WIPO Re:Search: Catalyzing Collaborations to ... - ACS Publications

He published widely and was as editor-in-chief of IP Management of Health and Agricultural Innovation: A Handbook of Best Practices (www.ipHandbook.or...
37 downloads 8 Views 3MB Size
Download PDF
Review pubs.acs.org/CR

WIPO Re:Search: Catalyzing Collaborations to Accelerate Product Development for Diseases of Poverty Roopa Ramamoorthi,† Katy M. Graef,† Anatole Krattiger,‡ and Jennifer C. Dent*,† †

BIO Ventures for Global Health, 401 Terry Avenue North, Seattle, Washington 98109, United States World Intellectual Property Organization, 34, Chemin des Colombettes, CH-1211 Geneva 20, Switzerland (NTDs), malaria, and tuberculosis, often lack safe and effective commercially available products. Many drugs used to treat these diseases are decades old, expensive, are contraindicated for certain populations, and have unacceptable toxicity. None of the parasitic diseases, including helminthiases and kinetoplastid infections, has an approved vaccine. Vaccines for the other diseases, including malaria, for which a vaccine is in phase III clinical trials, and tuberculosis, have limited efficacy. These diseases of poverty are not only partially responsible for the glaring differences in mortality rates between high- and lowincome countries, but also affect growth and development of children, school and work attendance, and economic development in endemic countries. CONTENTS Progress in reducing the significant burden caused by these diseases requires new and more effective treatments. However, 1. Introduction 11272 while more than a billion individuals suffer from NTDs, malaria, 1.1. Proactive Partnering 11272 and tuberculosis worldwide, many cannot afford the vaccines, 2. Natural Products for Tuberculosis 11273 diagnostics, or drugs to prevent, diagnose, or treat these 3. Kinase Inhibitors for Malaria and Tuberculosis 11274 infections.2,3 This lack of buying power offers little incentive to 4. Recycling Data for Global Health 11276 the private sector to invest in R&D for new products to treat 5. Conclusion 11277 neglected diseases. As a consequence, the number of products Author Information 11277 Corresponding Author 11277 specifically developed to treat diseases of poverty is limited. Notes 11277 The pharmaceutical industry is the undisputed expert in Biographies 11277 efficiently developing new drugs. Pharmaceutical companies Acknowledgments 11278 have spent decades honing their product development Abbreviations 11278 expertise, and their drug development programs have enabled References 11278 them to develop substantial compound libraries. To leverage this expertise and these assets, the World Intellectual Property Organization (WIPO), BIO Ventures for Global Health 1. INTRODUCTION (BVGH), and eight leading pharmaceutical companies The 20th century marked a turning point in the battle against [Alnylam, AstraZeneca, Eisai, GlaxoSmithKline (GSK), infectious disease. Penicillin was discovered, the polio vaccine MSD,4 Novartis, Pfizer, and Sanofi] joined forces to establish was developed, and smallpox was eradicated. Yet while these the WIPO Re:Search consortium. WIPO Re:Search seeks to and other breakthroughs have significantly reduced the accelerate the development of new drugs, vaccines, and morbidity and mortality associated with infection in higher diagnostics for NTDs, malaria, and tuberculosis by connecting income countries, communicable diseases remain a serious the resources of private industry to academic and nonprofit threat to individuals and communities in low- to middle-income researchers with novel product discovery or development ideas countries (LMICs). An average of 17% (ranging from 5% to for these diseases. Since the Consortium’s launch in October 49%) of all deaths in LMICs in 2010 was attributed to 2011, membership has nearly tripled and now involves 80 infection; this is in contrast to high-income countries, where only 5.5% of deaths were due to infectious diseases.1 This organizations representing the private, academic, and nonprofit difference is even more marked in childhood mortality: 40% of sectors of 22 countries and six continents. childhood deaths in LMICs versus 11% in high-income countries were due to communicable diseases in 2010.1 While Special Issue: 2014 Drug Discovery and Development for Neglected certain infectious diseases, such as measles and polio, affecting Diseases individuals living in LMICs may be prevented or treated by currently available vaccines or drugs, numerous other infections Received: February 4, 2014 endemic to these regions, specifically neglected tropical diseases Published: September 17, 2014 ‡

© 2014 American Chemical Society

11272

dx.doi.org/10.1021/cr5000656 | Chem. Rev. 2014, 114, 11272−11279

Chemical Reviews

Review

1.1. Proactive Partnering

WIPO Re:Search offers a mechanism for sharing intellectual property (IP) assets that have the potential to be used in discovery and development of new, more effective products to treat neglected diseases. These assets include compounds, compound libraries, screening data, hit-to-lead series, marketed products, enabling technologies, patent estates, diagnostic tools, and vaccine technologies. The pharmaceutical companies involved in WIPO Re:Search have also shared expertise in formulation and protein-purification, and have assisted with computational predictions of compounds’ pharmacokinetic properties. As the WIPO Re:Search Partnership Hub Administrator, BVGH ensures productive collaborations are developed. BVGH fields requests from researchers for these IP assets, identifies Member organizations able to fulfill these requests, and helps forge mutually beneficial collaborations with clearly defined roles and expectations. In addition, BVGH employs a customized, proactive, hands-on approach to identify research synergies and complementary expertise between the range of organizations that comprise the Consortium (Figure 1). These

Figure 2. WIPO Re:Search agreements by disease. To date, 44 agreements, representing one or more neglected disease, have been facilitated by the WIPO Re:Search Partnership Hub. Global disabilityadjusted life years (DALYs) attributed to individual disease in 2010.1 * indicates DALYs unavailable. Abbreviations follow: lymphatic filariasis (LF), soil-transmitted helminthiases (STH), human African trypanosomiasis (HAT).

