**1. Introduction**

Drug repurposing, synonymically, known as drug reprofiling, drug repositioning, drug re-tasking, drug redirection, drug recycling, drug rescuing, and therapeutic switching, is a strategy of identifying new pharmacological applications for an approved or investigational drug that are beyond the original scope of its medical indication. It can also be defined as use of the new drugs for the additional diseases other than its already intended use. It establishes new therapeutic uses for already known drugs, which are approved, abandoned, discontinued, or experimental drugs [1, 2]. Need for drug repurposing surfaced due to multifold challenges faced by global pharmaceutical industry [3]. Bringing new drugs into the market with changing regulatory requirements costs huge economy and time. Return benefits are lesser than the expenditure needs on research and development (R&D) [4], and this demoralized the investors from investing in pharmaceutical industry. Repurposing

a drug, on other hand, has lesser possibility of failure from a safety point of view because the repurposed drug has already been found to be adequately safe in preclinical models provided early-stage trials have been completed. Secondly, the time duration for development of drug can be reduced, as most of the safety assessment, preclinical testing, and, in some cases, formulation development are already completed. Thirdly, less expenditure is needed, though varies with the stage and process of development of the repurposing candidate. On average, on traditional drug discovery takes 5–7 years, and failure rate of 45% associated with only toxicity issues keeps the effort and cost of almost one decade at stake [5, 6]. Repurposed drug, in contrast, saves time and effort for preclinical, and phase I and II trials, although phase III and regulatory costs may remain more or less the same (**Figure 1**).

It is estimated that it takes on average 13.5 years to bring a new molecular entity to market, Drug repurposing is based on previous research & development, allowing compounds to progress through the drug development process more quickly as well as saving on the substantial costs associated with previous attrition [7]. It is well known that *de novo* drug discovery and development is a 10–17-year process from idea to marketed drug [8]. The probability of success is lower than 10% [9]. Drug repositioning offers the likelihood of abridged time *and* risk as several phases common to *de novo* drug discovery and development can be bypassed because repositioning candidates have frequently been through several phases of development for their original indication. ADMET, absorption, distribution, metabolism, excretion and toxicity; EMEA, European Medicines Agency; FDA, Food and Drug Administration; IP, intellectual property; MHLW, Ministry of Health Labour and Welfare.

Repurposing cost of a drug from lab to market is estimated to be US\$300 million on average, compared with an estimated ~\$2–3 billion for a new chemical entity [10]. The cost of developing a new drug has soared to \$2.6 billion [11], which has given drug repurposing strategy a substantial momentum to cover one-third of the total approvals given for new drugs and generate around 25% of the annual revenue for the pharmaceutical industry (**Figure 2**) [12].

Moreover, 30% of the US Food and Drug Administration (FDA) approved drugs and biologics (vaccines) constitute repurposed candidates. The global market for

#### **Figure 1.**

*Traditional drug discovery versus drug repurposing/A comparison of traditional* de novo *drug discovery and development versus drug repositioning.*

*Antituberculosis Drug Repurposing: A New Hope for Tackling Multi-Challenging TB in Timely… DOI: http://dx.doi.org/10.5772/intechopen.101642*

#### **Figure 2.**

*Bar chart representing year-on-year trends on funds granted for drug repurposing projects in the recent past (2012–2018), with the advent of time the drug repurposing projects are increasing with the increase of expenditure of funds granted for various repurposing projects. Funds raised for drug repurposing projects increased consistently from 2012 (US\$1 million) to 2015 (US\$100 million). In 2016, although the funds raised were comparatively low, there were more drug-repurposing projects initiated (47 projects). This emphasizes the fact that drug repurposing has gained traction in the recent past [13].*

drug repurposing is valued at 18 million US\$ in 2018 is expected to reach 35 million US\$ by the end of 2025, growing at a CAGR of 30% during 2019–2025.

### **2. Scope of drug repurposing**

Biggest interest of drug repurposing is the reduction of time and cost for achieving new drugs for disease. It also can be a source of treatment options for lesser known and rare diseases. Novel methods based on databases have been proposed to tackle diseases by repurposing of drugs. A suitable data organization can provide a web tool to facilitate the repurposing drugs to treat old and new; common; or rare diseases. But still use of such data is not widespread, though the benefits are well established and calculated. However, drug repurposing might turn out to be expensive, time consuming, and risky. Moreover, certain legal bumps make the road to drug repurposing tougher. Despite all these limitations, drug repurposing still promises of great scope if given better incentives, structured guidelines, and support. Currently, statistical screening of the approved drug can help find repurposing goal of the drug *via in silico* techniques to screen wide library of compounds and target data for successful repurposing technology. But influence of target is not much explored as is expected. The original and repurposed target exploration can yield information about similarities and dissimilarities, which can help to know about binding affinity of the drug. This aspect further needs molecular level study to strength the drug repurposing process. Globally, there are numerous diseases without suitable therapeutic options. Rapidly advancing understanding of human biology, increasing pool of actively studied moieties, and the need to produce cost-effective therapies are driving the need to study the existing set of molecules for relevance across multiple diseases. The promise of cost effectively realizing the full potential of existing drugs *vis à vis* new therapeutic purposes is too attractive for all stakeholders in the healthcare value chain—patients, providers, pharma, and payers, to pass (**Figure 3**).

