Pub Date : 2026-01-01DOI: 10.1016/j.drudis.2025.104583
Chinmay Shukla , Irwin Tendler , Neil Kumar , Andrew W. Lo
Biotech drug development is a high-risk, capital-intensive endeavor, requiring a balance between scientific advancement and financial reward. In this case study, we present BridgeBio’s portfolio-based operating model, which integrates genetically validated targets with operational discipline and innovative financial structuring to enable rapid and scalable development. We situate BridgeBio’s approach within the broader landscape of biotech operating archetypes and contrast it with more traditional approaches (e.g., single-asset, platform-based, venture-creation) models. This case study contributes to ongoing discussions about how portfolio-based strategies can improve the resilience and efficiency of biopharmaceutical innovation.
{"title":"Genetic Targets, Financial Creativity: BridgeBio’s Model for Sustainable Drug Development","authors":"Chinmay Shukla , Irwin Tendler , Neil Kumar , Andrew W. Lo","doi":"10.1016/j.drudis.2025.104583","DOIUrl":"10.1016/j.drudis.2025.104583","url":null,"abstract":"<div><div>Biotech drug development is a high-risk, capital-intensive endeavor, requiring a balance between scientific advancement and financial reward. In this case study, we present BridgeBio’s portfolio-based operating model, which integrates genetically validated targets with operational discipline and innovative financial structuring to enable rapid and scalable development. We situate BridgeBio’s approach within the broader landscape of biotech operating archetypes and contrast it with more traditional approaches (e.g., single-asset, platform-based, venture-creation) models. This case study contributes to ongoing discussions about how portfolio-based strategies can improve the resilience and efficiency of biopharmaceutical innovation.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104583"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145751475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.drudis.2025.104588
Michael S. Kinch , Aayan Alawi , Tyler Schwartz , Zachary Kraft
An analysis of the sources of new experimental drugs in the 21st century reveals a dramatic change in the location of organizations involved in new drug discovery. Overall, the number of new experimental drugs has risen robustly over the past 25 years. Whereas American private sector institutions have a long track record of leading the world in introducing new drugs to the clinic, China undertook a concerted effort during the mid-2010s to increase discovery efforts and now equals the USA. The growth of Chinese contributions is remarkable and reflects efforts by both the public and private sector. The rapid rise of China raises questions about future decision-making and leadership of the larger pharmaceutical enterprise.
{"title":"Geopolitical contributions to pharmaceutical innovation","authors":"Michael S. Kinch , Aayan Alawi , Tyler Schwartz , Zachary Kraft","doi":"10.1016/j.drudis.2025.104588","DOIUrl":"10.1016/j.drudis.2025.104588","url":null,"abstract":"<div><div>An analysis of the sources of new experimental drugs in the 21st century reveals a dramatic change in the location of organizations involved in new drug discovery. Overall, the number of new experimental drugs has risen robustly over the past 25 years. Whereas American private sector institutions have a long track record of leading the world in introducing new drugs to the clinic, China undertook a concerted effort during the mid-2010s to increase discovery efforts and now equals the USA. The growth of Chinese contributions is remarkable and reflects efforts by both the public and private sector. The rapid rise of China raises questions about future decision-making and leadership of the larger pharmaceutical enterprise.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104588"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145792855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.drudis.2025.104567
Sarine Markossian , Hannah M. Baskir , Abigail C. Grossman , Suchismita Chandran , Shyam Rele , Matthew D. Hall , Rommie E. Amaro , Alexander Tropsha , Alexey V. Zakharov
{"title":"In silico Drug Discovery: Bridging the Gaps in Preclinical Translation","authors":"Sarine Markossian , Hannah M. Baskir , Abigail C. Grossman , Suchismita Chandran , Shyam Rele , Matthew D. Hall , Rommie E. Amaro , Alexander Tropsha , Alexey V. Zakharov","doi":"10.1016/j.drudis.2025.104567","DOIUrl":"10.1016/j.drudis.2025.104567","url":null,"abstract":"","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104567"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.drudis.2025.104589
Tomasz Szostek, Daniel Szulczyk
Activity cliffs (ACs), defined as near structural neighbors with large potency differences, provide high-value information on structure–activity relationship discontinuities that medicinal chemists have leveraged for years. Yet modern artificial intelligence-based discovery frameworks often smooth this signal, yielding confident but unrealistic proposals. We present a three-layer roadmap that treats ACs as a first-class design feature: representation is tuned to expose AC signal during pretraining and sampling; evaluation focuses on steep regions with early recognition, pair-level retrieval, and calibrated uncertainty under fair, series-aware splits; and de novo generation is steered toward the best candidates. Integrated as a closed, self-improving loop, this framework helps practitioners build AC-aware drug design tools.
