Drug repositioning

Drug repositioning (also called drug repurposing) involves the investigation of existing drugs for new therapeutic purposes.^[1]^[2]^[3]

Repurposing achievements

Repurposing generics can have groundbreaking effects for patients: 35% of 'transformative' drugs approved by the US FDA are repurposed products.^[4] Repurposing is especially relevant for rare or neglected diseases.^[4]

A number of successes have been achieved, the foremost including sildenafil (Viagra) for erectile dysfunction and pulmonary hypertension and thalidomide for leprosy and multiple myeloma.^[3]^[5] Clinical trials have been performed on posaconazole and ravuconazole for Chagas disease.^[6]

Other antifungal agents clotrimazole and ketoconazole have been investigated for anti-trypanosome therapy.^[7] Successful repositioning of antimicrobials has led to the discovery of broad-spectrum therapeutics, which are effective against multiple infection types.^[8]

Strategy

Drug repositioning is a "universal strategy" for neglected diseases due to 1) reduced number of required clinical trial steps could reduce the time and costs for the medicine to reach market, 2) existing pharmaceutical supply chains could facilitate "formulation and distribution" of the drug, 3) known possibility of combining with other drugs could allow more effective treatment,^[1] 4) the repositioning could facilitate the discovery of "new mechanisms of action for old drugs and new classes of medicines",^[1]^[9] 5) the removal of “activation barriers” of early research stages can enable the project to advance rapidly into disease-oriented research.^[10]

Often considered as a serendipitous approach, where repurposable drugs are discovered by chance, drug repurposing has heavily benefited from advances in human genomics, network biology, and chemoproteomics. It is now possible to identify serious repurposing candidates by finding genes involved in a specific disease and checking if they interact, in the cell, with other genes which are targets of known drugs.^[11] It was shown that drugs against targets supported by human genetics are twice as likely to succeed than overall drugs in the pharmaceutical pipeline.^[12] Drug repurposing can be a time and cost effective strategy for treating dreadful diseases such as cancer^[13]^[14] and is applied as a means of solution-finding to combat the COVID-19 pandemic.

Computational drug repurposing is the in silico screening of approved drugs for use against new indications. It can use molecular, clinical or biophysical data.^[15] Electronic health records and real-world evidence gained popularity in drug repurposing, for instance for COVID 19.^[16] Computational drug repurposing is expected to reduce drug development costs and time.^[17] In 2020, during the COVID-19 pandemic, a European project, Exscalate4Cov conducted drug repurposing experiments, leading to the identification of raloxifene as a possible candidate for treating early-stage COVID-19 patients.^[18]

Drug repositioning evidence level (DREL) assessment of repositioning studies^[8]
Drug repositioning evidence level	Quality of scientific evidence
0	No evidence; includes in silico predictions without confirmation
1	In vitro studies with limited value for predicting in vivo/human situation
2	Animal studies with hypothetical relevance in humans
3	Incomplete studies in humans at the appropriate dose e.g. proof of concept; few cases from medical records; some clinical effects observed
4	Well-documented clinical end points observed for repositioned drug at doses within safety limits

Challenges

According to a 2022 systematic review, inadequate resources (financial and subject matter expertise), barriers to accessing shelved compounds and their trial data, and the lack of traditional IP protections for repurposed compounds are the key barriers to drug repurposing.^[19] There is a lack of financial incentives for pharmaceutical companies to explore the repurposing of generic drugs. Indeed, doctors can prescribe the drug off-label and pharmacists can switch the branded version for a cheaper generic alternative.^[20] According to Pharmacologist Alasdair Breckenridge and patent judge Robin Jacob this issue is so significant that: "If a generic version of a drug is available, developers have little or no opportunity to recoup their investment in the development of the drug for a new indication".^[21]

