Emulated Clinical Trials from Longitudinal Real-World Data Efficiently Identify Candidates for Neurological Disease Modification: Examples from Parkinson's Disease.

Daphna Laifenfeld,Michal Rosen-Zvi,Chen Yanover,Yaara Goldschmidt,Michal Ozery-Flato,Oded Shaham,Iris Grossman,Nirit Lev

doi:10.3389/fphar.2021.631584

Daphna Laifenfeld, Michal Rosen-Zvi + Show 6 more

Open Access

https://doi.org/10.3389/fphar.2021.631584

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Abstract

Real-world healthcare data hold the potential to identify therapeutic solutions for progressive diseases by efficiently pinpointing safe and efficacious repurposing drug candidates. This approach circumvents key early clinical development challenges, particularly relevant for neurological diseases, concordant with the vision of the 21st Century Cures Act. However, to-date, these data have been utilized mainly for confirmatory purposes rather than as drug discovery engines. Here, we demonstrate the usefulness of real-world data in identifying drug repurposing candidates for disease-modifying effects, specifically candidate marketed drugs that exhibit beneficial effects on Parkinson’s disease (PD) progression. We performed an observational study in cohorts of ascertained PD patients extracted from two large medical databases, Explorys SuperMart (N = 88,867) and IBM MarketScan Research Databases (N = 106,395); and applied two conceptually different, well-established causal inference methods to estimate the effect of hundreds of drugs on delaying dementia onset as a proxy for slowing PD progression. Using this approach, we identified two drugs that manifested significant beneficial effects on PD progression in both datasets: rasagiline, narrowly indicated for PD motor symptoms; and zolpidem, a psycholeptic. Each confers its effects through distinct mechanisms, which we explored via a comparison of estimated effects within the drug classification ontology. We conclude that analysis of observational healthcare data, emulating otherwise costly, large, and lengthy clinical trials, can highlight promising repurposing candidates, to be validated in prospective registration trials, beneficial against common, late-onset progressive diseases for which disease-modifying therapeutic solutions are scarce.

Highlights

Repurposing of marketed drugs, i.e., the identification of novel indications for existing compounds, known as drug repositioning, is an increasingly attractive prospect for drug developers and patients alike, given the ever-increasing costs of de novo drug development (Ashburn and Thor, 2004)
The present study used both electronic health records (EHRs) and insurance claims data to assess the effects of hundreds of concomitant drugs on the emergence of Parkinson’s disease (PD)-associated dementia as one of the more common hallmarks of PD progression
Those drugs for which a statistically significant effect was found independently in both EHR and claims data were further considered for their repurposing potential

Summary

Introduction

Repurposing of marketed drugs, i.e., the identification of novel indications for existing compounds, known as drug repositioning, is an increasingly attractive prospect for drug developers and patients alike, given the ever-increasing costs of de novo drug development (Ashburn and Thor, 2004). While the majority of repurposed drugs have been identified through serendipity, recent years have witnessed growth in systematic efforts to identify new indications for existing drugs These efforts include experimental screening approaches (Buckley et al, 2010; Deshmukh et al, 2013; Najm et al, 2015) and in silico approaches in which existing data are used to discover repurposing candidates [see (Cha et al, 2018) for in depth review of these methods]. Investigating the effects of related drugs, e.g., sharing target profile or mechanism of action (MoA), allows the extraction of mechanistic explanations for drug effect These effects, once validated in multiple independent sources of RWD, provide robust evidence on drug effectiveness, tolerability, and safety, as well as mechanistic insight on disease modification. No 114-255, 2016), and extending the European Medicines Agency (EMA) current use of RWD as an external control arm in rare disease clinical trials (Cave et al, 2019)

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