Enabling Technology and Data for Drug Repositioning

While there have been a number of approaches to use in silico approaches to identify new therapeutic applications of existing drugs or drug candidates, Melior Discovery has taken an alternative, more resource-intensive, approach of screening candidates using in vivo models. This is based upon the philosophy that the pharmacopoeia of ideal repositioning candidates is small, numbered in the hundreds, not thousands or tens of thousands of compounds. Therefore, there is little benefit to high throughput methodology. Moreover, the ideal candidates are “privileged” compounds known to be safe and well-tolerated in humans and have other favorable drug-like properties based upon years and tens of millions of dollars of research on each candidate. Accordingly, if the drug repositioning approach that one uses fails to correctly identify a new indication which actually exists for a given candidate then the opportunity cost is exceptionally high. Therefore, this “privileged” substrate should be approached with the highest quality tool that most accurately can predict alternative new uses for a compound. Generally speaking, in a preclinical setting we believe this to be animal models. Experience from 15 years of conducting this approach, with case examples, will be presented.

The goal of precision oncologyis to devise optimal treatment strategies tailored to the characteristics of the individual patient's disease. However, the widespread heterogeneity of cancer patients and drug responses pose a significant challenge in the design of effective personalized treatments. To address this challenge, we have developed a novel computational decision support framework that incorporates multi-omics and clinical data to guide precision cancer therapy. Our approach expands upon the traditional DNA-based approaches by integrating somatic mutations and copy number alterations with RNA-based drug repurposing and pathway analysis. We have applied our approach to multiple myeloma (MM), a mostly incurable malignancy of plasma cells with a median survival of 6 years, and have assessed its feasibility and effectiveness in a clinical trial with 64 relapsed/refractory MM patients seen at the Mount Sinai hospital. Our results demonstrated clinical response in the majority of patients treated based on our recommendations and provided proof of principle of how a precision medicine approach based on both DNA and RNA sequencing findings may identify more effective options and yield greater benefits than an approach based on mutations alone. Our study represents a significant step towards the development of an effective precision medicine approach for relapsed/refractory MM and provides a general framework for personalized therapy in oncology.

The ongoing outbreaks of the Ebola virus (EBOV) in Africa have brought global visibility to the shortage of available therapeutic options to treat patients with this or related viruses. We have recently computationally identified three molecules which have all demonstrated statistically significant efficacy in the mouse model of infection with mouse adapted Ebola virus (maEBOV). One of these molecules is the antimalarial pyronaridine tetraphosphate (EC50 range of 0.77-1.33 μM against three strains of EBOV and EC50 range of 1.57-2.96 μM against two strains of Marburg virus) which is an approved drug in the European Union and used in combination with artesunate. To date no small molecule drugs have shown statistically significant survival in the Guinea Pig. Pharmacokinetics and range-finding studies in mice directed us to a single 300mg/kg or 600mg/kg oral dose of pyronaridine 1 hr after infection. We performed a meta-analysis of vehicle controls from four independent studies using oral gavage (n=55). Pyronaridne resulted in statistically significant survival of 40% at 300mg/kg and protected from a lethal challenge with EBOV. In comparison as a positive control, oral favipiravir (300 mg/kg dosed once a day) had 43.5% survival. In summary, our in vitro and in vivo studies with pyronaridine in the stringent Guinea pig model demonstrate its utility for repurposing as an antiviral against different strains of EBOV and the closely related Marburg virus, providing justification for future testing in non-human primates.

Drug development is a daunting task requiring a delicate balance between demonstrating clinically relevant efficacy readouts, whilst navigating through increasingly complex regulatory requirements and commercial outlooks; all whilst minimizing spiraling costs.  These challenges have inspired innovative ways of working together collaboratively with key stakeholders across academic, government, and medical communities to combine cutting edge science, existing resources and funding, and defined compounds to deliver value to patients in a novel way. A salient example of a paradigm shift in this direction is the Open Innovation initiative at AstraZeneca to enable drug repositioning. Together with the external partner, we follow the science and utilise state of the art tools to repurpose compounds into areas of high unmet medical need.  Through our Open Innovation platform (www.openinnovation.astrazeneca.com), we invite external scientists and clinicians across all stages of drug discovery to collaborate. AstraZeneca provides access to optimized compounds, compound libraries, technologies, multi-disciplinary science, services and know-how to support preclinical and early-stage clinical exploration.  Launched five years ago, this model has proven to be a success.   Some examples of projects will be shared, together with the model we adopt.

Through its Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) program, NCATS aims to improve the process of developing new treatments and cures for disease by finding new uses for existing therapies that already have cleared several key steps along the development path.

Learn more: https://ncats.nih.gov/ntu

Parkinson’s disease is the fastest growing brain disorder, projected to reach pandemic proportions in 2040. All previous phase III trials failed to produce a drug that can slow or prevent the disease incurring billion-dollar costs. This is in part due to the limited ability of animals to predict human efficacy, broken trial design, and adverse events. Can we rethink drug development for Parkinson’s disease?

Autosomal dominant copy number mutations unequivocally implicate excess production of alphasynuclein as a causative factor in Parkinson’s disease. Using a repurposing drug screen targeting endogenous human gene expression, we discovered the beta2-adrenoreceptor (beta2AR) as a regulator of the alpha-synuclein gene (SNCA). During 11 years of follow up in four million Norwegians, the beta2AR agonist salbutamol, a brain-penetrant, catecholaminergic asthma medication, was prospectively linked to reduced risk of developing Parkinson’s disease (rate ratio = 0.66, 95% C.I. 0.58-0.76; Mittal et al., 2017).

Conversely, a beta2AR antagonist correlated with increased risk. beta2AR ligands modulated SNCA transcription via histone 3 lysine 27 acetylation of its promoter and enhancers. Similar associations were confirmed in Israel by Gronich et al. (2018), where particularly long-acting, lipophilic beta2AR drugs reduced risk independent of smoking and other potential confounders. In animal models, beta2AR activation was protective against MPTP-, rotenone- (Van Laar et al., in preparation), and neuroinflammation-induced disease (Qian et al., 2011) in multiple laboratories. Thus, old asthma drugs have new therapeutic potential in a neurodegenerative disease.

Could there be more? We propose a highly scalable strategy to find new therapies for Parkinson's centered on humans and computer models.

Coauthors: Amber Van Laar and J. Timothy Greenamyre, University of Pittsburgh; and Trond Riise, University of Bergen, Norway.

For many infectious diseases, approved therapies are either absent or unsatisfactory, and caregivers are forced to repurpose existing drugs for patients with difficult-to-treat infections. CURE ID is an FDA-NIH collaboration. It is a web-based tool which gives physicians an opportunity to share their real-world experiences treating such patients through a simple online case report form on their smartphone, computer, or other mobile device. The CURE ID repository will capture the clinical outcomes when drugs are used for new indications, new populations, in new doses or in new combinations.

By obtaining and organizing this information directly from clinicians, we believe promising new uses can be identified for formal study, and ineffective or harmful uses can be avoided. The systematic collection of real-world experience reported directly from clinicians to CURE ID will help with identification of drug candidates for further study, encourage further drug development, and may serve as a resource for practitioners making individual patient treatment decisions in the absence of established safe and effective options.

CURE ID provides a collection of cases that have already been reported (including successful and unsuccessful treatments) which doctors can browse. Clinicians can also participate in a Discussion Forum, allowing for engagement with fellow healthcare providers globally. We seek to make CURE ID a network connecting major treatment centers, academics, private practitioners, government facilities and other clinicians around the world into a global clinical care community.