Drug repositioning present other challenges. First, the dosage required for the treatment of a novel disease usually differs from that of its original target disease, and if this happens, the discovery team will have to begin from Phase I clinical trials, which effectively strips drug repositioning of its advantages of over de novo drug discovery.^[10] Second, the finding of new formulation and distribution mechanisms of existing drugs to the novel-disease-affected areas rarely includes the efforts of "pharmaceutical and toxicological" scientists.^[10] Third, patent right issues can be very complicated for drug repurposing due to the lack of experts in the legal area of drug repositioning, the disclosure of repositioning online or via publications, and the extent of the novelty of the new drug purpose.^[10]

Drug repurposing in psychiatry

Drug repurposing is considered a rapid, cost-effective, and reduced-risk strategy for the development of new treatment options also for psychiatric disorders.^[1]^[22]

Bipolar disorder

In bipolar disorder, repurposed drugs are emerging as feasible augmentation options. Several agents, all sustained by a plausible biological rationale, have been evaluated. Evidence from meta-analyses showed that adjunctive allopurinol and tamoxifen were superior to placebo for mania, and add-on modafinil/armodafinil and pramipexole seemed to be effective for bipolar depression, while the efficacy of celecoxib and N-acetylcysteine appeared to be limited to certain outcomes.^[1] Further, meta-analytic evidence exists also for adjunctive melatonin and ramelteon in mania, and for add-on acetylsalicylic acid, pioglitazone, memantine, and inositol in bipolar depression, but findings were not significant.^[1] The generally low quality of evidence does not allow making reliable recommendations for the use of repurposed drugs in clinical practice, but some of these drugs have shown promising results and deserve further attention in research.^[1]