Drug repurposing began serendipitously; however, with increasing interest from pharmaceutical companies and the identification of various bioinformatics

## *Drug Repurposing - Molecular Aspects and Therapeutic Applications*

**Figure 3.** *The developmental status of repurposed drugs from 2012 to 2018.*

and cheminformatics methodologies, it has evolved into an innovative, data-driven, cutting edge strategy. To understand the recent impact of drug repurposing on drug discovery and development, data on repurposed drugs were collated from Excelra's proprietary drug repurposing portal, news bodies, and social networking sites, and then analyzed to reveal any drug repurposing trends. From 2012 to 2017, almost 170 repurposed drugs entered the drug development pipeline. Currently, these drugs are at different stages of development. Most (72%) are in clinical development, especially Phase II, 7% are in PoC clinical studies, 8% in preclinical stages, 3% in research and development, and 10% have been approved [13].

#### **2.1 Challenges in drug repurposing**

Despite being an attractive drug option with multiple benefits, drug repurposing is a complex technology met with many challenges. The biggest challenge is to choose the approach to make full use of massive amounts of medical data. The issue of limited intellectual property (IP) protection for repurposed drugs is another challenge as IP protection to repurposed drugs is much limited [14]. On the other hand, IP protection of the old drugs prevents them from entering market as repositioned drugs. Moreover, forced closure of some repositioning projects happens due to risk for wastage of time and money [15]. An important principle in drug repurposing process is market exclusivity, which is defined as "method of use" patents valid for a period of 20 years. Conventional drug development process is characterized by "composition of matter" patents while the repurposing process is considered more contestable. "Composition of matter" is protected by the strongest patent protection [16] and is more easily attainable from *de novo* drug development, while as "Method of use" patents that cover repurposed drug can be challenged as merely incremental advances. However, under the right circumstances, a "method of use" patent can be as effective as a "composition of matter" patent in protecting a repositioned drug product depending on the availability of generic products to be substituted through off-label use to achieve expected results with the repurposed drug. The FDA allows physicians off-label prescription of drugs, but prohibits offline marketing of drugs by pharmaceutical companies [17]. IP issues act as barrier for marketing of certain repurposed drugs [18]. There are bleak chances for physicians to prescribe drugs without clinical trial evidence to support the new use; however, "composition of matter" protection may be available for repurposed drugs. Hence, from a legal perspective, a careful consideration of intellectual property rights and

*Antituberculosis Drug Repurposing: A New Hope for Tackling Multi-Challenging TB in Timely… DOI: http://dx.doi.org/10.5772/intechopen.101642*

acts is imperative. For antimicrobial reuse of agents, more limitations are added to the already described list. A big limitation of dosage, toxicity, and resistance development for re-purposed drug is a challenge in itself [19, 20]. If non-antibiotic drug is repurposed for infectious disease, efficacy is usually achieved at much higher doses than of those specified in the original registration, toxicity, and adverse events raise a concern. Another limitation is pharmacokinetic profiles of drugs, which upon repurposing might not serve the benefits which it served for the original use. This limitation affects antibacterial use of drugs as, plasma protein binding plays a major role and also impairs antimicrobial activity as it might narrow the therapeutic index for the antimicrobial indication. Thus, suitable pharmacokinetic profile is a big challenge effecting credibility of drug candidate for repurposing. A major limitation in the drug repurposing is the expenditure needed for clinical trials. Pharmaceutical companies show lesser interest in investment for clinical trials of repurposed drugs as these are usually generics or start with expiry of patent lifetime, there is little scope of turn over for companies. Solutions to address this problem have included raising economic support from public sources, as such sources prioritize health outcomes over commercial motives. Smaller clinical trial set can also be a set for repurposed drugs and such trials are designated as Phase II trials. But clinicians do not consider them much valid, even if high-quality data are generated. However, drug repurposing can be a practical approach, but the issues of funding and feeble interest of pharmaceutical industry hamper the prospects of its clinical usage.
