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, Emily; Davis, J. Wade; Degner, Jacob F.

doi:10.1101/513945

Cited by 103 publications

(101 citation statements)

References 29 publications

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“…We next assessed whether natural variation in the genetic locus encoding ASIC1a (ACCN1) is associated with ischemic diseases using human population statistical genetics. While fewer than 10% of new molecular entities pass through clinical trials and are approved for therapeutic use, evidence of human genetic association between the gene target and traits sufficiently similar to the indication being treated increase the likelihood of approval to as high as 50% 47 . We utilized summary data from genome-wide association studies (GWAS) 48 and calculated the statistical significance (using fastBAT 49 ) of genetic variants encompassing the ACCN1 locus with human cardiac and cerebral ischemic phenotypes.…”

Section: Resultsmentioning

confidence: 99%

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Acid sensing ion channel 1a is a key mediator of cardiac ischemia-reperfusion injury

Scheuer

Saez

et al. 2019

Preprint

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Ischemia reperfusion injury (IRI) is one of the major risk factors associated with primary graft dysfunction, the leading cause of early mortality in heart transplant recipients. Here, we show that the proton-gated acid-sensing ion channel 1a (ASIC1a) plays a key role during cardiac ischemia and demonstrate that ASIC1a is a promising new target to improve the tolerance of cardiac tissue to IRI.Genetic ablation of ASIC1a leads to improved functional recovery following global myocardial IRI in ex vivo mouse hearts, and this effect can be recapitulated by therapeutic blockade of ASIC1a using specific and potent venom-derived pharmacological inhibitors. Using two models of donor heart procurement and storage, we show that ASIC1a inhibition yields improved post-IRI cardiac viability and function as a pre-or post-conditioning agent, with organ recovery equal to benchmark drugs including the sodium-hydrogen exchange inhibitor, zoniporide. Using human pluripotent stem cells, we show that ASIC1a inhibition improves cardiomyocyte viability under conditions of acidosis or ischemia in vitro. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors have no impact on cardiac electromechanical coupling and physiological performance.Consistent with a key role for ASIC1a in human cardiac ischemia, we used summary data from GWAS to show that polymorphisms in the ASIC1 genetic locus are strongly associated with susceptibility to cardiac ischemic injuries. Collectively, our data provide compelling evidence for a novel pharmacological strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of donor hearts exposed to myocardial ischemia. Significance StatementIschemia-reperfusion injury (IRI) is the primary reason for early allograft failure after heart transplantation. IRI is also implicated in the pathophysiology of diverse post-ischemic heart diseases that are a leading cause of morbidity and mortality worldwide. There are currently no drugs available to protect the heart from IRI. This study uses genetic approaches to demonstrate a novel role for ASIC1a in mediating the response of the heart to IRI. In addition, we identify venom-derived ASIC1a inhibitors as novel pharmacological therapeutics for cardiovascular medicine, in particular for the preservation of donor hearts destined for transplantation.

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Section: Resultsmentioning

confidence: 99%

“…Given that drug targets with genetic evidence of disease association are twice as likely to succeed in clinical trials and lead to approved drug candidates 47 19 .…”

Section: Discussionmentioning

confidence: 99%

Acid sensing ion channel 1a is a key mediator of cardiac ischemia-reperfusion injury

Scheuer

Saez

et al. 2019

Preprint

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“…In an important study, Nelson et al [19] showed that the proportion of drugs with direct genetic support increased along the development pipeline, increasing from 2.0% at the preclinical stage to 8.2% among the approved drugs. In a more updated analysis by King et al [20] , they reported similar findings that genetically supported targets were more likely to be successful in Phases II and III clinical trials, especially when the genes implicated are likely causal.…”

Section: Overview Of Gwas and Its Potential In Guiding Drug Discoverimentioning

confidence: 86%

Turning genome-wide association study findings into opportunities for drug repositioning

Lau

2020

Computational and Structural Biotechnology Journal

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“…MR has been used successfully to help prioritise intervention and drug targets and to identify causal factors for several diseases [19][20][21][22][23]. In general, candidate drugs with genetic evidence for effectiveness are more successful in drug trials compared to those without such genetic support [24].…”

Section: Introductionmentioning

confidence: 99%

Mendelian randomisation analysis of red cell distribution width in pulmonary arterial hypertension

et al. 2019

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Pulmonary arterial hypertension (PAH) is a rare disease that leads to premature death from right heart failure. It is strongly associated with elevated red cell distribution width (RDW), a correlate of several iron status biomarkers. High RDW values can signal early-stage iron deficiency or iron deficiency anaemia. This study investigated whether elevated RDW is causally associated with PAH.A two-sample Mendelian randomisation (MR) approach was applied to investigate whether genetic predisposition to higher levels of RDW increases the odds of developing PAH. Primary and secondary MR analyses were performed using all available genome-wide significant RDW variants (n=179) and five genome-wide significant RDW variants that act via systemic iron status, respectively.We confirmed the observed association between RDW and PAH (OR 1.90, 95% CI 1.80–2.01) in a multicentre case–control study (cases n=642, disease controls n=15 889). The primary MR analysis was adequately powered to detect a causal effect (odds ratio) between 1.25 and 1.52 or greater based on estimates reported in the RDW genome-wide association study or from our own data. There was no evidence for a causal association between RDW and PAH in either the primary (ORcausal 1.07, 95% CI 0.92–1.24) or the secondary (ORcausal 1.09, 95% CI 0.77–1.54) MR analysis.The results suggest that at least some of the observed association of RDW with PAH is secondary to disease progression. Results of iron therapeutic trials in PAH should be interpreted with caution, as any improvements observed may not be mechanistically linked to the development of PAH.

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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

Cited by 103 publications

References 29 publications

Acid sensing ion channel 1a is a key mediator of cardiac ischemia-reperfusion injury

Acid sensing ion channel 1a is a key mediator of cardiac ischemia-reperfusion injury

Turning genome-wide association study findings into opportunities for drug repositioning

Mendelian randomisation analysis of red cell distribution width in pulmonary arterial hypertension

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