Editorial Special Focus: Horizons in Medicinal Chemistry For reprint orders, please contact [email protected]
How can we discover safer drugs? “Ultimately, if fully integrated, discovery safety will, in addition to ensuring that drug candidates with a safety risk indeed fail early, enable the generation of drug candidates with a superior safety profile.” Keywords: discovery safety n drug discovery n exploratory toxicology n lead optimization n predictive toxicology n safety assessment
Discovery safety: from failing early to increasing success It appears that the declining trend for the number of new drug registrations has halted in the past couple of years [1]. Still, drug development is an inefficient process: it is costly, it takes a long time and approximately 90% of clinical candidates do not make it to the market [2–5]. Most drug-development failures can be explained by lack of efficacy or safety issues [6]. Toxicologyrelated attrition occurs frequently as a result of preclinical animal toxicology studies, but still approximately 30% of clinical programs are discontinued for safety reasons. Even for programs that fail in the final clinical or registration phases, some 20% do so because of a safety issue [7]. Human safety is furthermore the main reason for the regulatory authorities to suspend market registrations, issue label warnings and impose use restrictions. In order to improve the success of drug development, predictive safety and toxicology studies are nowadays carried out in relatively early project stages, with the aim of halting drug candidates with a particular safety risk from progressing into the development pipeline [8]. ‘Fail early, fail cheap’ is a commonly used one-liner. However, failing early is not the same as increasing success. We cannot simply assume that compounds with a superior safety profile will emerge automatically if we stop candidates with a less safe profile. In order to reduce safety-related attrition and increase the success of bringing safer candidates forward, ‘discovery safety’ needs to be a fully integrated discipline in the drugdiscovery process [9–12]. The aim of discovery safety is to ensure that safety liabilities resulting from hitting the primary target, from secondary pharmacology or from specific chemical features are identified early and subsequently mitigated. As part of this, safety has to be actively designed into the molecular entities, just like other drug properties within drug-discovery programs.
How should discovery safety work in practice? As many safety issues can arise from hitting the primary target, it is important to generate a target safety assessment. This encompasses an overview of safety issues that may result from hitting the primary target, based on the available knowledge on the biological function of the target as well as on information (if available) on adverse reactions that emerged in clinical studies with candidates that hit the same target or pathway. If the target safety assessment is carried out in a timely manner, it will enable teams to assess safety aspects during target validation studies, for example, identify hazards using knockout models or pharmacological tool compounds, or to perform specific target safety studies using specialized models to investigate whether the particular target is viable. In addition, it provides time to identify and validate predictive biomarkers which, if they can be translated to the clinic, may enable a project to monitor a particular target safety concern in humans. Besides target safety, it is of course essential to assess compound safety. But when should one start safety testing in a discovery project? One could argue that very early compounds should not be screened on safety end points because, due to the many structural modifications that will be incorporated during the course of lead optimization, the results for very early compounds will not be representative for the final candidate. However, this is the case for all results that are obtained for early compounds, including potency on target, selectivity, solubility, stability, target organ exposure, and so on. The purpose of all data gathered during the hit-tolead process is to assess which of the compound series are suitable to take forward. Most often, this comes down to prioritizing a small number of series over the rest of the compound series that have been identified. This process benefits from having relevant data on the series of interest from
10.4155/FMC.14.15 © 2014 Future Science Ltd
Future Med. Chem. (2014) 6(5), 481–483
Jorrit J Hornberg Author for correspondence: Department of Exploratory Toxicology, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark Tel.: +45 36433783 Fax: +45 36438313 [email protected]
Tomas Mow Department of Exploratory Toxicology, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark
ISSN 1756-8919
481
Editorial | Hornberg & Mow all disciplines, including safety. Several in silico and in vitro methods can be easily employed at this stage [10,12–14], such as identifying structural alerts, screening for high risk off targets (e.g., hERG), genotoxicity (e.g., GreenScreen®) or molecular toxicity (e.g., mitochondrial toxicity, cell death, oxidative stress) and broad selectivity profiling. If a particular safety end point is hit, testing analogues may shed light on whether the issue is intrinsic in the series. Such information should not necessarily be used to stop a particular series, but rather be incorporated in an assessment of all relevant pros and cons of each series. Based on that, teams decide what chemistry to work on going forward.
