Drug discovery effectiveness from the standpoint of therapeutic mechanisms and indications

Shih, Hsin-Pei; Zhang, Xiaodan; Aronov, Alex M.

doi:10.1038/nrd.2017.194

Cited by 126 publications

(110 citation statements)

References 75 publications

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“…We also included the amount of time each target is known to have been under development as a predictor, with the rationale that if accumulating genetic evidence informs drug development, targets supported by genetic evidence might be newer on average. Finally, we included gene ontology (GO) terms and high level MeSH terms for each indication as predictors to control for known differences [14,28] in approval probability among indication and target classes.…”

Section: Statistical Modeling Of Genetic Effect On Drug Approvalmentioning

confidence: 99%

Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval

King

Davis

Degner

2019

Preprint

104

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Despite strong vetting for disease activity, only 10% of candidate new molecular entities in early stage clinical trials are eventually approved. Analyzing historical pipeline data, Nelson et al. 2015 (Nat. Genet.) concluded pipeline drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. Taking advantage of recent clinical development advances and rapid growth in GWAS datasets, we extend the original work using updated data, test whether genetic evidence predicts future successes and introduce statistical models adjusting for target and indication-level properties. Our work confirms drugs with genetically supported targets were more likely to be successful in Phases II and III. When causal genes are clear (Mendelian traits and GWAS associations linked to coding variants), we find the use of human genetic evidence increases approval from Phase I by greater than two-fold, and, for Mendelian associations, the positive association holds prospectively. Our findings suggest investments into genomics and genetics are likely to be beneficial to companies deploying this strategy.

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Section: Statistical Modeling Of Genetic Effect On Drug Approvalmentioning

confidence: 99%

Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval

King

Davis

Degner

2019

Preprint

104

View full text Add to dashboard Cite

show abstract

“…In light of the relative lack of prospects for novel anti-obesity therapy and the high attrition rate associated with drug development (Chan & Ye, 2013), more recently, researchers and clinicians have begun to turn to drug repurposing strategies in an attempt to broaden therapeutic options (Shih, Zhang, & Aronov, 2017). Glucagon-like peptide-1 (GLP-1) based therapy represents one of the best examples of anti-obesity therapy deriving from this strategy.…”

Section: Targeting Obesity With Lifestyle and Pharmacotherapiesmentioning

confidence: 99%

Pathobiological mechanisms underlying metabolic syndrome (MetS) in chronic obstructive pulmonary disease (COPD): clinical significance and therapeutic strategies

Chan

Selemidis

Bozinovski

et al. 2019

Pharmacology & Therapeutics

116

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a b s t r a c t a r t i c l e i n f oChronic obstructive pulmonary disease (COPD) is a major incurable global health burden and is currently the 4th largest cause of death in the world. Importantly, much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities (e.g. skeletal muscle wasting, ischemic heart disease, cognitive dysfunction) and infective viral and bacterial acute exacerbations (AECOPD). Current pharmacological treatments for COPD are relatively ineffective and the development of effective therapies has been severely hampered by the lack of understanding of the mechanisms and mediators underlying COPD. Since comorbidities have a tremendous impact on the prognosis and severity of COPD, the 2015 American Thoracic Society/European Respiratory Society (ATS/ERS) Research Statement on COPD urgently called for studies to elucidate the pathobiological mechanisms linking COPD to its comorbidities. It is now emerging that up to 50% of COPD patients have metabolic syndrome (MetS) as a comorbidity. It is currently not clear whether metabolic syndrome is an independent co-existing condition or a direct consequence of the progressive lung pathology in COPD patients. As MetS has important clinical implications on COPD outcomes, identification of disease mechanisms linking COPD to MetS is the key to effective therapy. In this comprehensive review, we discuss the potential mechanisms linking MetS to COPD and hence plausible therapeutic strategies to treat this debilitating comorbidity of COPD.

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“…For example, a small molecule that is designed to occupy a specific pocket or a binding site can also interact with many off‐targets, such as homologous proteins or ion channel proteins (eg, the hERG ion channel in the heart) that could induce unwanted side effects. In fact, the inadequate efficiency, toxicity, and poor pharmacokinetics of many small‐molecule inhibitors have been the main reasons for high attrition rates in pharmaceutical industries . Thus, developing small‐molecule inhibitors of immune checkpoints with favorable drug‐like features, strong efficacy and highly target specific properties remain a significant challenge.…”

Section: Fusion Proteins and Mabs Targeting B7‐1mentioning

confidence: 99%

Targeting B7‐1 in immunotherapy

Chen

Okoye

Arutyunova

et al. 2019

Medicinal Research Reviews

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Modulation of T‐cell immune functions by blocking key immune checkpoint protein interactions using monoclonal antibodies (mAbs) has been an innovative immunotherapeutic strategy. T‐cells are regulated by different checkpoint proteins at the immunological synapse including the B7 ligands (B7‐1 or CD80 and B7‐2 or CD86), which is discussed in this review. These ligands are typically expressed on antigen presenting cells and interact with CD28 and cytotoxic T lymphocyte antigen‐4 (CTLA‐4) receptors on T‐cells. Their interactions with CD28 trigger a costimulatory signal that potentiates T‐cell activation, function and survival in response to cognate antigen. In addition, their interactions with CTLA‐4 can also inhibit certain effector T‐cell responses, particularly in response to sustained antigen stimulation. Through these mechanisms, the balance between T‐cell activation and suppression is maintained, preventing the occurrence of immunopathology. Given their crucial roles in immune regulation, targeting B7 ligands has been an attractive strategy in cancer and autoimmunity. This review presents an overview of the essential roles of B7‐1, highlighting the therapeutic benefits of modulating this protein in immunotherapy, and reviewing earlier and state‐of‐the‐art efforts in developing anti‐B7‐1 inhibitors. Finally, we discuss the challenges facing the design of selective B7‐1 inhibitors and present our perspectives for future developments.

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Drug discovery effectiveness from the standpoint of therapeutic mechanisms and indications

Cited by 126 publications

References 75 publications

Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval

Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval

Pathobiological mechanisms underlying metabolic syndrome (MetS) in chronic obstructive pulmonary disease (COPD): clinical significance and therapeutic strategies

Targeting B7‐1 in immunotherapy

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