Recommended

New webinar with Fujifilm: Monocyte activation test (MAT): Insight into examining regulations and markets prospects
New webinar: The path to optimisation in pharmaceutical microbiology
Join our webinar: An alternative medium to support sterility testing using the Growth Direct® Rapid Sterility System
Discover more in our new application note: validating recombinant cascade reagents in 3 simple steps
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.

References

  1. Oprea TI, Bauman JE, Bologa CG, Burunda T, et al. 2011. Drug Repurposing from an Academic Perspective. Drug Discov Today Ther. Strateg. 8(3-4), 2011, 61–69.
  2. Unlicensed and “off-label” medicines. Information for patients, parent and carers. Oxford university hospitals, NHS Foundation Trust. https://www.ouh.nhs.uk/patient-guide/leaflets/files/12048Punlicensed.pdf. Accessed on 12 June 2020.
  3. Radley DC, et al. Off-label prescribing among office-based physicians. Arch. Intern. Med., 166, 2006, 1021-1026.
  4. van Riet-Nales DA, de Jager KE, Schobben AFAM, Egberts TCG. The availability and age-appropriateness of medicines authorized for children in the Netherlands. Br. J. Clin. Pharmacol., 72(3), 2011,465–473.
  5. Fetro C, Scherman D. Drug repurposing in rare diseases: Myths and reality. Therapies, 75(2), 2020, 157-160.
  6. Ashburn TT, Thor KB. Drug Repositioning: Identifying and Developing New Uses for Existing Drugs. Nat. Rev. Drug Discov., 8, 2004, 673-83.
  7. Deotarse P, Jain A, Baile MB, et al. Drug Repositioning: A review. Int. J. Pharma. Res. Rev., 4, 2015, 51-58.
  8. Ismail HM, Dorchies OM, Scapozza, L. The potential and benefits of repurposing existing drugs to treat rare muscular dystrophies. Expert Opin. Orphan Drugs, 6(4), 2018, 259-271.
  9. Baker NC, Ekins S, Williams AJ, Tropsha A. A bibliometric review of drug repurposing Drug Disc.Today. 23(3), 2018, 661-672.
  10. Liu C, Zhou Q, Li Y, Garner LV, et al. 2020. Research and development on therapeutic agents and vaccines for covid-19 and related human corona virus diseases. ACS Cent. Sci. 2020, 6, 3, 315–331, https://doi.org/10.1021/acscentsci.0c00272
  11. Rao, MS, Gupta, R, Liguori, MJ, Hu, M, et al. Novel Computational Approach to Predict Off-Target Interactions for Small Molecules. Front. Big Data, 17 July 2019, https://doi.org/10.3389/fdata.2019.00025. https://www.frontiersin.org/articles/10.3389/fdata.2019.00025/full. Accessed on 12 June 2020.
  12. Car BD. The relevance of off-target polypharmacology. In. Polypharmacology in Drug Discovery. Ed: Peters, JU. Wiley, 2012. https://doi.org/10.1002/9781118098141.ch1
  13. Dar AC, Das TK, Shokat KM, Cagan RL. Chemical genetic discovery of targets and anti-targets in cancer polypharmacology. Nature, 486(7401), 2012, 80-84.
  14. DeBusk RF, Peppine CJ, Glasser DB, Shpilksy A et al. Efficacy and safety of sildenafil citrate in men with erectile dysfunction and stable coronary artery disease. Am. J. Cardiol., 93(2), 2004, 147-153.
  15. Bradley DP, Kulstad R, Racine N, Shenker Y, et al. Alterations in energy balance following exenatide administration. Appl. Physiol. Nutr. Metab., 37(5), 201, 893-899.
  16. Palumbo A, Facon T, Sonneveld P, Blade J, et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood, 111(8), 2008, 3968-3977.
  17. MRC, 2014. World’s largest collection of deprioritised pharma compounds opens to researchers. 08 December 2014. https://mrc.ukri.org/news/browse/world-s-largest-collection-of-deprioritised-pharma-compounds-opens-to-researchers/. Accessed on 12 June 2020.
  18. Pantziarka P, BoucheG, Meheus L, Sukhatme V, et al. The repurposing drugs in oncology project (ReDo). Ecancermedicalscience, 8, 2014, 442. https://pubmed.ncbi.nlm.nih.gov/25075216/. Accessed on 12 June 2020.
  19. Pantziarka P, Sukhatme V, Bouche G, Meheus L, et al. Repurposing Drugs in Oncology (ReDO)—diclofenac as an anti-cancer agent. Ecancermedicalscience. 10, 2016, 610.
  20. DRP, 2020. http://www.drugrepurposingportal.com/. Accessed on 12 June 2020.
  21. EC, 2018. https://ec.europa.eu/health/sites/health/files/files/committee/stamp/stamp_10_44_annex_en.pdf. Accessed on 16 June 2020.
  22. Allinson M, 2012. NCATS Launches Drug Repurposing Program. Nat. Biotechnol., 30(7), 2012, 571-572.
  23. FDA, 2019. Repurposing Off-Patent Drugs: Research & Regulatory Challenges. December 5 – 6, 2019. https://www.fda.gov/drugs/news-events-human-drugs/repurposing-patent-drugs-research-regulatory-challenges-12052019-12062019. Accessed on 16 June 2020.
  24. Papanikolaou N, Pavlopoulos GA, Theodosiou T, Vizirianakis IS, et al. DrugQuest – A text mining workflow for drug association discovery. BMC Bioinformatics, 17(S.5), 2016, 182.