“Discovery safety has to be perceived as a discipline that increases the success of a project (i.e., long-term progression), rather than as the traditional toxicology hurdle (‘bad news’) that may end the project.” During the lead optimization process, it should be assessed how the structural modifications affect safety end points, and in order to avoid that, a potential liability is introduced. Therefore, several safety assays have to be a standard component of the assay flow chart for discovery projects. When a particular safety risk is encountered, identifying structure–activity relationships (SAR) will be essential to enable optimization of the series on the relevant end point. SAR studies are most effective if the relevant safety assays have reasonably high throughput and allow for rapid feedback of quantitative data to the medicinal chemist and also benefit from predictive in silico SAR models on the particular end point to guide chemistry. A tight interaction between the discovery toxicologist, the medicinal chemist and other core team members is essential to make this process efficient. As part of selection of the drug candidate to be progressed towards first-in-man enabling safety studies, exploratory safety pharmacology and in vivo toxicology studies give insight into the nature and severity of the most acute and/or most likely safety issues for the particular compound as well as provide an estimation of the therapeutic index (TI) [15,16]. It is noteworthy that the size of the TI as well as the estimated efficacious drug concentration are relatively predictive for whether a compound will pass or fail during the toxicology studies [17]. Therefore, rather than only establishing whether the most 482
Future Med. Chem. (2014) 6(5)
efficacious compound is safe enough to progress, it is worthwhile to test multiple compounds in exploratory in vivo studies. Identifying the compound with the largest TI will increase the chance of success in later stages. What are the key factors to make discovery safety work? First, there may be organizational challenges. On the one hand, discovery safety has its roots within the nonclinical safety area and requires strong interactions with the drug-development organization. This provides perspectives on regulatory requirements and on possibilities to handle a safety risk in later stages of development. On the other hand, discovery safety must be closely connected to the discovery organization, instead of being a distant support function. In order to enable discovery safety scientists to make an impact within discovery projects, they need to be part of the core teams as an equal partner to the chemist, biologist, pharmacologist, and others. Only then will they have real influence on the decisions regarding the validation of novel drug targets, the selection of chemical series, the optimization process and candidate selection. In this way, discovery safety scientists can assume shared responsibility to bring projects forward, rather than only to prevent projects with a less favorable safety profile to progress into the first-in-man enabling safety studies. Discovery safety scientists have to create acceptance of their strategy and the methods and readouts they employ. Optimization on safety end points may in many instances be possible, but it may also be difficult, especially if SAR cannot be generated. Drug discovery is difficult enough as it is and teams need to be willing to make that extra effort. To achieve that, discovery safety has to be perceived as a discipline that increases the success of a project (i.e., long-term progression), rather than as the traditional toxicology hurdle (‘bad news’) that may end the project. Safety readouts have to be properly validated, such that the predictivity of an early assay for preclinical toxicity or clinical safety can be established, and open discussions with the other disciplines on the science, assays, data, conclusions and consequent decisions are required. Finally, the discovery safety strategy has to be part of the overall research strategy, with support from relevant management boards and clear safety-related criteria for lead compounds and development candidates. Although such criteria should not be carved in stone, as safety future science group
How can we discover safer drugs? issues should always be placed into context of the project and the medical need of the envisaged indication, they should provide guidance on what properties are required to eliminate the most overt safety risks. It will be challenging for most organizations to screen for all potential safety risks in early projects. In order to indeed reduce safety-related attrition, there has to be focus on those liabilities that emerge often (liver, cardiovascular and nervous system toxicity), have high impact (genotoxicity) or are related to the target [9,10]. Due to the long duration of drug-development programs, the impact of discovery safety on the overall success of drug development will be hard to measure in the short term. A surrogate success criterion could be passing first-in-man enabling safety studies, which should at least increase the chance that a project team can test its therapeutic concept in the clinic. Still, some safety issues do not present themselves until a larger patient
| Editorial
population has been exposed, such as idiosyncratic drug-induced liver injury [18], and they can actually be influenced during drug discovery [19]. Ultimately, if fully integrated, discovery safety will, in addition to ensuring that drug candidates with a safety risk indeed fail early, enable the generation of drug candidates with a superior safety profile. This should decrease safety-related attrition and increase the overall success of drug development. Financial & competing interests disclosure The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
References 1
Mullard A. 2012 FDA drug approvals. Nat. Rev. Drug Discov. 12(2), 87–90 (2013).