Figure 1. Roles and responsibilities of WIPO Re:Search participants. BVGH proactively identifies research synergies and fields requests from Users, connects Users to Providers, and facilitates discussions between participants. Upon reaching an agreement, a Provider will contribute the necessary asset to the User, who is responsible for undertaking the research utilizing the asset.

address the need for new products to be provided to vulnerable populations in a cost-effective manner, but also provide guidelines for rights and ownership of intellectual property created during a collaboration. The Guiding Principles state that the Member who develops the new intellectual property retains its rights; the provider of the original intellectual property has no claim to the new intellectual property. However, each partnership facilitated by BVGH is regulated by each collaboration’s individual legal agreement. In the event that a partnership results in a promising candidate, BVGH will identify new partners to assist with product optimization, preclinical and clinical studies, and production, as necessary. The same applies to collaborations that show promise for the advancement of vaccines and diagnostics. The objective is to drive as many of the promising products to the market, and thus positively affect developing world populations. This Review presents several examples of how researchers are utilizing the assets and proactive partnering offered through WIPO Re:Search to accelerate their own neglected disease programs.

collaboration opportunities are then presented to the Members for their consideration. Once mutual interest is established, BVGH facilitates communication and negotiations to formalize a partnership agreement. To date, BVGH has facilitated 44 agreements between WIPO Re:Search Members. These collaborations involve a wide range of diseases, from high-impact, global diseases, such as tuberculosis, malaria, soiltransmitted helminthiases, and schistosomiasis, to diseases with lower incidences, but which nonetheless, place a significant burden on the individuals they affect. These include leprosy, Buruli ulcer, and human African trypanosomiasis (Figure 2). In certain instances, BVGH has facilitated collaborations involving other pathogens, such as those causing diarrheal diseases. While not considered “neglected” by the World Health Organization (WHO), these pathogens still heavily burden those living in poverty. These agreements demonstrate the commitment of the Consortium’s Members to reducing the burden of disease in low-resource settings. Members of the Consortium are governed by the WIPO Re:Search Guiding Principles. These Principles not only

2. NATURAL PRODUCTS FOR TUBERCULOSIS Mycobacterium tuberculosis, the causative agent of tuberculosis, has caused significant morbidity and mortality in humans throughout history, reaching epidemic proportions in the 18th and 19th centuries. While modern medicine and hygiene substantially reduced the number of infections in the late 19th and early 20th centuries, tuberculosis remains a serious public health threat.5 It has been estimated that, in 2012, 8.6 million new tuberculosis cases occurred, resulting in 1.3 million deaths.6 While this number may appear relatively low compared to other infectious diseases, for example malaria, which was estimated to cause 207 million infections in 2012,7 or dengue, which may cause as many as 390 million infections each year,8 M. tuberculosis resides, in latency, in approximately one-third of the world’s population.9 Ten percent of these infections will advance to an acute, transmissible infection.10 This potential for disease is only exacerbated by HIV coinfection, which increases the risk of developing active tuberculosis by 21−34-fold.10 Further compounding the burden of tuberculosis has been the development of multidrug resistant (MDR) M. tuberculosis 11273

dx.doi.org/10.1021/cr5000656 | Chem. Rev. 2014, 114, 11272−11279

Chemical Reviews

Review

strains that are resistant to at least the two most potent first-line tuberculosis drugs, isoniazid and rifampin.9 Of even greater concern, some drug-resistant isolates of M. tuberculosis are resistant to at least one second-line tuberculosis drug, in addition to isoniazid and rifampin.11,12 The standard treatment for tuberculosis requires that several drugs (isoniazid, rifamycin/rifampin, ethambutol, and pyrazinamide) are taken in combination for six to nine months. The development of MDR tuberculosis has resulted in the addition of three drugs (capreomycin, kanamycin, and amikacin) to the regimen, and extension of treatment duration to two years.9 The duration and complexity of treatments, coupled with the intensification of drug-resistance and the generation of extensively (XDR) and totally drug-resistant (TDR) mycobacteria, highlights the need for new drugs.13 Furthermore, the first-line drug, rifampicin, which induces cytochrome P450, has been demonstrated to elevate metabolism and reduce systemic exposure of HIV protease inhibitors, reducing their efficacy.14 One-third of HIV-positive individuals are infected with M. tuberculosis;15,16 thus, rifampicin’s side effect reduces the options for tuberculosis treatment in a substantial portion of the population needing tuberculosis treatment. Nature has an undeniable history of providing effective treatments for infectious diseases. The antibiotic penicillin was obtained from Penicillium fungi, the antimalarial, artemisinin, from the annual wormwood plant, and kanamycin, a secondline tuberculosis drug, originated from Streptomyces kanamyceticus. Through WIPO Re:Search, researchers are exploring how natural products may lead to the development of novel tuberculosis treatments. Prior to the facility’s closure in mid-2014, researchers from AstraZeneca’s Bangalore, India, facility were screening a set of 200 000 semipurified natural product fractions from the Eskitis Institute’s Nature Bank against M. tuberculosis. The Nature Bank includes 45 000 samples from over 14 000 species of plants and marine organisms, as well as over 200 000 semipurified fractions and 3000 pure compounds isolated from these species. The marine organisms stored at the Nature Bank were harvested from the Great Barrier Reef and temperate reefs near Tasmania, whereas the plants were collected from the forests of Queensland, Australia, South East China, and Papua New Guinea.17 This collaboration was facilitated after scientists at AstraZeneca’s Bangalore facility expressed an interest in assessing natural products against M. tuberculosis. BVGH suggested the Eskitis Institute, discussions were initiated, and a material transfer agreement was signed. The AstraZeneca researchers began to screen the natural product fractions; however, due to the Bangalore facility shutting down, the screens were not completed. The Infectious Disease Research Institute (IDRI) develops new products for diseases of poverty, including tuberculosis. Researchers at IDRI expressed an interest in screening natural products against M. tuberculosis. Upon reviewing the Consortium Members’ assets, BVGH recommended that IDRI acquire natural products from the Natural Products Branch (NPB) of the National Cancer Institute at the National Institutes of Health (NCI/NIH). The NPB maintains a repository of extracts from plant and marine organisms, including 50 000 plant samples and 10 000 marine invertebrate and marine algae samples. The plant samples were collected from Africa, Central and South America, South East Asia, and arid regions of the United States. The marine samples were collected primarily from the Indo-Pacific region, as well as the

