Drug Repurposing and Orphan Disease Therapeutics

Drug repurposing (or drug repositioning) is an innovative way to find out the new indications of a drug that already exists in the market with known therapeutic indications. It offers an effective way to drug developers or the pharmaceutical companies to identify new targets for FDA-approved drugs. Less time consumption, low cost and low risk of failure are some of the advantages being offered with drug repurposing. Sildenafil (Viagra), a landmark example of a repurposed drug, was introduced into the market as an antianginal drug. But at present, its use is repurposed as drug for erectile dysfunction. In a similar way, numerous drugs are there that have been successfully repurposed in managing the clinical conditions. The chapter would be highlighting the various drug repurposing strategies, drugs repurposed in the past and the current status of repurposed drugs in the orphan disease therapeutics along with regulatory guidelines for drug repurposing

A Rational Approach to Drug Repositioning in β-thalassemia: Induction of Fetal Hemoglobin by Established Drugs

Drug repositioning and the relevance of orphan drug designation for β-thalassemia is reviewed. Drug repositioning and similar terms ('drug repurposing', 'drug reprofiling', 'drug redirecting', 'drug rescue', 'drug re-tasking' and/or 'drug rediscovery') have gained great attention, especially in the field or rare diseases (RDs), and represent relevant novel drug development strategies to be considered together with the 'off-label' use of pharmaceutical products under clinical trial regimen. The most significant advantage of drug repositioning over traditional drug development is that the repositioned drug has already passed a significant number of short- and long-term toxicity tests, as well as it has already undergone pharmacokinetic and pharmacodynamic (PK/PD) studies. The established safety of repositioned drugs is known to significantly reduce the probability of project failure. Furthermore, development of repurposed drugs can shorten much of the time needed to bring a drug to market. Finally, patent filing of repurposed drugs is expected to catch the attention of pharmaceutical industries interested in the development of therapeutic protocols for RDs. Repurposed molecules that could be proposed as potential drugs for β-thalassemia, will be reported, with some of the most solid examples, including sirolimus (rapamycin) that recently has been tested in a pilot clinical trial

The Drug Repurposing Ecosystem: Intellectual Property Incentives, Market Exclusivity, and the Future of New Medicines

The pharmaceutical industry is in a state of fundamental transition. New drug approvals have slowed, patents on blockbuster drugs are expiring, and costs associated with developing new drugs are escalating and yielding fewer viable drug candidates. As a result, pharmaceutical firms have turned to a number of alternative strategies for growth. One of these strategies is drug repurposing -finding new ways to deploy approved drugs or abandoned clinical candidates in new disease areas. Despite the efficiency advantages of repurposing drugs, there is broad agreement that there is insufficient repurposing activity because of numerous intellectual property protection and market failures. This Article examines the system that surrounds drug repurposing, including serendipitous discovery, the application of big data methods to prioritize promising repurposing candidates, the unorthodoxly regulated off-label prescription practices of providers, and related prohibitions on pharmaceutical firms\u27 off-label marketing. The Article argues that there is a complex ecosystem in place and that additional or disruptive IP or market exclusivity incentives may harm as much as help in promoting repurposing activity. To illustrate this threat, the Article traces the trajectory of metformin, a common diabetes drug that shows promise for conditions ranging from polycystic ovary syndrome to breast cancer. From the initial reasons for Bristol-Myers Squibb to refuse to invest in promising alternative uses, to the institutions, researchers, and regulators who identified possibilities for metformin treatment, this Article aims to map the role of intellectual property protection, market exclusivity, and search for capital that led to metformin\u27s ascent as a repurposed drug. The Article contributes a concrete understanding to an important problem in pharmaceutical law and policy, one for which scholars have quickly suggested more powerful patent and market exclusivity protection when doing so may undermine the very processes now leading to effective alternative uses for existing drugs

The Drug Repurposing Ecosystem: Intellectual Property Incentives, Market Exclusivity, and the Future of New Medicines

The pharmaceutical industry is in a state of fundamental transition. New drug approvals have slowed, patents on blockbuster drugs are expiring, and costs associated with developing new drugs are escalating and yielding fewer viable drug candidates. As a result, pharmaceutical firms have turned to a number of alternative strategies for growth. One of these strategies is drug repurposing -finding new ways to deploy approved drugs or abandoned clinical candidates in new disease areas

In silico and in vitro drug screening identifies new therapeutic approaches for Ewing sarcoma.