{"title":"From obstacle to design advantage: activity cliff aware modeling for small-molecule drug discovery","authors":"Tomasz Szostek, Daniel Szulczyk","doi":"10.1016/j.drudis.2025.104589","DOIUrl":"10.1016/j.drudis.2025.104589","url":null,"abstract":"<div><div>Activity cliffs (ACs), defined as near structural neighbors with large potency differences, provide high-value information on structure–activity relationship discontinuities that medicinal chemists have leveraged for years. Yet modern artificial intelligence-based discovery frameworks often smooth this signal, yielding confident but unrealistic proposals. We present a three-layer roadmap that treats ACs as a first-class design feature: representation is tuned to expose AC signal during pretraining and sampling; evaluation focuses on steep regions with early recognition, pair-level retrieval, and calibrated uncertainty under fair, series-aware splits; and <em>de novo</em> generation is steered toward the best candidates. Integrated as a closed, self-improving loop, this framework helps practitioners build AC-aware drug design tools.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104589"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145792878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.drudis.2025.104593
The DISRUPT-DS Industry Roundtable
Generative AI (GenAI) is reshaping pharmaceutical R&D, offering transformative potential across research and development. Applications of GenAI include scientific insight generation, mining large biological datasets to study diseases, molecule design, clinical document drafting, and many others. The DISRUPT-DS roundtable, a forum that brings together data science leaders from major pharmaceutical companies, has recently conducted an analysis of GenAI in R&D. Here, the roundtable participants report key findings from this effort. Specifically, we discuss areas that are regulatory-relevant, including GenAI-powered document drafting and statistical programming, and we explore emerging topics, such as AI agents and foundation models. The goal of this work is to provide an industry-wide perspective of where GenAI is today and how it might evolve in the future.
{"title":"Generative AI in pharmaceutical R&D: From large language models to AI agents to regulation","authors":"The DISRUPT-DS Industry Roundtable","doi":"10.1016/j.drudis.2025.104593","DOIUrl":"10.1016/j.drudis.2025.104593","url":null,"abstract":"<div><div>Generative AI (GenAI) is reshaping pharmaceutical R&D, offering transformative potential across research and development. Applications of GenAI include scientific insight generation, mining large biological datasets to study diseases, molecule design, clinical document drafting, and many others. The DISRUPT-DS roundtable, a forum that brings together data science leaders from major pharmaceutical companies, has recently conducted an analysis of GenAI in R&D. Here, the roundtable participants report key findings from this effort. Specifically, we discuss areas that are regulatory-relevant, including GenAI-powered document drafting and statistical programming, and we explore emerging topics, such as AI agents and foundation models. The goal of this work is to provide an industry-wide perspective of where GenAI is today and how it might evolve in the future.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104593"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.drudis.2025.104586
Bei Wang , Yiqian Ren , Xianghua Xiao , Xianning Liu , Yani Wang , Yao Wang
Mesenchymal stem cell (MSC)-derived exosomes (MSC-EXOs), nanovesicles carrying bioactive molecules, hold potential for tissue repair, but face targeting and rapid clearance challenges. Hydrogels, bioabsorbable scaffolds comprising 3D hydrophilic polymers with high biocompatibility and some mechanical strength, offer a promising solution. Injectable thermosensitive hydrogels, transitioning from liquid to gel at body temperature, enable localized, sustained EXO delivery by forming biocompatible reservoirs at injury sites. These hydrogels enhance EXO retention and therapeutic efficacy through controlled release. In this review, we discuss MSC-EXO biology, hydrogel design (gelation mechanisms and fabrication), and applications of EXO-encapsulated thermosensitive hydrogels, emphasizing injectability, controlled release, and improved site-specific dosing. Future priorities involve refining EXO purification, optimizing hydrogel porosity and mechanical tunability, and assessing long-term safety and efficacy for clinical translation.