Caribbean and Alaska. This repository is supported by the National Cancer Institute in an effort to obtain, screen, and identify new cancer drugs. Approximately 5000 diverse natural product extracts from the NPB will be screened by IDRI in a whole-cell assay against actively replicating M. tuberculosis bacteria. In the event that promising extracts are identified, the NPB has offered to suggest researchers who may be able to identify the active component of the extract. The Eskitis Institute’s Nature Bank and the NIH’s Natural Products Repository samples were collected from regions of the world with some of the highest biodiversity densities, and thus may contain compounds with novel and unique chemical structures. These unique compounds may be the springboard toward the development of new drugs that could add to, or replace, existing tuberculosis therapies.

3. KINASE INHIBITORS FOR MALARIA AND TUBERCULOSIS While significant efforts in drug discovery are focused on phenotypic screening of large, diverse chemical sets, such as the efforts mentioned above, WIPO Re:Search Members are also examining the effects of specific classes of molecules, including protein kinase inhibitors, on targets and molecular pathways of pathogens of global health concern. Protein kinases, which transfer a phosphate group from an ATP molecule to a protein substrate, are essential for proper cellular functions. These kinases regulate key cellular processes, such as apoptosis,18 DNA replication and damage repair,19,20 cellular metabolism,21 immune activation,22 and intracellular trafficking,23 with the biological effect depending upon the individual kinase’s protein substrate. Because these enzymes are critical to the proper regulation of cellular functions, they are of interest to commercial drug discovery programs; 20−30% of active drug discovery programs are focused on developing protein kinase inhibitors,24 with the majority in development for cancer indications. Marketed protein kinase inhibitor-based chemotherapies include Novartis’ blockbuster drug, Gleevec (imatinib mesylate), which targets the tyrosine kinase, BcrAbl.25,26 While it is undisputed that kinases are tractable targets for new oncology therapies, the human kinome map is incomplete. This represents a substantial gap in our knowledge of the signaling pathways and molecular effects of a key class of enzymes. Kinases rely on their ability to bind and hydrolyze ATP, a feature that most kinase inhibitors target. The ATP binding sites of kinases are highly conserved,27,28 and thus many kinase inhibitors, with varying degrees of affinity, are able to inhibit multiple kinases. This capacity provides a foundation upon which to examine the cellular role of underexplored protein kinases. Exploiting these characteristics to address the lack of quality chemical probes for biological evaluation and pharmacological understanding of the unmapped kinome, GlaxoSmithKline (GSK) developed two kinase inhibitor sets, Published Kinase Inhibitor Sets (PKIS) 1 and 229 (Figure 3). GSK selected kinase inhibitors for inclusion into these two sets that were not only readily available in sufficient quantities in GSK’s compound repository, but were well-studied, as evidenced by the number of publications describing each individual inhibitor. These sets were further refined to limit over-representation of the kinase targets and inhibitor chemotypes, thus increasing the potential for broader kinome coverage. The sets include several compounds within each chemical series to facilitate the examination of the structure− 11274

