

We fully endorse the 3Rs principles. Throughout the history of medical research, animalWe fully endorse the 3Rs principles. Throughout the history of medical research, animalmodels have been used indiscriminately in laboratory testing. But nowadays, the scienti�cmodels have been used indiscriminately in laboratory testing. But nowadays, the scienti�ccommunity and the different biopharma, cosmetic, and chemical sectors are committed tocommunity and the different biopharma, cosmetic, and chemical sectors are committed toupholding higher ethical standards. Recent bans have a low impact on zebra�sh testingupholding higher ethical standards. Recent bans have a low impact on zebra�sh testingrelative to other vertebrate models for the simple reason that most of the safety and e�cacyrelative to other vertebrate models for the simple reason that most of the safety and e�cacyassays are carried out with zebra�sh larvae at very early phases of embryonic development:assays are carried out with zebra�sh larvae at very early phases of embryonic development:from 2 to 5 days post fertilization (dpf). At those stages, organs are already fully developed,from 2 to 5 days post fertilization (dpf). At those stages, organs are already fully developed,and data generated is biologically relevant, but the embryos themselves lack independentand data generated is biologically relevant, but the embryos themselves lack independentmotility and rely exclusively on their yolk sac, to which they are still attached, for nutrientmotility and rely exclusively on their yolk sac, to which they are still attached, for nutrientuptake.uptake.

For all of these reasons, Directive 2010/63/EU of the European Parliament regulates thatFor all of these reasons, Directive 2010/63/EU of the European Parliament regulates thatzebra�sh larvae up to 5 dpf are classi�ed as zebra�sh larvae up to 5 dpf are classi�ed as in vitro in vitro models. Therefore, for all practicalmodels. Therefore, for all practicalpurposes, it is accurate to regard zebra�sh embryos as 3Rs-compliant and comparable topurposes, it is accurate to regard zebra�sh embryos as 3Rs-compliant and comparable toother commonly used in vitro models, such as the hen’s egg chorioallantoic membrane testother commonly used in vitro models, such as the hen’s egg chorioallantoic membrane test(HET-CAM).(HET-CAM).

Consequently, companies that are 3Rs compliant can offer their services to clients not onlyConsequently, companies that are 3Rs compliant can offer their services to clients not onlyin the pharma, biotech, and chemical sectors, but also the heavily regulated cosmeticsin the pharma, biotech, and chemical sectors, but also the heavily regulated cosmetics

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3/4/2019 DRUG DISCOVERY - Zebrafish in Preclinical Drug Development - A Small Fish With Big Returns

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sector. Other in vitro human-relevant models, such as organs-on-chip, organoids, or 3Dsector. Other in vitro human-relevant models, such as organs-on-chip, organoids, or 3Dcultures, also have great potential in combination with in silico forecasts and biologicallycultures, also have great potential in combination with in silico forecasts and biologicallyrelevant models, such as zebra�sh. However, further validation is still needed before theyrelevant models, such as zebra�sh. However, further validation is still needed before theycan become a viable substitute to current animal models.can become a viable substitute to current animal models.

NO LONGER IMPOSSIBLENO LONGER IMPOSSIBLE

What’s required here is synergy. The ZeCardio platform serves as an example of in vivoWhat’s required here is synergy. The ZeCardio platform serves as an example of in vivocardiovascular work that can easily complement human cardiomyocyte research withcardiovascular work that can easily complement human cardiomyocyte research withvascular readouts.vascular readouts. Data such as vein and artery blood �ow velocity would be impossible Data such as vein and artery blood �ow velocity would be impossibleto obtain otherwise. Hopefully, after the 2019 Parliamentary Elections, the EU will regardto obtain otherwise. Hopefully, after the 2019 Parliamentary Elections, the EU will regardzebra�sh as the animal testing alternative that the Commission is calling for in order tozebra�sh as the animal testing alternative that the Commission is calling for in order toaddress the 3Rs and the serious problem of late-phase attrition.address the 3Rs and the serious problem of late-phase attrition.