2
Kaitin KI, Dimasi JA. Pharmaceutical innovation in the 21st century: new drug approvals in the first decade, 2000–2009. Clin. Pharmacol. Ther. 89(2), 183–188 (2011).
3
Morgan S, Grootendorst P, Lexchin J, Cunningham C, Greyson D. The cost of drug development: a systematic review. Health Policy 100(1), 4–17 (2011).
4
Paul SM, Mytelka DS, Dunwiddie CT et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat. Rev. Drug Discov. 9(3), 203–214 (2010).
5
Pammolli F, Magazzini L, Riccaboni M. The productivity crisis in pharmaceutical R&D. Nat. Rev. Drug Discov. 10(6), 428–438 (2011).
6
Kola I , Landis J. Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov. 3(8), 711–715 (2004).
7
Arrowsmith J. Trial watch: Phase III and submission failures: 2007–2010. Nat. Rev. Drug Discov. 10, 87 (2011).
8
Sasseville VG, Lane JH, Kadambi VJ et al. Testing paradigm for prediction of development-limiting barriers and human
future science group
drug toxicity. Chem. Biol. Interact. 150(1), 9–25 (2004). 9
Hornberg JJ, Laursen M, Brenden N et al. Exploratory toxicology as an integrated part of drug discovery. Part I: why and how. Drug Discov. Today doi:10.1016/j. drudis.2013.12.008 (2013) (Epub ahead of print).
10 Hornberg JJ, Laursen M, Brenden N et al.
Exploratory toxicology as an integrated part of drug discovery. Part II: screening strategies. Drug Discov. Today doi:10.1016/j. drudis.2013.12.009 (2013) (Epub ahead of print). 11 Kramer JA, Sagartz JE, Morris DL. The
application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates. Nat. Rev. Drug Discov. 6(8), 636–649 (2007). 12 Thomas CE , Will Y. The impact of assay
technology as applied to safety assessment in reducing compound attrition in drug discovery. Expert. Opin. Drug Discov. 7(2), 109–122 (2012). 13 Will Y , Schroeter T. Deployment of in silico
and in vitro safety assays in early-stage drug discovery. Future Med. Chem. 4(10), 1211–1213 (2012).
www.future-science.com
14 Segall MD, Barber C. Addressing toxicity risk
when designing and selecting compounds in early drug discovery. Drug Discov. Today doi:10.1016/j.drudis.2014.01.006 (2014) (Epub ahead of print). 15 Bass AS, Cartwright ME, Mahon C et al.
Exploratory drug safety: a discovery strategy to reduce attrition in development. J. Pharmacol. Toxicol. Methods 60(1), 69–78 (2009). 16 Muller PY , Milton MN. The determination
and interpretation of the therapeutic index in drug development. Nat. Rev. Drug Discov. 11(10), 751–761 (2012). 17 Wager TT, Kormos BL, Brady JT et al.
Improving the odds of success in drug discovery: choosing the best compounds for in vivo toxicology studies. J. Med. Chem. 56(23), 9771–9779 (2013). 18 Kaplowitz N. Idiosyncratic drug
hepatotoxicity. Nat. Rev. Drug Discov. 4(6), 489–499 (2005). 19 Persson M, Loye AF, Mow T, Hornberg JJ.
A high content screening assay to predict human drug-induced liver injury during drug discovery. J. Pharmacol. Toxicol. Methods 68(3), 302–313 (2013).
