article

The many advantages of repurposing existing drugs

Repurposing existing drugs can be attractive as the process is often less risky, more cost effective and can be undertaken in less time. This article discusses the logic behind drug repurposing and the approaches that are currently being explored.

Drug repurposing

DRUG REPURPOSING, sometimes termed drug repositioning or drug re-profiling, is the process of redeveloping an existing drug for licensed use in a different therapeutic indication or indications1 and/ or via a different drug delivery route. In contrast, off-label use (OLU) describes a drug being used in a fashion that is not covered by the current license, eg, using higher doses, paediatric use or for another illness.2 One fifth of the prescriptions in the US may be for OLU;3 however, there is an increased risk of adverse events because OLU drugs are not fully investigated in controlled clinical studies.

Drug repurposing can often be an integral part of a company’s lifecycle management (LCM) strategy, for example, the development of age-appropriate dosage forms as product line extensions (PLEs). It can also be in response to an unmet clinical need, often driven by extensive OLU.4 It is often undertaken because it is less risky, with lower costs and shorter timelines.5 Repurposed drugs have been estimated to require only three to four years to reach pivotal clinical trials6 and the estimated cost is $1.6 billion compared with $12 billion for a new molecular entity (NME).7,8 Many drugs have been extensively assessed from a repurposing perspective; for example, prednisolone has been evaluated in over 1,340 therapeutic disorders.9 Repurposing is often utilised when treating rare, orphan or neglected diseases,5,8 or during pandemics, where there is an urgent need to find a rapid treatment.10

The logic of repurposing

Drug repurposingTypically, when a drug exhibits activity at more than one biological target, this off-target activity is viewed negatively, leading to unwanted molecular promiscuity and undesirable side effects.11 However, this so called “polypharmacology” may present opportunities in treating other disorders, particular if the disease pathology is complex.12 Systems biology linked with polypharmacological assessments are currently being used to identify beneficial off-target activity that can be utilised for drug repurposing.13

A repurposed drug may currently be approved for a different primary indication, withdrawn because of unacceptable side effects, discontinued because of sub-optimal efficacy or superseded by more efficacious drugs in the designated primary indication, ie, abandoned. Repurposing exploits the fact that approved, withdrawn or abandoned drugs have already undergone extensive pre-clinical and clinical safety assessments and that “detailed information is available on their pharmacology, formulation, dose”.6 An example of repurposing in a different indication is sildenafil (Viagra®), which was initially developed as an anti-angina drug but repurposed as a treatment for erectile dysfunction based on observations made during early-stage clinical development.14 Likewise, exenatide (Byetta®) was originally utilised as a treatment for type 2 diabetes and repurposed to treat non-diabetic obese patients due to observed off-target weight loss.15 One example of repurposing a withdrawn drug is thalidomide, which was originally developed for emesis but then withdrawn due to significant teratogenicity side effects. Thalidomide has now been repurposed for multiple myeloma and leprosy, excluding woman of childbearing potential.16

Overview of drug repurposing initiatives

There are also active industry, governmental and academia initiatives to repurpose drugs in numerous therapeutic areas. Nearly 70 “abandoned” drugs, mostly deprioritised due to sub-optimal efficacy in their primary indication, were made available for repurposing by a consortium of pharmaceutical companies and the British Medical Research Centre (MRC).8,17 In oncology, the Repurposing Drugs in Oncology (ReDO) collaboration is an international initiative between the US GlobalCures and the Belgium Anticancer Fund.18,19 There is also a bespoke drug repurposing portal, where interested parties can access the latest repurposing information.20

Many repurposed drugs are dosed at levels smaller than the lowest strength of marketed products”

Regulatory agencies on both sides of the Atlantic are supportive of repurposing initiatives. In the EU, the Safe and Timely Access to Medicines for Patients (STAMP) Expert Group has issued guidance to foster the authorisation of a new indication to an unprotected off-patent medicinal product.21 In the US, the National Institute of Health (NIH) initiated a drug repurposing programme in 201222 and the US Food and Drug Administration (FDA) recently launched a workshop with industry, academia and the patient advocacy community to discuss activities that support drug repurposing.23

