A Review on Drug Repurposing a New Approach to Drug Development

Figure 1:-Drug repositioning through  technology

DEFINITION OF DRUG REPURPOSING :

Drug repurposing (or repositioning) is the practice of investigating existing, approved, or shelved medications for entirely new medical conditions. Because these drugs already have established human safety data, the approach drastically cuts development costs and timelines by skipping the early, lengthy phases of drug design.

A well-known example is Sildenafil (Viagra), which was originally studied and prescribed for angina and heart conditions until its side effects revealed its efficacy for erectile dysfunction and pulmonary hypertension.

Why Drug Repurposing Matters :

Faster to Market: Traditional drug discovery often takes over a decade, while repurposed drugs can sometimes reach clinical implementation in just 3 years since their toxicity and dosing parameters are already known.

Lower Risk: Since the safety profile in humans is well-understood, these drugs are less likely to fail in advanced clinical trials due to unexpected toxicity.

Cost-Efficient: Pharmaceutical companies and researchers save millions by bypassing the initial preclinical testing phases.

Historical Context and Evolution of Drug Repurposing:

Throughout history, DRP has often occurred opportunistically and by chance. When a drug exhibited an unintended off‐target effect or a newly discovered on‐target effect, it was then explored for potential commercial use. Notably, many successful instances of DRP were not the result of a systematic approach. For instance, sildenafil citrate, initially developed as an antihypertensive medication, found unexpected success in treating erectile dysfunction after retrospective clinical observations. Similarly, thalidomide, originally introduced as a sedative but later withdrawn due to its association with severe birth defects, was fortuitously repurposed for conditions such as erythema nodosum leprosum (ENL) and multiple myeloma (MM) . Thalidomide, originally withdrawn due to teratogenic effects, received FDA approval in 1998 for ENL and in 2006 for MM, following clinical trials demonstrating significant improvements in progression‐free survival.

Sildenafil, marketed as Viagra for erectile dysfunction treatment by Pfizer, captured a significant market share, generating worldwide sales of $2.05 billion in 2012 [. Thalidomide, despite its initial setbacks, emerged as an effective therapy for ENL in 1964 and later for MM in 1999 . Its success led to the development of derivative drugs like , Celgene), which achieved global sales of $8.2 billion in 2017. While some successful DRP cases stemmed from an understanding of drug pharmacology or retrospective clinical analyses, others resulted from more systematic approaches. These systematic approaches have identified numerous promising candidate drugs, many of which are undergoing advanced clinical trials for various diseases, both common and rare. However, significant technical, regulatory and organizational challenges persist, hindering the progress of DRP efforts. by streamlining compound screening and predicting new indications. Today, repurposing offers a cost-effective, time-efficient approach to drug discovery, promising to address unmet Despite challenges such as regulatory hurdles and intellectual property issues, interdisciplinary collaboration and technological innovation signal a bright future for drug repurposing, with potential improvements in patient care and public health outcomes.

STAGES OF DRUG REPURPOSING :

The stages of repurposing are elucidated

IMPORTANTC OF DRUG REPURPOSING :

Repurposing can identify new compounds based on phenotypic benefits without explicitly defining the mechanism of action. This can be directly tested in preclinical animal models, and these results are more applicable to clinical applications and research. It may progress directly straight to Phase II clinical trials  There is a minimum risk of failure with repurposed drugs . The difference between traditional drug discovery and drug repurposing is describe.

Main approaches to drug repurposing:

Pharmaceutical organizations typically take one of three approaches to drug repurposing as part of a systematic strategy: drug, disease and target centric. They each explore the relationships between drugs, diseases and targets in different ways based on the therapeutic action of a drug. Disease- and target-centric approaches are the most commonly used approaches.1

Drug centric

A drug-centric approach expands the application of an existing drug to a new indication. Drug-centric repurposing may begin by:

Discovering off-label use of an approved drug for a new patient population or medical condition outside the scope of a medicine’s existing license or patent

Reviewing investigational or abandoned drugs that initially showed poor efficacy for another indication or did not secure regulatory approval

Identifying new uses for drugs pulled from circulation due to safety or post-market issues that are still efficacious for other medicinal uses

Repositioning drugs that have reached the end of the patent exclusivity period and have generic competitors for new conditions

Disease centric

A disease-centric approach matches diseases with no treatments or with partially effective treatments with approved or failed compounds with therapeutic impact. It is particularly valuable in drug repurposing efforts for rare diseases. It involves identifying diseases with homologous underlying biological mechanisms to the indication the original drug treats. For example, a drug developed to treat cancer could also treat other diseases with uncontrolled cell growth, such as psoriasis.