dx.doi.org/10.1021/cr5000656 | Chem. Rev. 2014, 114, 11272−11279

Chemical Reviews

Review

present, to examine the molecular signaling pathways and mechanisms of pathogens’ lifecycles. Researchers at the National Institute of Immunology (NII) in New Delhi, India, are utilizing the GSK PKIS1 to examine the essential molecular mechanisms of M. tuberculosis cell wall synthesis. The mycobacterial cell wall is made up of three covalently linked molecules: peptidoglycan, arabinogalactan, and mycolic acid, as well as free glycolipids.30 Elucidating the molecular mechanisms by which production and trafficking of these molecules is regulated may provide researchers with novel antimycobacterial drug targets. Furthermore, the free glycolipids interact with the mycolyl moiety to form a bilayer that greatly reduces the permeability of the cell wall. In comparison to the cell wall of Gram-positive and Gram-negative bacteria, the mycobacterial cell wall presents a substantial entry barrier for antibiotics.14 Therefore, disrupting proper cell wall synthesis may not only inhibit mycobacterial growth, but also facilitate the uptake of other antibiotics, thus increasing the efficacy of existing antimycobacterial drugs and enhancing mycobacterial infection outcomes. To examine cell wall synthesis, the NII researchers will screen GSK’s PKIS1 for inhibitors of an M. tuberculosis serine/ threonine protein kinase. The NII researchers will identify small molecules within the PKIS1 that inhibit M. tuberculosis kinases believed to be involved in cell wall synthesis in vitro, followed by examination of the effect of diminished kinase activity on downstream events. By utilizing the inhibitors contained within PKIS1, the NII team will not only be mapping the mycobacterial cell wall synthesis signaling pathway, but also identifying new targets for mycobacterial drug discovery. Similarly to tuberculosis, malaria represents a serious threat to individuals across the globe. Transmitted by the female Anopheles mosquito, the Plasmodium parasite is endemic in tropical and subtropical regions, with the highest disease burden experienced in sub-Saharan Africa. Two species of Plasmodium, P. falciparum and P. vivax, are responsible for the majority of malaria-associated morbidities and mortalities.31 Currently, there is no commercially available vaccine, and the emergence of drug resistance to the two first-line drug types, quinolines and artemisinins, is a growing concern.32 While malaria incidence has decreased globally by 45% since 2000, half of the world’s population is still at risk of infection, and with 207 million malaria cases occurring in 2012,31 malaria still represents a significant burden in endemic regions. Within its human host, the Plasmodium parasite transverses two separate stages: liver-stage and blood-stage. These stages present unique antimalarial drug targets; specific Plasmodium proteins are differentially expressed during these two distinct stages. Upon entering its human host, the sporozoite form of the malaria parasite migrates to the liver where it matures into schizonts within the hepatocytes. These schizonts burst, releasing merozoites, which subsequently infect circulating erythrocytes, thus entering the blood-stage of the malaria infection. Within the erythrocytes, the merozoites undergo asexual replication, transforming first into trophozoites and then into schizonts. These blood-stage schizonts burst, releasing additional merozoites into the bloodstream, which subsequently infect additional erythrocytes to continue the cycle of asexual replication. A small percentage of the merozoites will instead mature into gametocytes within the erythrocytes. The human stage of the parasite’s lifecycle is completed when the gametocyte-infected erythrocyte is ingested by a female mosquito during a bloodmeal.33 It is the

Figure 3. Red dots depict the kinases against which each member of the Published Kinase Inhibitor Set 1 (PKIS1) was tested, in order to create a comprehensive activity map.55,56 The inhibitory activities of the PKIS1 were examined against 224 kinases, with the screens performed at the Km of ATP for each kinase. Each inhibitor was assessed at 1.0 and 0.1 μM. Abbreviations follow: CAMK, calmodulin/ calcium regulated kinases; AGC, protein kinase A, G, and C family kinases; CK1, casein kinase 1; STE, yeast STE7, STE11, and STE20 homologues; CMGC, CDK, MAPK, GSK3, and CLK kinase family; TK, tyrosine kinase; TKL, tyrosine kinase-like.57 * denotes kinase group containing point mutant(s), kinases bound to varying cyclins, or splice variants that were also tested against the PKIS1. Illustration created with data from Dr. David Drewry and reproduced using an illustration program courtesy of Cell Signaling Technology, Inc. (www. cellsignal.com).

activity relationship(s) (SAR) in the phenotypic screens, which can subsequently help identify kinase targets responsible for the phenotype observed during the screens. The wealth of structural information for protein kinases suggests further optimization could be performed to generate a more discriminating kinase inhibitor. GSK provides these two sets, which, in total, contain over 30 different inhibitor chemotypes, to researchers with the capacity and expertise to examine and identify the molecular targets of these inhibitors. This, in turn, promotes the identification of new kinases and pathways that may serve as the foundation for further drug discovery and lead development, as well as catalyzes the completion of the human kinome map. Similarly to humans, prokaryotes, as well as other eukaryotes, rely on kinases to maintain proper cellular activity. Thus, protein kinases are important targets for drug development. Due to kinase inhibitors targeting the ATP binding site, compounds that inhibit kinases found in humans may also inhibit those found in other families of organisms. The GSK PKIS may be utilized by WIPO Re:Search Members to inhibit specific microbial targets, or, as the following paragraphs 11275