ZEBRAFISH CROS OFFER DIVERSE SERVICESZEBRAFISH CROS OFFER DIVERSE SERVICES

Zebra�sh CROs, such as ZeClinics, offer a broad range of diverse, multidisciplinary servicesZebra�sh CROs, such as ZeClinics, offer a broad range of diverse, multidisciplinary servicesand expertise across numerous therapeutic areas. Therapeutic areas include, but are notand expertise across numerous therapeutic areas. Therapeutic areas include, but are notlimited to the following:limited to the following:

-Cardiovascular diseases-Cardiovascular diseases

-Diseases of the Central Nervous System (CNS)-Diseases of the Central Nervous System (CNS)

-Atherosclerosis-Atherosclerosis

-Hearing Loss-Hearing Loss

-Retinal degeneration • Muscular dystrophy-Retinal degeneration • Muscular dystrophy

-Epilepsy-Epilepsy

-Endocrine disruptors-Endocrine disruptors

-Oncology-Oncology

Services include the following:Services include the following:

-Toxicology assays: High-throughput and organ-speci�c safety assessments-Toxicology assays: High-throughput and organ-speci�c safety assessments

-E�cacy assays: Phenotypic models for biologically relevant e�cacy assessments in-E�cacy assays: Phenotypic models for biologically relevant e�cacy assessments inmultiple therapeutic areasmultiple therapeutic areas

-CRISPR/Cas 9: KO and KI genetic editing to generate site-speci�c, a la carte mutations, to-CRISPR/Cas 9: KO and KI genetic editing to generate site-speci�c, a la carte mutations, toidentify and validate targets, test the effect of different compounds during development, andidentify and validate targets, test the effect of different compounds during development, andassess phenotypic responsesassess phenotypic responses

-Crispants: sgRNAs design and F0 physiological and phenotypical assays in just 1 week-Crispants: sgRNAs design and F0 physiological and phenotypical assays in just 1 week

CRISPR/CAS9: GENETICALLY MODIFIED ORGANISMS?CRISPR/CAS9: GENETICALLY MODIFIED ORGANISMS?

Earlier last year, the European Court of Justice (ECJ) ruled that gene-editing techniques,Earlier last year, the European Court of Justice (ECJ) ruled that gene-editing techniques,such as CRISPR/Cas9, would be regulated as Genetically Modi�ed Organisms (GMOs).such as CRISPR/Cas9, would be regulated as Genetically Modi�ed Organisms (GMOs).CRISPR experts at Ze-Clinics believe the recent ruling mostly concerns sectors other thanCRISPR experts at Ze-Clinics believe the recent ruling mostly concerns sectors other thanhealthcare. Why? Zebra�sh gene-edited lines are employed as part of in-house preclinicalhealthcare. Why? Zebra�sh gene-edited lines are employed as part of in-house preclinicalassays under controlled and contained conditions, which do not fall under Directiveassays under controlled and contained conditions, which do not fall under Directive2001/18/EC, the piece of European legislation on the deliberate release of GMOs into the2001/18/EC, the piece of European legislation on the deliberate release of GMOs into theenvironment that is also the main source of controversy in some circles. High-precisionenvironment that is also the main source of controversy in some circles. High-precisiontargeted mutagenesis with CRISPR/Cas9 will remain an irreplaceable tool for the study oftargeted mutagenesis with CRISPR/Cas9 will remain an irreplaceable tool for the study oflife-threatening diseases and the understanding at the molecular level of drug/targetlife-threatening diseases and the understanding at the molecular level of drug/targetinteractions, leading ultimately to speeding personalized medicine development.interactions, leading ultimately to speeding personalized medicine development.

DRUG DISCOVERY & DEVELOPMENT IS GLOBALDRUG DISCOVERY & DEVELOPMENT IS GLOBAL

The zebra�sh CRO community is collaborative and international in reach. That’s becauseThe zebra�sh CRO community is collaborative and international in reach. That’s becausesponsors choose CROs not on the basis of location but on the basis of expertise in relatedsponsors choose CROs not on the basis of location but on the basis of expertise in relateddrug development, speci�c technological prowess, or experience with speci�c diseasedrug development, speci�c technological prowess, or experience with speci�c diseasestates. Whether the CRO is located in the US, Europe, or Asia-Paci�c is far less relevant thanstates. Whether the CRO is located in the US, Europe, or Asia-Paci�c is far less relevant thanthe know-how that leads to completion of projects in a timely, cost-effective manner.the know-how that leads to completion of projects in a timely, cost-effective manner.