483
How can we discover safer drugs? “Ultimately, if fully integrated, discovery safety will, in addition to ensuring that drug candidates with a safety risk indeed fail early, enable the generation of drug candidates with a superior safety profile.” Keywords: discovery safety n drug discovery n exploratory toxicology n lead optimization n predictive toxicology n safety assessment
Discovery safety: from failing early to increasing success It appears that the declining trend for the number of new drug registrations has halted in the past couple of years [1]. Still, drug development is an inefficient process: it is costly, it takes a long time and approximately 90% of clinical candidates do not make it to the market [2–5]. Most drug-development failures can be explained by lack of efficacy or safety issues [6]. Toxicologyrelated attrition occurs frequently as a result of preclinical animal toxicology studies, but still approximately 30% of clinical programs are discontinued for safety reasons. Even for programs that fail in the final clinical or registration phases, some 20% do so because of a safety issue [7]. Human safety is furthermore the main reason for the regulatory authorities to suspend market registrations, issue label warnings and impose use restrictions. In order to improve the success of drug development, predictive safety and toxicology studies are nowadays carried out in relatively early project stages, with the aim of halting drug candidates with a particular safety risk from progressing into the development pipeline [8]. ‘Fail early, fail cheap’ is a commonly used one-liner. However, failing early is not the same as increasing success. We cannot simply assume that compounds with a superior safety profile will emerge automatically if we stop candidates with a less safe profile. In order to reduce safety-related attrition and increase the success of bringing safer candidates forward, ‘discovery safety’ needs to be a fully integrated discipline in the drugdiscovery process [9–12]. The aim of discovery safety is to ensure that safety liabilities resulting from hitting the primary target, from secondary pharmacology or from specific chemical features are identified early and subsequently mitigated. As part of this, safety has to be actively designed into the molecular entities, just like other drug properties within drug-discovery programs.
How should discovery safety work in practice? As many safety issues can arise from hitting the primary target, it is important to generate a target safety assessment. This encompasses an overview of safety issues that may result from hitting the primary target, based on the available knowledge on the biological function of the target as well as on information (if available) on adverse reactions that emerged in clinical studies with candidates that hit the same target or pathway. If the target safety assessment is carried out in a timely manner, it will enable teams to assess safety aspects during target validation studies, for example, identify hazards using knockout models or pharmacological tool compounds, or to perform specific target safety studies using specialized models to investigate whether the particular target is viable. In addition, it provides time to identify and validate predictive biomarkers which, if they can be translated to the clinic, may enable a project to monitor a particular target safety concern in humans. Besides target safety, it is of course essential to assess compound safety. But when should one start safety testing in a discovery project? One could argue that very early compounds should not be screened on safety end points because, due to the many structural modifications that will be incorporated during the course of lead optimization, the results for very early compounds will not be representative for the final candidate. However, this is the case for all results that are obtained for early compounds, including potency on target, selectivity, solubility, stability, target organ exposure, and so on. The purpose of all data gathered during the hit-tolead process is to assess which of the compound series are suitable to take forward. Most often, this comes down to prioritizing a small number of series over the rest of the compound series that have been identified. This process benefits from having relevant data on the series of interest from
10.4155/FMC.14.15 © 2014 Future Science Ltd
Future Med. Chem. (2014) 6(5), 481–483
Jorrit J Hornberg Author for correspondence: Department of Exploratory Toxicology, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark Tel.: +45 36433783 Fax: +45 36438313 [email protected]
Tomas Mow Department of Exploratory Toxicology, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark
ISSN 1756-8919
481
Editorial | Hornberg & Mow all disciplines, including safety. Several in silico and in vitro methods can be easily employed at this stage [10,12–14], such as identifying structural alerts, screening for high risk off targets (e.g., hERG), genotoxicity (e.g., GreenScreen®) or molecular toxicity (e.g., mitochondrial toxicity, cell death, oxidative stress) and broad selectivity profiling. If a particular safety end point is hit, testing analogues may shed light on whether the issue is intrinsic in the series. Such information should not necessarily be used to stop a particular series, but rather be incorporated in an assessment of all relevant pros and cons of each series. Based on that, teams decide what chemistry to work on going forward.