dx.doi.org/10.1021/cr5000656 | Chem. Rev. 2014, 114, 11272−11279

Chemical Reviews

Review

There are several pathogens associated with this disease; viruses (e.g., rotavirus, noroviruses), bacteria (e.g., E. coli, Shigella spp. Vibrio cholerae), and protozoa (e.g., Giardia, Cryptosporidium, Entamoeba) all cause diarrheal diseases. Antibiotics may be used to treat some bacterial infections; however, there are no available antivirals or antiparasitics to treat the two other main causes of diarrhea. Furthermore, while GSK and MSD both developed vaccines to prevent rotavirus infection, most of the other causes of infectious diarrhea remain without an available vaccine. Thus, there is a continued need for effective drugs, especially in regions with limited access to clean drinking water and proper sanitation. A drug that targets the symptoms of infection, rather than the specific pathogen, would be extremely useful and would have the potential to reduce the burden of diarrheal diseases in all regions of the globe, regardless of the endemic diarrheal pathogens. Current therapies for diarrhea include oral rehydration therapy (ORT) and zinc administration. ORT using oral rehydration solutions (ORS) containing glucose and sodium reduces fluid loss and dehydration.47 Zinc administration reduces the duration and severity of diarrhea.48,49 These therapies, in combination, can reduce the number of child deaths due to diarrhea, without the risk of promoting antibiotic resistance.45 Yet while these two therapies are highly effective at preventing deaths associated with diarrheal disease, another drug that more directly addresses the cause of diarrhea may prove more effective in reducing the acute and long-term burden of these diseases. In addition, perturbing the dysregulation of stool production will enhance absorption of the ORS and zinc. Diarrhea, or watery stool, occurs when the absorption and secretion of fluids and electrolytes between the intestinal lumen and surrounding epithelial cells is not properly regulated. Ion exchange through epithelial cell ion transporters or through tight junctions between cells is critical to managing proper fluid absorption and secretion. Several pathogens associated with diarrheal disease induce diarrhea by altering the ion exchange across intestinal epithelial cells.50 The altered ion transport results in increased concentration of chloride and sodium ions within the intestinal lumen, which subsequently induces the secretion of fluid into the lumen. These pathogens may directly perturb ion channels or indirectly influence secretion and absorption by inducing an inflammatory response. Scientists at PATH and Children’s Hospital in Boston previously demonstrated that inhibitors of the calciumregulated potassium channel, KCa3.1, effectively reduced cholera toxin-mediated diarrhea in vivo.51 The inhibitor, Senicapoc, was previously developed to treat sickle cell disease.52 Phase I and II clinical trials of Senicapoc demonstrated that the drug was safe and well-tolerated; however, a phase III trial was ended early due to the low probability that Senicapoc would reach its clinical end point of reducing vaso-occlusive pain.53 Intracellular efflux of potassium, regulated by KCa3.1, is necessary for numerous biological activities, including cell proliferation, chemokine and cytokine production, and the regulation of mast cell receptors known to contribute to inflammatory airway diseases.53,54 Thus, Icagen, which was subsequently acquired by Pfizer, and is the developer of Senicapoc, also assessed the drug’s efficacy against asthma. A phase II trial demonstrated encouraging results against allergic asthma, but no effect on exercise-induced asthma.53 PATH contacted BVGH to request access to Senicapoc’s preclinical and clinical data in order to accelerate the

blood-stage that causes the symptoms associated with malaria infection, including high fever, headache, and vomiting. Thus, understanding the mechanisms of erythrocyte invasion is essential to developing therapies that prevent malaria morbidities and mortalities. Second messengers, such as calcium and cAMP, regulate important parasitic processes, including invasion of host erythrocytes,34 often by regulating protein kinases. Researchers at NII are elucidating the role and regulation of several protein kinases that are essential to P. falciparum viability.35−39 Attempts to knock out genes encoding several of these kinases were unsuccessful, and suggested that these kinases are essential for parasite development.40 Therefore, additional tools to investigate the regulation and function of these kinases are needed. The researchers at NII will utilize GSK’s PKIS1 to identify compounds capable of inhibiting parasite kinases and subsequently use the identified inhibitors to dissect the role of the kinases during human infection, including substrate identification and validation. Both of these research projects using GSK’s PKIS1 are the result of BVGH’s proactive partnering: BVGH ascertained NII’s interest in kinase inhibitors and subsequently facilitated productive discussions between the NII researchers and GSK’s tuberculosis and malaria groups. Material transfer agreements were established, and the inhibitor sets were shipped to the researchers for testing.

4. RECYCLING DATA FOR GLOBAL HEALTH The path from discovery to market is a complex, iterative process requiring expertise in several fields. Upon screening compounds against a particular pathogen or target, identified hits undergo lead optimization, which involves optimizing the compounds’ drug-like properties, such as potency, selectivity, and absorption, distribution, metabolism, and excretion (ADME) characteristics, as well as examining in vitro toxicity. Following optimization, the lead candidate is examined in an array of preclinical experiments, including pharmacokinetic and pharmacodynamic assessments and in vivo toxicology studies. The data acquired during these tests must be reviewed by regulatory authorities prior to gaining approval to initiate testing of the drug in humans. Following discovery, a drug may require as many as 15 years41 and more than a billion USD42 before being approved for commercial distribution. Despite the vast amount of resources put into these efforts, the attrition rate for investigational new drugs (INDs) is staggering: 83% of all lead candidates that enter clinical trials will not survive to commercialization,43 many simply because they do not exhibit a satisfactory efficacy against the indication for which they were developed. Regardless of whether the candidate drug enters the market, a wealth of data is accumulated, information that may be of use to others. WIPO Re:Search Members are taking advantage of this information to accelerate their research to identify novel antidiarrheal drugs. The effects of diarrheal diseases are multifaceted: the acute disease is the second leading cause of death in children under the age of five, resulting in 760 000 deaths annually,44 while repetitive infections result in malnutrition, leading to diminished physical and mental development.45 These acute infections and their chronic sequelae result in decreased school attendance and IQ scores, which consequently negatively affect economic growth and development.46 Thus, diarrheal diseases affect not only the individual, but negatively impact entire endemic countries. 11276

dx.doi.org/10.1021/cr5000656 | Chem. Rev. 2014, 114, 11272−11279

Chemical Reviews

Review

Biographies

repurposing of this drug. Discussions between PATH and the current owner of the drug’s intellectual property and legacy data, Pfizer, were facilitated by BVGH. Pfizer subsequently offered to provide PATH with the Senicapoc investigator’s brochure (IB). In addition, Icagen had previously assessed Senicapoc against diarrheal disease, and Pfizer provided PATH with the data from that study as well. The PATH scientists will use these data to inform their next steps. If they decide to enter the drug into clinical trials and file an IND application with the US Food and Drug Administration (FDA) for diarrheal indications, PATH will have saved significant time and money that would have been spent reproducing Pfizer’s extensive data.