SUMMARYSUMMARY

In this article we explored the bene�ts of preclinical outsourcing, the value of zebra�sh as anIn this article we explored the bene�ts of preclinical outsourcing, the value of zebra�sh as analternative model, as well as the challenges and opportunities of managing a highlyalternative model, as well as the challenges and opportunities of managing a highlydiversi�ed portfolio and providing customized solutions.diversi�ed portfolio and providing customized solutions.

REFERENCESREFERENCES

1. Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev DrugKola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev DrugDiscov. 2004;3(8):711-5.Discov. 2004;3(8):711-5.

2. Waring MJ, Arrowsmith J, Leach AR, Leeson PD, Mandrell S, Owen RM, Pairaudeau G,Waring MJ, Arrowsmith J, Leach AR, Leeson PD, Mandrell S, Owen RM, Pairaudeau G,Pennie WD, Pickett SD, Wang J, Wallace O, Weir A. An analysis of the attrition of drugPennie WD, Pickett SD, Wang J, Wallace O, Weir A. An analysis of the attrition of drugcandidates from four major pharmaceutical companies. Nat Rev Drug Discov.candidates from four major pharmaceutical companies. Nat Rev Drug Discov.2015;14(7):475-86.2015;14(7):475-86.

3. MacRae CA, Peterson RT. Zebra�sh as tools for drug discovery. Nat Rev Drug Discov.MacRae CA, Peterson RT. Zebra�sh as tools for drug discovery. Nat Rev Drug Discov.2015;14(10):721-31.2015;14(10):721-31.

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3/4/2019 DRUG DISCOVERY - Zebrafish in Preclinical Drug Development - A Small Fish With Big Returns

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4. Cornet C, Calzolari S, Miñana-Prieto R, Dyballa S, van Doornmalen E, Rutjes H, Savy T,Cornet C, Calzolari S, Miñana-Prieto R, Dyballa S, van Doornmalen E, Rutjes H, Savy T,D’Amico D, Terriente J. ZeGlobalTox: An Innovative Approach to Address Organ DrugD’Amico D, Terriente J. ZeGlobalTox: An Innovative Approach to Address Organ DrugToxicity Using Zebra�sh. Int J Mol Sci. 2017; 19, 18(4): E864.Toxicity Using Zebra�sh. Int J Mol Sci. 2017; 19, 18(4): E864.

5. Zakaria Z. Using Zebra�sh for Investigating the Molecular Mechanisms of Drug-InducedZakaria Z. Using Zebra�sh for Investigating the Molecular Mechanisms of Drug-InducedCardiotoxicity. BioMed Research International. 2018(4):1-10.Cardiotoxicity. BioMed Research International. 2018(4):1-10.

6. Cornet C, Di Donato V, Terriente J. Combining Zebra�sh and CRISPR/Cas9: Toward a MoreCornet C, Di Donato V, Terriente J. Combining Zebra�sh and CRISPR/Cas9: Toward a MoreE�cient Drug Discovery Pipeline. Front Pharmacol. 2018 Jul 3;9:703.E�cient Drug Discovery Pipeline. Front Pharmacol. 2018 Jul 3;9:703.

To view this issue and all back issues online, please visit To view this issue and all back issues online, please visit www.drug-dev.comwww.drug-dev.com..

Dr. Rafael MiñanaDr. Rafael Miñana is Services Manager of ZeClinics, a CRO that is Services Manager of ZeClinics, a CRO thatfocuses on preclinical drug testing with zebra�sh in multiplefocuses on preclinical drug testing with zebra�sh in multipletherapeutic areas. Dr. Miñana spends most of his day managingtherapeutic areas. Dr. Miñana spends most of his day managingsafety and e�cacy assays, gene editing for target validation,safety and e�cacy assays, gene editing for target validation,monitoring �sh facilities, and above all, coordinating amonitoring �sh facilities, and above all, coordinating amultidisciplinary team to best satisfy the requirements of theirmultidisciplinary team to best satisfy the requirements of theirpharma, biotech, and cosmetics clients. In view of all these, it is nopharma, biotech, and cosmetics clients. In view of all these, it is nosurprise he does not hesitate when being asked about the bene�tssurprise he does not hesitate when being asked about the bene�tsand challenges of outsourcing drug-candidate identi�cation andand challenges of outsourcing drug-candidate identi�cation anddiscovery.discovery.

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