The long-term overall survival of Ewing sarcoma (EWS) patients remains poor; less than 30% of patients with metastatic or recurrent disease survive despite aggressive combinations of chemotherapy, radiation and surgery. To identify new therapeutic options, we employed a multi-pronged approach using in silico predictions of drug activity via an integrated bioinformatics approach in parallel with an in vitro screen of FDA-approved drugs. Twenty-seven drugs and forty-six drugs were identified, respectively, to have anti-proliferative effects for EWS, including several classes of drugs in both screening approaches. Among these drugs, 30 were extensively validated as mono-therapeutic agents and 9 in 14 various combinations in vitro. Two drugs, auranofin, a thioredoxin reductase inhibitor, and ganetespib, an HSP90 inhibitor, were predicted to have anti-cancer activities in silico and were confirmed active across a panel of genetically diverse EWS cells. When given in combination, the survival rate in vivo was superior compared to auranofin or ganetespib alone. Importantly, extensive formulations, dose tolerance, and pharmacokinetics studies demonstrated that auranofin requires alternative delivery routes to achieve therapeutically effective levels of the gold compound. These combined screening approaches provide a rapid means to identify new treatment options for patients with a rare and often-fatal disease

Drug repurposing using biological networks

Drug repositioning is a strategy to identify new uses for existing, approved, or research drugs that are outside the scope of its original medical indication. Drug repurposing is based on the fact that one drug can act on multiple targets or that two diseases can have molecular similarities, among others. Currently, thanks to the rapid advancement of high-performance technologies, a massive amount of biological and biomedical data is being generated. This allows the use of computational methods and models based on biological networks to develop new possibilities for drug repurposing. Therefore, here, we provide an in-depth review of the main applications of drug repositioning that have been carried out using biological network models. The goal of this review is to show the usefulness of these computational methods to predict associations and to find candidate drugs for repositioning in new indications of certain diseases

Repositioning drugs for rare immune diseases: Hopes and challenges for a precision medicine

Human primary immunodeficiency diseases (PIDs) are a large group of rare diseases and are characterized by a great genetic and phenotypic heterogeneity. A large subset of PIDs is genetically defined, which has a crucial impact for the understanding of the molecular basis of disease and the development of precision medicine. Discovery and development of new therapies for rare diseases has long been de-privileged due to the length and cost of the processes involved. Interest has increased due to stimulatory regulatory and supportive reimbursement environments enabling viable business models. Advancements in biomedical and computational sciences enable the development of rational, designed approaches for identification of novel indications of already approved drugs allowing faster delivery of new medicines. Drug repositioning is based either on clinical analogies of diseases or on understanding of the molecular mode of drug action and mechanisms of the disease. All of these are the basis for the development of precision medicine

Drug Repurposing in Oncotherapeutics

Repurposing or repositioning means validating and application of previously approved drugs in the treatment of another disease that might be relevant or irrelevant to existing use in disease based on the principle of polypharmacology. Repurposed drugs are already well documented for pharmacokinetic, pharmacodynamic, drug interaction, and toxicity parameters. In 1962, thalidomide treatment in pregnant women led to phocomelia in their newborn but while repurposed based on anti-angiogenesis property, it showed efficacy in hematologic malignancies like multiple myeloma. The repurposing is becoming an essential tool in the anti-cancer drug development due to existing drugs are not effective, high cost of treatment, therapy may degrade the quality of life, improvement of survival after treatment is not guaranteed, relapse may occur, and drug resistance may develop due to tumor heterogeneity. Repurposing can be addressed well with the help of literature-based discovery, high throughput technology, bioinformatics multi-omics approaches, side effects, and phenotypes. Many regulatory bodies like EML, NIH, and FDA promote repurposing programs that support the identification of alternative uses of existing medicines. Cancer becomes the major health issue, and the need to discover promising anti-cancer drugs through repurposing remains very high due to decline in FDA approval since 1990, huge expenses incurred in the drug development and prediction of dangerous future burden

Applications of Genome-Wide Screening and Systems Biology Approaches in Drug Repositioning

Simple Summary Drug repurposing is an accelerated route for drug development and a promising approach for finding medications for orphan and common diseases. Here, we compiled databases that comprise both computationally- or experimentally-derived data, and categorized them based on quiddity and origin of data, further focusing on those that present high throughput omic data or drug screens. These databases were then contextualized with genome-wide screening methods such as CRISPR/Cas9 and RNA interference, as well as state of art systems biology approaches that enable systematic characterizations of multi-omic data to find new indications for approved drugs or those that reached the latest phases of clinical trials. Modern drug discovery through de novo drug discovery entails high financial costs, low success rates, and lengthy trial periods. Drug repositioning presents a suitable approach for overcoming these issues by re-evaluating biological targets and modes of action of approved drugs. Coupling high-throughput technologies with genome-wide essentiality screens, network analysis, genome-scale metabolic modeling, and machine learning techniques enables the proposal of new drug-target signatures and uncovers unanticipated modes of action for available drugs. Here, we discuss the current issues associated with drug repositioning in light of curated high-throughput multi-omic databases, genome-wide screening technologies, and their application in systems biology/medicine approaches