5. CONCLUSION Roopa Ramamoorthi is the Associate Director, Partnering & Scientific

Through advances in technology and travel, the world is more connected than ever before. Despite these developments, health disparities still exist in many regions of the world. A concerted effort to combine the resources of the public, private, and philanthropic sectors is essential to correcting this imbalance. While some progress has been achieved, there is no room for complacency. Resources are limited, and time is of the essence. Additional initiatives that combine the efforts and expertise of organizations across industries and geographies are required. By providing nonprofit and academic researchers working on neglected diseases with the opportunity to access compounds and expertise from pharmaceutical companies, WIPO Re:Search is opening new doors and creating additional avenues for product development for diseases of poverty. These collaborations create opportunities to expand scientific understanding of the basic molecular mechanisms of pathogens, to accelerate identification and development of new candidate drugs, and to support the repurposing of compounds for new and neglected indications. These, and similar projects initiated through the WIPO Re:Search consortium, bridge the divide between industry and nonprofit researchers, creating collaborations with the common goal of reducing the burden that neglected diseases impose on individuals living in poverty around the world.

Affairs, at BIO Ventures for Global Health. Prior to joining BVGH, Roopa was a senior research analyst with the consulting firm, Strategic Perspectives. She worked for Bayer in California for more than five years as a scientist and senior scientist. While at Bayer, Roopa was responsible for developing purification processes for antibodies and other complex proteins. In her role, she also led external collaborations to evaluate and ensure the successful integration of new platform technologies. Roopa received her Ph.D. in biochemical engineering from the California Institute of Technology and conducted postdoctoral research at the University of Washington and at the Massachusetts Institute of Technology. Roopa grew up in India where she received her B.S. in chemical engineering from the Indian Institute of Technology in Mumbai.

AUTHOR INFORMATION Corresponding Author

*Email: [email protected]. Phone: (206) 732-2131. Notes

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the World Intellectual Property Organization. The authors declare the following competing financial interest(s): J.C.D., R.R., and K.M.G. are employees of BIO Ventures for Global Health, which receives WIPO Re:Search sponsorship funding from Alnylam, Eisai, GlaxoSmithKline, MSD, Novartis, Pfizer, and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Katy M. Graef is a Senior Manager at BIO Ventures for Global Health. She obtained her bachelor’s degree in Microbiology and completed her Ph.D. in Virology at the University of Oxford. Her graduate studies examined host−pathogen interactions of influenza viruses. Following her graduate work, she became a postdoctoral research fellow at the Rocky Mountain Laboratories in Montana, where she studied tickborne flaviviruses. 11277

dx.doi.org/10.1021/cr5000656 | Chem. Rev. 2014, 114, 11272−11279

Chemical Reviews

Review

ABBREVIATIONS BVGH BIO Ventures for Global Health DALY disability-adjusted life year FDA US Food and Drug Administration GSK GlaxoSmithKline IDRI Infectious Disease Research Institute IND investigational new drug LMIC low-to-middle income country MDR multidrug resistant NCI National Cancer Institute NIH US National Institutes of Health NII National Institute of Immunology NPB Natural Products Branch NTD neglected tropical disease ORS oral rehydration solution PKIS Published Kinase Inhibitor Set R&D research and development USD United States Dollar WIPO World Intellectual Property Organization

Anatole Krattiger leads the Global Challenges Division at WIPO, working on global health, climate change, and food security. Originally a farmer from Switzerland, he holds an M.Phil. in genetics and a Ph.D. in biotechnology from the University of Cambridge, England. He worked at the CGIAR (CIMMYT); led ISAAA during the 1990s, a nonprofit international broker of Ag-Biotech; consulted widely at the crossroads of development, government, science, businesses, and philanthropy; served as Executive to the Humanitarian Board for Golden Rice; and has been teaching innovation management in health and agriculture at Cornell University and Arizona State University. He published widely and was as editor-in-chief of IP Management of Health and Agricultural Innovation: A Handbook of Best Practices (www. ipHandbook.org).