  25. Su EW, Sanger TM. Systematic drug repositioning through mining adverse event data in ClinicalTrials.gov. PeerJ., 5,2017. https://peerj.com/articles/3154/. Accessed on 12 June 2020.
  26. Lamb J, Crawford ED, Peck D, Modell JW, et al. The Connectivity Map: Using the gene-expression signatures to connect small molecules, genes and disease. Science, 313(5795), 2004, 1929-1935.
  27. Iorio E, Bosotti R, Scacheri E, Belcastro V, et al. Discovery of drug mode of action and drug repositioning from transcripitional responses. Proc. Natl. Acad. Sci. USA, 107(33), 2010, 14621-14626.
  28. Chung FH, Chiang YR, Tseng AL, Sung YC, et al. Functional Module Connectivity Map (FMCM): A framework for searching repurposed drug compounds for system treatment of cancer and colorectal adenocarcinoma. PLoS One, 9(1), 2014. https://doi.org/10.1371/journal.pone.0086299. Accessed on 12 June 2020.
  29. Narod SA, Salmena L. BRCA1 and BRCA2 Mutations and Breast Cancer. Discov. Med. 12(66), 2012, 445-53.
  30. Vazquez-Ortiz G, Chisholm C, Xu X, Lahusen TJ, et al. Drug repurposing screen identifies lestaurtinib amplifies the ability of the poly (ADP-ribose) polymerase 1 inhibitor AG14361 to kill breast cancer associated gene-1 mutant and wild type breast cancer cells. Breast Can. Res., 16, 2014, . R67. https://doi.org/10.1186/bcr3682. Accessed on 12 June 2020.
  31. Van Noort V, Scolch S, Zeller IM, Ostertag K, et al. Novel drug candidates for the treatment of metastatic colorectal cancer through global inverse gene-expression profiling. Cancer Res., 74(20), 2014, 5690-5699.
  32. Nowak-Sliwinska P, Scapozza L, Ruiz i Altaba A. Drug repurposing in oncology: Compounds, pathways, phenotypes and computational approaches for colorectal cancer. Biochim. Biophys. Acta Rev. Cancer. 1871(2), 2019, 434–454.
  33. Yang L, Argawal P. Systematic drug repositioning based on clinical side effects. PLoS One, 6(12),2011. https://doi.org/10.1371/journal.pone.0028025. Accessed on 12 June 2020.
  34. Mattes RD, Shaw LM, Edling-Owens J, Engelman K, Elsohly MA. Bypassing the first-pass effect for the therapeutic use of cannabinoids. Pharmacol. Biochem. Behav., 44(3), 1993, 745-747.
  35. Herman TF, Santos C. First Pass Effect. SatPearls, 2019. https://www.ncbi.nlm.nih.gov/books/NBK551679/. Accessed on 12 June 2020.
  36. Greaves A. The Use of Midazolam as an Intranasal Sedative in Dentistry. SAAD Dig.,32, 2016, 46-9.
  37. Yoshihara T, Horimoto M, Kitamura T, Osugi N, et al. 25 mg versus 50 mg dose of rectal diclofenac for prevention of post-ERCP pancreatitis in Japanese patients: a retrospective study. BMJ Open 2015;5:e006950. doi:10.1136/bmjopen-2014-006950. Accessed on 12 June 2020.
  38. Zhao XM, Iskar M, Zeller G, Kuhn M, et al. 2011. Prediction of drug combinations by integrating molecular and pharmacological data. PLoS Comput. Biol. 2011 Dec;7(12):e1002323. https://pubmed.ncbi.nlm.nih.gov/22219721/. Accessed on 12 June 2020.
  39. Batman G, Hampson L, Hampson IN. Lessons from repurposing HIV drugs: a prospective novel strategy for drug design. Future Virol., 6(9), 2011, 1021-1023.
  40. Battah B, Chemi G, Butini S, Campiani G, et al. A Repurposing Approach for Uncovering the Anti-Tubercular Activity of FDA-Approved Drugs with Potential Multi-Targeting Profiles. Molecules, 24(23), 2019, 4373-4385.
  41. Talha B, Dhamoon AS. Ritonavir. StatPearls. 2019. https://www.ncbi.nlm.nih.gov/books/NBK544312/. Accessed on 12 June 2020.
  42. Achenbach CJ, Darin KM, Murphy RL, Katlama C. Atazanavir/ritonavir-based combination antiretroviral therapy for treatment of HIV-1 infection in adults. Future Virol., 6(2), 2011, 157–177.
  43. Hicks CB, Cahn P, Cooper DA, Walmsley SL, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. The Lancet, 368(9534), 2006, 466-475.
  44. Hsu A, Isaacson J, Brun S, Bernstein B, Lam W, et al. Pharmacokinetic-Pharmacodynamic Analysis of Lopinavir-Ritonavir in Combination with Efavirenz and Two Nucleoside Reverse Transcriptase Inhibitors in Extensively Pretreated Human Immunodeficiency Virus-Infected Patients. Antimicrob. Agents Chemother., 47(1), 2003, 350–359.
  45. Sun W, Sanderson PE, Zheng W.. Drug combination therapy increases successful drug repositioning. Drug Discov. Today, 21(7), 2016, 1189-1195.
  46. Muralidharan N, Sakthivel R, Velmurugan D, Gromiha MM. Computational Studies of Drug Repurposing and Synergism of Lopinavir, Oseltamivir and Ritonavir Binding With SARS-CoV-2 Protease Against COVID-19 . J .Biomol. Struct. Dyn., 16, 2020, 1-6. Talha B, Dhamoon AS. Ritaonavir. StatPearls, 2019. https://www.ncbi.nlm.nih.gov/books/NBK544312/. Accessed on 12 June 2020.
  47. Kola L, LandisJ. Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov., 3(8), 2004, 711-715.