Target centric

A target-centric approach matches a new indication without a treatment, with an established drug and its known target; the old and new indications typically differ quite significantly. It involves investigating the specific molecular targets that are implicated in the pathology of a disease and using the existing drug proven to modulate those targets. This approach is also particularly useful when seeking to repurpose drugs to treat rare diseases.

Drug repurposing challenges:

A) .Technical challenges to drug repurposing :

There are several technical challenges that pharmaceutical organizations may face when pursuing computational methods to support drug repurposing projects.

B)  Data volume and hygiene

Drug repurposing requires access to considerable volumes of data, including compound libraries, patent data, pharmacological data, and published scientific literature. Large datasets are more likely to suffer from poor data hygiene, increasing the likelihood of errors, inconsistencies and duplications. Some datasets may be restricted by privacy and security concerns, regulatory rules, or are inaccessible externally. Yet missing data impacts outcomes.

C)  Data heterogeneity

The types of data required to support drug repurposing are varied and originate from multiple sources. Data are often siloes and stored in multiple formats, such as unstructured text files and images, electronic lab notebooks, spreadsheets and databases. Repurposing also uses many data types, such as biology/omics and chemistry data. The heterogeneity of the data poses significant challenges for integration, analysis and management.

D) Tooling and platform barriers

Significant and highly scalable computing power is needed to collect, store, process, manage and analyze data as volumes expand and the number of sources increase. Platforms that can easily connect data via APIs are essential to “serve” data to internal audiences who are not data science experts. Specialist techniques to organize data are also important, for example, expert ontologies, taxonomies, indexing and metadata tagging.

E) Lack of technical expertise

Building a knowledge graph or graph neural network, or creating an in silico model or digital twin, requires cross-domain expertise that spans science and technology. Smaller to medium-sized pharmaceutical organizations may not have teams capable of both integrating and harmonizing fragmented and disparate datasets, and who can parse a drug repurposing research question with access to the full context of the question.

F) Efficacy and safety

A repurposed drug candidate may prove to be less effective for a new indication than it was for the original licensed purpose, or it may not show a marked increase in efficacy over treatments that already exist. In some cases, there may be limited clinical evidence to support the use of the new indication being pursued.

Additionally, drug repurposing candidates may not be as beneficial when newly employed in combination therapies than in their previous usage as a single therapy. Combining drugs also necessitates new clinical trials; expensive and time-consuming clinical studies may then negate the cost savings of a repurposed drug. Where a generic equivalent for the drug exists, the subsequently lower potential profit margin also does not support the business case for clinical trials.

G) Regulatory challenges to drug repurposing

• As in de novo development, securing marketing authorization for repurposed drugs from regulatory agencies like the FDA, EMA and MHRA can be a barrier. While typically, existing drugs do have an easier path to approval for new indications because of their known safety profile and established use in humans, challenges still occur.
• While preclinical testing is eliminated in repurposing projects, clinical trials are still required in most scenarios to demonstrate efficacy and safety in the target indication. The extent of the trials required varies depending on what data are available on the drug and the nature of the repurposing project. For instance, there are more stringent rules around drugs for children. Moreover, in rare diseases, difficulties with finding enough patients in the target cohort to conduct a statistically significant trial may halt a project completely.
• Human clinical trials are the most expensive research phase, and the cost may outweigh the potential return on investment from a repurposed asset. It can also be harder to obtain reimbursement from payers because reimbursement codes (used by insurance companies in healthcare billing and claims) may not apply for a new use, which will also limit adoption in practice

H) Repurposing process

• Optimizing inclusion and exclusion criteria in target population selection is crucial. The primary responsibility for assessing the drug’s anticipated effect is choosing treatment groups. Inadequate subject selection may lead to unintended adverse effects rather than therapeutic benefits .
• Timely achievement: When repurposing an old medication for a new indication, many factors must be taken into account, such as the dosage schedule and administration method, to achieve a notable benefit for the new indication. One obstacle is to optimize the formulation without making the medicine unstable .
• Repurposing a medicine to target a different patient group with a distinct set of physiological parameters may result in unanticipated adverse outcomes, necessitating a thorough examination of each reaction.
• Prerequisite information on drug–drug interactions, pharmacodynamics, and pharmacokinetics of the drugs, with a focus on toxicity profile, is necessary for repurposing medication combinations.
• By solving issues in repurposing across regulatory agencies, industry, and academia, the area of drug discovery can attain unprecedented levels of efficiency, accuracy, and impact through the use of AI capabilities. This collaborative model accelerates discovery while ensuring accessible, effective, and safe medications for patients globally

Figure 2:-Process of drug repurposing