REFERENCES (1) Institute for Health Metrics and Evaluation. Global Burden of Disease Compare; Seattle, 2013. (2) Bethony, J. M.; Cole, R. N.; Guo, X.; Kamhawi, S.; Lightowlers, M. W.; Loukas, A.; Petri, W.; Reed, S.; Valenzuela, J. G.; Hotez, P. J. Immunol. Rev. 2011, 239, 237. (3) Hotez, P. Vaccine 2011, 29 (Suppl 4), D104. (4) MSD is known as Merck in the U.S. and Canada. (5) Daniel, T. M. Respir. Med. 2006, 100, 1862. (6) Baddeley, A.; Dean, A.; Dias, H. M.; Falzon, D.; Floyd, K.; Garcia, I.; Glaziou, P.; Hiatt, T.; Law, I.; Lienhardt, C.; Nguyen, L.; Sismanidis, C.; Timimi, H.; van Gemert, W.; Zignol, M. Global Tuberculosis Report 2013; World Health Organization: Geneva, 2013. (7) Andrews, K.; Aregawi, M.; Cibulskis, R.; Fergus, C.; Lynch, M.; Newman, R.; Szilagyi, Z.; Williams, R. World Malaria Report 2013; World Health Organization: Geneva, 2013. (8) Bhatt, S.; Gething, P. W.; Brady, O. J.; Messina, J. P.; Farlow, A. W.; Moyes, C. L.; Drake, J. M.; Brownstein, J. S.; Hoen, A. G.; Sankoh, O.; Myers, M. F.; George, D. B.; Jaenisch, T.; Wint, G. R.; Simmons, C. P.; Scott, T. W.; Farrar, J. J.; Hay, S. I. Nature 2013, 496, 504. (9) Koul, A.; Arnoult, E.; Lounis, N.; Guillemont, J.; Andries, K. Nature 2011, 469, 483. (10) Baddeley, A.; Dias, H. M.; Falzon, D.; Fitzpatrick, C.; Floyd, K.; Gilpin, C.; Glaziou, P.; Hiatt, T.; Pantoja, A.; Sculier, D.; Sismanidis, C.; Timimi, H.; Uplekar, M.; van Gemert, W. Global Tuberculosis Control 2011; World Health Organization: Geneva, 2011. (11) Centers for Disease Control and Prevention. TB Elimination Multidrug-Resistant Tuberculosis (MDR TB); Atlanta, 2012. (12) World Health Organization. Multidrug-Resistant Tuberculosis (MDR-TB) 2013 Update; Geneva, 2013. (13) Klopper, M.; Warren, R. M.; Hayes, C.; Gey van Pittius, N. C.; Streicher, E. M.; Muller, B.; Sirgel, F. A.; Chabula-Nxiweni, M.; Hoosain, E.; Coetzee, G.; David van Helden, P.; Victor, T. C.; Trollip, A. P. Emerging Infect. Dis. 2013, 19, 449. (14) Koul, A.; Arnoult, E.; Lounis, N.; Guillemont, J.; Andries, K. Nature 2011, 469, 483. (15) Pawlowski, A.; Jansson, M.; Skold, M.; Rottenberg, M. E.; Kallenius, G. PLoS Pathog. 2012, 8, e1002464. (16) Getahun, H.; Gunneberg, C.; Granich, R.; Nunn, P. Clin. Infect. Dis. 2010, 50 (Suppl 3), S201. (17) Camp, D.; Newman, S.; Pham, N. B.; Quinn, R. J. Comb. Chem. High Throughput Screening 2014, 17, 201. (18) Wada, T.; Penninger, J. M. Oncogene 2004, 23, 2838. (19) Henneke, G.; Koundrioukoff, S.; Hubscher, U. EMBO Rep. 2003, 4, 252.

Jennifer C. Dent is the President of BIO Ventures for Global Health. Jennifer began her career as a sales representative in Canada working in a variety of positions for Parke Davis/Pfizer and Genentech. Following the acquisition of Genentech Canada by Roche, Jennifer held a number of senior management positions in marketing, life cycle management, global product strategy, business development, and alliance management at Roche and Genentech in Canada, Switzerland, New Jersey, and South San Francisco. Jennifer cofounded Sound Biotechnology, and, prior to that, served as Vice President, Business Development, Marketing and Sales at CombiMatrix Corporation in Washington State. Jennifer graduated from the University of Western Ontario with a B.Sc., and she received her executive M.B.A. at Western’s Richard Ivey School of Business.

ACKNOWLEDGMENTS The authors thank AstraZeneca, Eskitis Institute, GlaxoSmithKline, IDRI, NIH, NII, PATH, and Pfizer for their review and helpful suggestions. 11278