“Discovery safety has to be perceived as a discipline that increases the success of a project (i.e., long-term progression), rather than as the traditional toxicology hurdle (‘bad news’) that may end the project.” During the lead optimization process, it should be assessed how the structural modifications affect safety end points, and in order to avoid that, a potential liability is introduced. Therefore, several safety assays have to be a standard component of the assay flow chart for discovery projects. When a particular safety risk is encountered, identifying structure–activity relationships (SAR) will be essential to enable optimization of the series on the relevant end point. SAR studies are most effective if the relevant safety assays have reasonably high throughput and allow for rapid feedback of quantitative data to the medicinal chemist and also benefit from predictive in silico SAR models on the particular end point to guide chemistry. A tight interaction between the discovery toxicologist, the medicinal chemist and other core team members is essential to make this process efficient. As part of selection of the drug candidate to be progressed towards first-in-man enabling safety studies, exploratory safety pharmacology and in vivo toxicology studies give insight into the nature and severity of the most acute and/or most likely safety issues for the particular compound as well as provide an estimation of the therapeutic index (TI) [15,16]. It is noteworthy that the size of the TI as well as the estimated efficacious drug concentration are relatively predictive for whether a compound will pass or fail during the toxicology studies [17]. Therefore, rather than only establishing whether the most 482
Future Med. Chem. (2014) 6(5)
efficacious compound is safe enough to progress, it is worthwhile to test multiple compounds in exploratory in vivo studies. Identifying the compound with the largest TI will increase the chance of success in later stages. What are the key factors to make discovery safety work? First, there may be organizational challenges. On the one hand, discovery safety has its roots within the nonclinical safety area and requires strong interactions with the drug-development organization. This provides perspectives on regulatory requirements and on possibilities to handle a safety risk in later stages of development. On the other hand, discovery safety must be closely connected to the discovery organization, instead of being a distant support function. In order to enable discovery safety scientists to make an impact within discovery projects, they need to be part of the core teams as an equal partner to the chemist, biologist, pharmacologist, and others. Only then will they have real influence on the decisions regarding the validation of novel drug targets, the selection of chemical series, the optimization process and candidate selection. In this way, discovery safety scientists can assume shared responsibility to bring projects forward, rather than only to prevent projects with a less favorable safety profile to progress into the first-in-man enabling safety studies. Discovery safety scientists have to create acceptance of their strategy and the methods and readouts they employ. Optimization on safety end points may in many instances be possible, but it may also be difficult, especially if SAR cannot be generated. Drug discovery is difficult enough as it is and teams need to be willing to make that extra effort. To achieve that, discovery safety has to be perceived as a discipline that increases the success of a project (i.e., long-term progression), rather than as the traditional toxicology hurdle (‘bad news’) that may end the project. Safety readouts have to be properly validated, such that the predictivity of an early assay for preclinical toxicity or clinical safety can be established, and open discussions with the other disciplines on the science, assays, data, conclusions and consequent decisions are required. Finally, the discovery safety strategy has to be part of the overall research strategy, with support from relevant management boards and clear safety-related criteria for lead compounds and development candidates. Although such criteria should not be carved in stone, as safety future science group
How can we discover safer drugs? issues should always be placed into context of the project and the medical need of the envisaged indication, they should provide guidance on what properties are required to eliminate the most overt safety risks. It will be challenging for most organizations to screen for all potential safety risks in early projects. In order to indeed reduce safety-related attrition, there has to be focus on those liabilities that emerge often (liver, cardiovascular and nervous system toxicity), have high impact (genotoxicity) or are related to the target [9,10]. Due to the long duration of drug-development programs, the impact of discovery safety on the overall success of drug development will be hard to measure in the short term. A surrogate success criterion could be passing first-in-man enabling safety studies, which should at least increase the chance that a project team can test its therapeutic concept in the clinic. Still, some safety issues do not present themselves until a larger patient
| Editorial
population has been exposed, such as idiosyncratic drug-induced liver injury [18], and they can actually be influenced during drug discovery [19]. Ultimately, if fully integrated, discovery safety will, in addition to ensuring that drug candidates with a safety risk indeed fail early, enable the generation of drug candidates with a superior safety profile. This should decrease safety-related attrition and increase the overall success of drug development. Financial & competing interests disclosure The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
References 1
Mullard A. 2012 FDA drug approvals. Nat. Rev. Drug Discov. 12(2), 87–90 (2013).