In silico approaches to drug repurposing

Text mining or literature-based discovery

With the existing computational power of modern search engines, this is a viable strategy. In addition to existing sources, ie, MEDLINE and PUBMED, several new strategies have been developed. DrugQuest was designed to highlight connections between specified drugs and diseases24 while ClinicalTrials.gov is a registry of clinical trials that has been text mined for adverse events as part of a systematic repurposing strategy.25

Transciptomics

Transciptomic data allows the identification of under- and over-expressed genes in disease states and can be used to assess networks or pathways leading to gene deregulation. This approach of matching gene expression signatures from disease to therapeutic drug(s) sharing a mechanism of action is commonly referred to as connectivity mapping (cMap). The cMap was used to facilitate the repurposing of some 1,300 approved drugs.26,27 A related initiative, Functional Module Connectivity Map (FMCM), was established in 2014 to identify potential drugs for repurposing in the treatment of complex disorders.28

Genomics and genetics

Historically, genetics has established many causal links between specific genes and diseases. This has led to potential drug(s) being identified for repurposing if the drug’s known protein target is also genetically associated with a disease, which is different from their established applications. For example, a gene signature of metastatic potential, ie, BRAC-1/2 genes linked to breast cancer29 can be used to repurpose drugs in this new area. Vazquez-Ortiz et al.30 used a drug repurposing screen and identified that lestaurtinib amplifies the ability of AG14361 to kill breast cancer-associated BRCA-1 mutant. Van Noort et al.31 used gene expressions and gene profiles together with cMap to identify drugs for repurposing as oncolytics.

Phenotypic side effects

Side effects deriving from treatment can often serve as a phenotypic biomarker.32 The SIDER (Side Effect Resource) database has been used for systematic drug repositioning based on clinical side effects.33 Drugs used to treat similar diseases were found to typically generate similar side effect profiles, which could indicate a comparable mode of action; hence drugs with similar side effects could potentially be used to treat similar diseases (clinical phenotyping).

Formulation development approaches to drug repurposing

Modification of dose strengths

LCM and OLU often highlights the need for different dosage strength to those that are currently available, where dividing an existing marketed tablet or tablets are not viable options. Many repurposed drugs are dosed at levels smaller than the lowest strength of marketed products. These additional dose(s) will require additional safety, efficacy and chemistry, manufacturing and controls (CMC) data.

Change of dosing routes

If the original commercial product’s oral bioavailability was not optimised and the pharmacokinetics are straightforward, (ie, there is a linear relationship between efficacy and side effects such that lower dosing leads to lesser side effects) but lower efficacy, then it may be possible to switch to enhance fraction absorbed using a different formulation or to avoid first pass loss using alternative routes of delivery.34,35 For instance, midazolam is an anxiolotic drug used for patient sedation; however, its use is constrained to parenteral delivery because of extensive first pass metabolism. Efforts have recently been undertaken to repurpose the drug for intranasal delivery for use in routine operations in dentistry and clinical settings. The level of conscious sedation is rapid and equivalent to that achievable via intravenous routes.36 Non-steroidal anti-inflammatory drugs (NSAIDs) show great utility in pain management but long-term oral use is often limited because of gastric irritation. Repurposing oral diclofenac to be delivered rectally addresses this key impediment to long-term use.37

Change of dosing regimen

Medicine formulationThere are occasions where the dosing regimen of an approved drug may be non-optimal. As part of drug repurposing programmes an attempt to improve efficacy and/or reduce side effects and to reduce pill burden (such as switching from immediate release doses twice a day to a modified release format dosed once a day) could be explored. However, if the efficacy and safety profile of the drug are not straightforward it may be the case that by changing the dosing regimen, the pharmacokinetics are also modified sufficiently for the regulatory agency to require further clinical studies. For example, if a drug is metabolised by an enzyme but the same drug also inhibits the enzyme at higher concentrations, it is possible that a reduced dosing level might lead to an increase in metabolites that could lead to unanticipated side effects.