dx.doi.org/10.1021/cr5000656 | Chem. Rev. 2014, 114, 11272−11279

Chemical Reviews

Review

(20) Trovesi, C.; Manfrini, N.; Falcettoni, M.; Longhese, M. P. J. Mol. Biol. 2013, 425, 4756. (21) Gehart, H.; Kumpf, S.; Ittner, A.; Ricci, R. EMBO Rep. 2010, 11, 834. (22) Arthur, J. S.; Ley, S. C. Nat. Rev. Immunol. 2013, 13, 679. (23) Piper, R.; Bryant, N. Trafficking Inside Cells: Pathways, Mechanisms and Regulation; Landes Bioscience and Springer Science + Business Media: Austin, TX, 2009, 363. (24) Kondapalli, L.; Soltani, K.; Lacouture, M. E. J. Am. Acad. Dermatol. 2005, 53, 291. (25) Pray, L. A. Nat. Educ. 2008, 1, 37. (26) Druker, B. J.; Talpaz, M.; Resta, D. J.; Peng, B.; Buchdunger, E.; Ford, J. M.; Lydon, N. B.; Kantarjian, H.; Capdeville, R.; Ohno-Jones, S.; Sawyers, C. L. N. Engl. J. Med. 2001, 344, 1031. (27) Taylor, S. S.; Radzio-Andzelm, E. Structure 1994, 2, 345. (28) Hanks, S. K.; Hunter, T. FASEB J. 1995, 9, 576. (29) Knapp, S.; Arruda, P.; Blagg, J.; Burley, S.; Drewry, D. H.; Edwards, A.; Fabbro, D.; Gillespie, P.; Gray, N. S.; Kuster, B.; Lackey, K. E.; Mazzafera, P.; Tomkinson, N. C.; Willson, T. M.; Workman, P.; Zuercher, W. J. Nat. Chem. Biol. 2013, 9, 3. (30) Favrot, L.; Ronning, D. R. Expert Rev. Anti-Infect. Ther. 2012, 10, 1023. (31) World Health Organization. Malaria Fact Sheet No. 94; Geneva, 2014. (32) Kim, Y.; Schneider, K. A. Nat. Educ. Knowl. 2013, 4, 6. (33) Cowman, A. F.; Berry, D.; Baum, J. J. Cell Biol. 2012, 198, 961. (34) Sharma, P.; Chitnis, C. E. Curr. Opin. Microbiol. 2013, 16, 432. (35) Kumar, A.; Vaid, A.; Syin, C.; Sharma, P. J. Biol. Chem. 2004, 279, 24255. (36) Vaid, A.; Sharma, P. J. Biol. Chem. 2006, 281, 27126. (37) Vaid, A.; Thomas, D. C.; Sharma, P. J. Biol. Chem. 2008, 283, 5589. (38) Ahmed, A.; Gaadhe, K.; Sharma, G. P.; Kumar, N.; Neculai, M.; Hui, R.; Mohanty, D.; Sharma, P. FASEB J. 2012, 26, 3212. (39) Ranjan, R.; Ahmed, A.; Gourinath, S.; Sharma, P. J. Biol. Chem. 2009, 284, 15267. (40) Solyakov, L.; Halbert, J.; Alam, M. M.; Semblat, J. P.; DorinSemblat, D.; Reininger, L.; Bottrill, A. R.; Mistry, S.; Abdi, A.; Fennell, C.; Holland, Z.; Demarta, C.; Bouza, Y.; Sicard, A.; Nivez, M. P.; Eschenlauer, S.; Lama, T.; Thomas, D. C.; Sharma, P.; Agarwal, S.; Kern, S.; Pradel, G.; Graciotti, M.; Tobin, A. B.; Doerig, C. Nat. Commun. 2011, 2, 565. (41) Dickson, M.; Gagnon, J. P. Discovery Med. 2004, 4, 172. (42) Levine, D. S. New Estimate of Drug Development Costs Pegs Total at $1.5 Billion. The Burrill Report, Dec 7, 2012. (43) DiMasi, J. A.; Feldman, L.; Seckler, A.; Wilson, A. Clin. Pharmacol. Ther. 2010, 87, 272. (44) World Health Organization. Diarrhoeal Disease Fact Sheet No. 330; Geneva, 2013. (45) Keusch, G. T.; Fontaine, O.; Bhargava, A.; Boschi-Pinto, C.; Bhutta, Z. A.; Gotuzzo, E.; Rivera, J.; Chow, J.; Shahid-Salles, S.; Laxminarayan, R. Disease Control Priorities in Developing Countries, 2nd Ed.; World Bank: Washington, DC, 2006; p 371. (46) Guerrant, R. L.; Oria, R. B.; Moore, S. R.; Oria, M. O.; Lima, A. A. Nutr. Rev. 2008, 66, 487. (47) Hirschhorn, N.; Kinzie, J. L.; Sachar, D. B.; Northrup, R. S.; Taylor, J. O.; Ahmad, S. Z.; Phillips, R. A. N. Engl. J. Med. 1968, 279, 176. (48) Bajait, C.; Thawani, V. Indian J. Pharmacol. 2011, 43, 232. (49) Khan, W. U.; Sellen, D. W. In e-Library of Evidence for Nutrition Actions (eLENA); World Health Organization: Geneva, 2011. (50) Hodges, K.; Gill, R. Gut Microbes 2010, 1, 4. (51) Rufo, P. A.; Merlin, D.; Riegler, M.; Ferguson-Maltzman, M. H.; Dickinson, B. L.; Brugnara, C.; Alper, S. L.; Lencer, W. I. J. Clin. Invest. 1997, 100, 3111. (52) Stocker, J. W.; De Franceschi, L.; McNaughton-Smith, G. A.; Corrocher, R.; Beuzard, Y.; Brugnara, C. Blood 2003, 101, 2412. (53) Wulff, H.; Castle, N. A. Expert Rev. Clin. Pharmacol. 2010, 3, 385.

(54) Duffy, S. M.; Cruse, G.; Lawley, W. J.; Bradding, P. FASEB J. 2005, 19, 1006. (55) Drewry, D.; Zuercher, B. 2nd RSC Symposium on Chemical Biology for Drug Discovery, Macclesfield, U. K., March 20−21, 2012. (56) Drewry, D. H.; Willson, T. M.; Zuercher, W. J. Curr. Top. Med. Chem. 2014, 14, 340. (57) Manning, G.; Whyte, D. B.; Martinez, R.; Hunter, T.; Sudarsanam, S. Science 2002, 298, 1912.

11279

dx.doi.org/10.1021/cr5000656 | Chem. Rev. 2014, 114, 11272−11279