{"title":"An emerging MSC-exosome delivery strategy: injectable temperature-sensitive hydrogels encapsulate exosomes for enhanced therapeutic efficacy","authors":"Bei Wang , Yiqian Ren , Xianghua Xiao , Xianning Liu , Yani Wang , Yao Wang","doi":"10.1016/j.drudis.2025.104586","DOIUrl":"10.1016/j.drudis.2025.104586","url":null,"abstract":"<div><div>Mesenchymal stem cell (MSC)-derived exosomes (MSC-EXOs), nanovesicles carrying bioactive molecules, hold potential for tissue repair, but face targeting and rapid clearance challenges. Hydrogels, bioabsorbable scaffolds comprising 3D hydrophilic polymers with high biocompatibility and some mechanical strength, offer a promising solution. Injectable thermosensitive hydrogels, transitioning from liquid to gel at body temperature, enable localized, sustained EXO delivery by forming biocompatible reservoirs at injury sites. These hydrogels enhance EXO retention and therapeutic efficacy through controlled release. In this review, we discuss MSC-EXO biology, hydrogel design (gelation mechanisms and fabrication), and applications of EXO-encapsulated thermosensitive hydrogels, emphasizing injectability, controlled release, and improved site-specific dosing. Future priorities involve refining EXO purification, optimizing hydrogel porosity and mechanical tunability, and assessing long-term safety and efficacy for clinical translation.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104586"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145792862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.drudis.2025.104584
Hector A. Cabrera-Fuentes , Elisa A. Liehn , Ebtesam A. Al-Suhaimi
The plasma proteome offers a dynamic window into human physiology, enabling biomarker discovery, target prioritization, and drug repurposing for cardiovascular disease. Advances in high-throughput platforms, protein quantitative trait loci mapping, and machine learning reveal pleiotropic proteins and candidate causal targets, but translation requires rigorous safeguards. We propose a rigorous, tiered pipeline: discovery, mandatory orthogonal confirmation (targeted mass spectrometry or independent immunoassay), genetic prioritization with colocalization and sensitivity analyses, tissue-resolved functional validation, and prospective clinical evaluation with regulatory qualification. Integration with multi-omics, diverse cohorts, and electronic health record-embedded implementation studies, using HL7 Fast Healthcare Interoperability Resources and the Observational Medical Outcomes Partnership Common Data Model, can accelerate reproducible, equitable development of precision cardiovascular therapeutics.
{"title":"Decoding the plasma proteome: Advancing precision medicine in cardiovascular health","authors":"Hector A. Cabrera-Fuentes , Elisa A. Liehn , Ebtesam A. Al-Suhaimi","doi":"10.1016/j.drudis.2025.104584","DOIUrl":"10.1016/j.drudis.2025.104584","url":null,"abstract":"<div><div>The plasma proteome offers a dynamic window into human physiology, enabling biomarker discovery, target prioritization, and drug repurposing for cardiovascular disease. Advances in high-throughput platforms, protein quantitative trait loci mapping, and machine learning reveal pleiotropic proteins and candidate causal targets, but translation requires rigorous safeguards. We propose a rigorous, tiered pipeline: discovery, mandatory orthogonal confirmation (targeted mass spectrometry or independent immunoassay), genetic prioritization with colocalization and sensitivity analyses, tissue-resolved functional validation, and prospective clinical evaluation with regulatory qualification. Integration with multi-omics, diverse cohorts, and electronic health record-embedded implementation studies, using HL7 Fast Healthcare Interoperability Resources and the Observational Medical Outcomes Partnership Common Data Model, can accelerate reproducible, equitable development of precision cardiovascular therapeutics.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104584"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145754720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.drudis.2025.104585
Joseph Twomey , Leonhard Kersten , Edward W. Zhou , Fred D. Ledley
This study examines the finances of 11 public companies that commercialize 21 out of the 25 drugs subject to price negotiation in 2024 or 2025, respectively under the Inflation Reduction Act (IRA) of 2022. From 2019 to 2023, these companies reported US$2.5 trillion in revenue with US$412.8 billion from sales of IRA drugs, including US$260.8 billion US sales, less than cumulative earnings or shareholder distributions. Estimated margins on sales were greater than reported average industry investments in development. Overall, reducing revenue from these drugs would not limit funds for operations or required returns on investment, although impacts on individual companies could vary and should be considered in price negotiations.