2
Kaitin KI, Dimasi JA. Pharmaceutical innovation in the 21st century: new drug approvals in the first decade, 2000–2009. Clin. Pharmacol. Ther. 89(2), 183–188 (2011).
3
Morgan S, Grootendorst P, Lexchin J, Cunningham C, Greyson D. The cost of drug development: a systematic review. Health Policy 100(1), 4–17 (2011).
4
Paul SM, Mytelka DS, Dunwiddie CT et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat. Rev. Drug Discov. 9(3), 203–214 (2010).
5
Pammolli F, Magazzini L, Riccaboni M. The productivity crisis in pharmaceutical R&D. Nat. Rev. Drug Discov. 10(6), 428–438 (2011).
6
Kola I , Landis J. Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov. 3(8), 711–715 (2004).
7
Arrowsmith J. Trial watch: Phase III and submission failures: 2007–2010. Nat. Rev. Drug Discov. 10, 87 (2011).
8
Sasseville VG, Lane JH, Kadambi VJ et al. Testing paradigm for prediction of development-limiting barriers and human
future science group
drug toxicity. Chem. Biol. Interact. 150(1), 9–25 (2004). 9
Hornberg JJ, Laursen M, Brenden N et al. Exploratory toxicology as an integrated part of drug discovery. Part I: why and how. Drug Discov. Today doi:10.1016/j. drudis.2013.12.008 (2013) (Epub ahead of print).
10 Hornberg JJ, Laursen M, Brenden N et al.
Exploratory toxicology as an integrated part of drug discovery. Part II: screening strategies. Drug Discov. Today doi:10.1016/j. drudis.2013.12.009 (2013) (Epub ahead of print). 11 Kramer JA, Sagartz JE, Morris DL. The
application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates. Nat. Rev. Drug Discov. 6(8), 636–649 (2007). 12 Thomas CE , Will Y. The impact of assay
technology as applied to safety assessment in reducing compound attrition in drug discovery. Expert. Opin. Drug Discov. 7(2), 109–122 (2012). 13 Will Y , Schroeter T. Deployment of in silico
and in vitro safety assays in early-stage drug discovery. Future Med. Chem. 4(10), 1211–1213 (2012).
www.future-science.com
14 Segall MD, Barber C. Addressing toxicity risk
when designing and selecting compounds in early drug discovery. Drug Discov. Today doi:10.1016/j.drudis.2014.01.006 (2014) (Epub ahead of print). 15 Bass AS, Cartwright ME, Mahon C et al.
Exploratory drug safety: a discovery strategy to reduce attrition in development. J. Pharmacol. Toxicol. Methods 60(1), 69–78 (2009). 16 Muller PY , Milton MN. The determination
and interpretation of the therapeutic index in drug development. Nat. Rev. Drug Discov. 11(10), 751–761 (2012). 17 Wager TT, Kormos BL, Brady JT et al.
Improving the odds of success in drug discovery: choosing the best compounds for in vivo toxicology studies. J. Med. Chem. 56(23), 9771–9779 (2013). 18 Kaplowitz N. Idiosyncratic drug
hepatotoxicity. Nat. Rev. Drug Discov. 4(6), 489–499 (2005). 19 Persson M, Loye AF, Mow T, Hornberg JJ.
A high content screening assay to predict human drug-induced liver injury during drug discovery. J. Pharmacol. Toxicol. Methods 68(3), 302–313 (2013).
483