References

^ ^a ^b ^c ^d ^e ^f ^g Bartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, et al. (November 2021). "Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials". Journal of Psychiatric Research. 143: 230–238. doi:10.1016/j.jpsychires.2021.09.018. PMID 34509090. S2CID 237485915.
^ Sleigh SH, Barton CL (23 August 2012). "Repurposing Strategies for Therapeutics". Pharmaceutical Medicine. 24 (3): 151–159. doi:10.1007/BF03256811. S2CID 25267555.
^ ^a ^b Ashburn TT, Thor KB, et al. (Institute of Medicine; Board on Health Sciences Policy; Roundtable on Translating Genomic-Based Research for Health) (August 2004). "Drug repositioning: identifying and developing new uses for existing drugs". Nature Reviews. Drug Discovery. 3 (8): 673–683. doi:10.1038/nrd1468. PMID 15286734. S2CID 205475073.
^ ^a ^b Kesselheim AS, Tan YT, Avorn J (February 2015). "The roles of academia, rare diseases, and repurposing in the development of the most transformative drugs". Health Affairs. 34 (2): 286–293. doi:10.1377/hlthaff.2014.1038. PMID 25646109.
^ Beachy SH, Johnson SG, Olson S, Berger AC (2014). Drug Repurposing and Repositioning: Workshop Summary. National Academies Press. doi:10.17226/18731. ISBN 978-0-309-30204-3. PMID 24872991.
^ Porta EO, Kalesh K, Steel PG (27 July 2023). "Navigating drug repurposing for Chagas disease: advances, challenges, and opportunities". Frontiers in Pharmacology. 14: 1233253. doi:10.3389/fphar.2023.1233253. PMC 10416112. PMID 37576826.
^ Gambino D, Otero L (2019). "13. Metal Compounds in the Development of Antiparasitic Agents: Rational Design from Basic Chemistry to the Clinic". In Sigel A, Freisinger E, Sigel RK, Carver PL (eds.). Essential Metals in Medicine: Therapeutic Use and Toxicity of Metal Ions in the Clinic. Vol. 19. Berlin: de Gruyter GmbH. pp. 331–357. doi:10.1515/9783110527872-019. ISBN 978-3-11-052691-2. PMID 30855114. S2CID 73728129.Section 2.2.2. "Repositioning of Drugs"
^ ^a ^b Firth A, Prathapan P (1 January 2021). "Broad-spectrum therapeutics: A new antimicrobial class". Current Research in Pharmacology and Drug Discovery. 2: 100011. doi:10.1016/j.crphar.2020.100011. ISSN 2590-2571. PMC 8035643. PMID 34870144.
^ Rosa SG, Santos WC (2020). "Clinical trials on drug repositioning for COVID-19 treatment". Revista Panamericana de Salud Pública. 44: e40. doi:10.26633/RPSP.2020.40. PMC 7105280. PMID 32256547.
^ ^a ^b ^c ^d Oprea TI, Bauman JE, Bologa CG, Buranda T, Chigaev A, Edwards BS, et al. (2011). "Drug Repurposing from an Academic Perspective". Drug Discovery Today: Therapeutic Strategies. 8 (3–4): 61–69. doi:10.1016/j.ddstr.2011.10.002. PMC 3285382. PMID 22368688.
^ Nabirotchkin S, Peluffo AE, Rinaudo P, Yu J, Hajj R, Cohen D (April 2020). "Next-generation drug repurposing using human genetics and network biology". Current Opinion in Pharmacology. 51: 78–92. doi:10.1016/j.coph.2019.12.004. PMID 31982325.
^ King EA, Davis JW, Degner JF (December 2019). "Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval". PLOS Genetics. 15 (12): e1008489. doi:10.1371/journal.pgen.1008489. PMC 6907751. PMID 31830040.
^ Kale VP, Habib H, Chitren R, Patel M, Pramanik KC, Jonnalagadda SC, et al. (January 2021). "Old drugs, new uses: Drug repurposing in hematological malignancies". Seminars in Cancer Biology. 68: 242–248. doi:10.1016/j.semcancer.2020.03.005. PMID 32151704.
^ Kale VP, Amin SG, Pandey MK (October 2015). "Targeting ion channels for cancer therapy by repurposing the approved drugs". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1848 (10 Pt B): 2747–2755. doi:10.1016/j.bbamem.2015.03.034. PMID 25843679.
^ Paranjpe MD, Taubes A, Sirota M (August 2019). "Insights into Computational Drug Repurposing for Neurodegenerative Disease". Trends in Pharmacological Sciences. 40 (8): 565–576. doi:10.1016/j.tips.2019.06.003. PMC 6771436. PMID 31326236.
^ Zong N, Wen A, Moon S, Fu S, Wang L, Zhao Y, et al. (June 2022). "Computational drug repurposing based on electronic health records: a scoping review". npj Digital Medicine. 5 (1): 77. doi:10.1038/s41746-022-00617-6. PMC 9198008. PMID 35701544.
^ Park K (June 2019). "A review of computational drug repurposing". Translational and Clinical Pharmacology. 27 (2): 59–63. doi:10.12793/tcp.2019.27.2.59. PMC 6989243. PMID 32055582.
^ Allegretti M, Cesta MC, Zippoli M, Beccari A, Talarico C, Mantelli F, et al. (January 2022). "Repurposing the estrogen receptor modulator raloxifene to treat SARS-CoV-2 infection". Cell Death and Differentiation. 29 (1): 156–166. doi:10.1038/s41418-021-00844-6. PMC 8370058. PMID 34404919.
^ Krishnamurthy N, Grimshaw AA, Axson SA, Choe SH, Miller JE (July 2022). "Drug repurposing: a systematic review on root causes, barriers and facilitators". BMC Health Services Research. 22 (1): 970. doi:10.1186/s12913-022-08272-z. PMC 9336118. PMID 35906687.
^ Liddicoat J, Liddell K, Aboy M, Wested J (2021-08-01). "Has the EU Incentive for Drug Repositioning Been Effective? An Empirical Analysis of the "+1" Regulatory Exclusivity". IIC - International Review of Intellectual Property and Competition Law. 52 (7): 825–851. doi:10.1007/s40319-021-01088-0. ISSN 2195-0237. S2CID 237717052.
^ Breckenridge A, Jacob R (January 2019). "Overcoming the legal and regulatory barriers to drug repurposing". Nature Reviews. Drug Discovery. 18 (1): 1–2. doi:10.1038/nrd.2018.92. PMID 29880920.
^ Fava M (February 2018). "The promise and challenges of drug repurposing in psychiatry". World Psychiatry. 17 (1): 28–29. doi:10.1002/wps.20481. PMC 5775121. PMID 29352538.