{"title":"Contribution of revenue from drugs subject to price negotiation under the Inflation Reduction Act to the revenue, profit, and returns of pharmaceutical manufacturers","authors":"Joseph Twomey , Leonhard Kersten , Edward W. Zhou , Fred D. Ledley","doi":"10.1016/j.drudis.2025.104585","DOIUrl":"10.1016/j.drudis.2025.104585","url":null,"abstract":"<div><div>This study examines the finances of 11 public companies that commercialize 21 out of the 25 drugs subject to price negotiation in 2024 or 2025, respectively under the Inflation Reduction Act (IRA) of 2022. From 2019 to 2023, these companies reported US$2.5 trillion in revenue with US$412.8 billion from sales of IRA drugs, including US$260.8 billion US sales, less than cumulative earnings or shareholder distributions. Estimated margins on sales were greater than reported average industry investments in development. Overall, reducing revenue from these drugs would not limit funds for operations or required returns on investment, although impacts on individual companies could vary and should be considered in price negotiations.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104585"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145754771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.drudis.2026.104597
Ivar T. van der Zee , Joyce M. Hoek , Jarno Hoekman , Marie L. De Bruin
Although integrating novel technologies into nonclinical drug development can counteract declining R&D success, their path to regulatory acceptance is often unclear and uncertain as they are not subject to a single, predictable regulatory approval framework like medicinal products. Existing literature on regulatory acceptance is mostly confined to specific technologies or regulatory pathways, hindering cross-domain learning. Therefore this scoping review develops a more context-agnostic understanding of regulatory acceptance by characterizing its commonalities across a range of technological and regulatory contexts. Our analysis of 54 articles found that regulatory acceptance can take on multiple forms, shaped by a particular scope (technological, contextual, and geographical) and formation process involving a driving need, gaining regulatory confidence, and interaction between actor groups. As technological specificity increases, the nature of the aforementioned elements shifts from broad discussions of potential to formal, evidence-based procedures. Understanding acceptance as a diverse process unified by core conceptual elements, rather than a single hurdle, provides a common language that cuts across technological domains and helps contextualize future research, thereby enabling regulators and developers to better integrate novel technologies in nonclinical drug development.
{"title":"Gaining regulatory acceptance for novel technologies in nonclinical drug development: A scoping review of its conceptualization in scientific literature","authors":"Ivar T. van der Zee , Joyce M. Hoek , Jarno Hoekman , Marie L. De Bruin","doi":"10.1016/j.drudis.2026.104597","DOIUrl":"10.1016/j.drudis.2026.104597","url":null,"abstract":"<div><div>Although integrating novel technologies into nonclinical drug development can counteract declining R&D success, their path to regulatory acceptance is often unclear and uncertain as they are not subject to a single, predictable regulatory approval framework like medicinal products. Existing literature on regulatory acceptance is mostly confined to specific technologies or regulatory pathways, hindering cross-domain learning. Therefore this scoping review develops a more context-agnostic understanding of regulatory acceptance by characterizing its commonalities across a range of technological and regulatory contexts. Our analysis of 54 articles found that regulatory acceptance can take on multiple forms, shaped by a particular scope (technological, contextual, and geographical) and formation process involving a driving need, gaining regulatory confidence, and interaction between actor groups. As technological specificity increases, the nature of the aforementioned elements shifts from broad discussions of potential to formal, evidence-based procedures. Understanding acceptance as a diverse process unified by core conceptual elements, rather than a single hurdle, provides a common language that cuts across technological domains and helps contextualize future research, thereby enabling regulators and developers to better integrate novel technologies in nonclinical drug development.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104597"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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