Targeting a different patient population

Another area where regulatory agencies may require further study is potentially where an oral drug is repurposed into a patient population that is different from the original. It is perhaps easy to understand that it would be more difficult to justify a repurposed “adult” drug that was originally studied in otherwise healthy adults into paediatric, geriatric, special population (such as pregnant women) or a different disease state (perhaps one that involves changes in liver function). With the passing of time, there is ever more information about genotypes and phenotypes present in the human population. Many people assume that since a commercial drug product was originally approved that there would be no need to review the original basis of approval for a potential successor. As a result, it is essential to hold a meeting early on with regulatory agencies to confirm alignment with the overall repurposing strategy and requirements for supporting clinical studies and to review these regularly to make sure any assumptions and agreements still apply.

Matching mechanism of action to disease

Knowledge of the mechanism of action of each drug could enable combination of two (or more) existing marketed products, ie, fixed dose combinations (FDCs) to exploit potential synergies and improve efficacy and/or reduce side effects with any of the approaches suggested above.38 This strategy could be useful for modulating two aspects of a biological target that could improve efficacy and help delay or prevent adaptations that lead to drug resistance, ie, HIV,39 tuberculosis40 or oncology.32 Although ritonavir was originally developed as a stand-alone treatment to inhibit HIV protease, subsequent studies found that it effectively inhibits cytochrome P450-3A4 (CYP450-3A4) and drug efflux mechanisms, which are PgP-mediated. Ritonavir is currently used in combination with other HIV therapies to boost or augment the bioavailability of co-administered anti-retroviral drugs.41 Ritonavir has been used in combination with atazanavir,42 tipranavir43 and lopinavir.44 Patient adherence is also improved by developing FDCs as it reduces pill burden.45 The recent COVID-19 pandemic has seen a huge drive towards repurposing existing anti-viral drugs to treat the disease.10 Based on the known structure of the virus, computational studies have been utilised to assess the potential efficacy of lopinavir, oseltamivir and ritonavir in this disease.46

Conclusion

Drug repurposing can often be an integral part of a company’s life cycle management strategy or in response to an unmet clinical need driven by extensive OLU. This can involve different strengths of the existing dosage form, different delivery systems, ie, oral to intranasal switch or fixed dose combinations to enhance the efficacy, tolerability and adherence of existing drugs. While the repurposing of drugs with good pre-clinical and clinical safety profiles can theoretically lead to rapid approval for the same route of administration, CMC is often a critical path. The overall success rate of repositioned drugs (six percent) is similar to NMEs (five percent) and lack of efficacy still remains the greatest hurdle to any new or repositioned drugs.32,47 In addition, if different delivery routes are being contemplated, eg, intranasal versus oral, then substantial pre-clinical and clinical safety, PK32 as well as CMC activities will be required.

About the authors

Dave Elder ICH Q12David Elder has nearly 40 years of service within the pharmaceutical industry at Sterling, Syntext and GlaxoSmithKline. He is now an independent GMC consultant. He is a visiting professor at King’s College, London and is a member of the British Pharmacopoeia. He is a member of the Joint Pharmaceutical Analysis Group (JPAG) and the Analytical Division Council of the Royal Society of Chemistry

Stephen TindallStephen Tindall holds a bachelor’s degree in Chemistry and Analytical Science from Loughborough University and specialises in forensic data analysis. He has worked at Catalent for 33 years (16 years in the USA between 2003 and 2019) and is now based at the Swindon location. Stephen has held leadership positions in formulation development, process development and both clinical and commercial operations at FDA & EMA regulated facilities. Stephen served as an expert panel member on USP committees for Dissolution Testing of Liquid Filled Capsules and Use of Enzymes in Dissolution Testing of Gelatin Capsules from 2010-2015.

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