Drug repositioning explained

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

Repurposing achievements

Repurposing generics can have groundbreaking effects for patients: 35% of 'transformative' drugs approved by the US FDA are repurposed products.[3] Repurposing is especially relevant for rare or neglected diseases.[3]

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.[4] [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.

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, 4) the repositioning could facilitate the discovery of "new mechanisms of action for old drugs and new classes of medicines",[8] 5) the removal of “activation barriers” of early research stages can enable the project to advance rapidly into disease-oriented research.[9]

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.[10] It was shown that drugs against targets supported by human genetics are twice as likely to succeed than overall drugs in the pharmaceutical pipeline.[11] Drug repurposing can be a time and cost effective strategy for treating dreadful diseases such as cancer[12] [13] 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.[14] Electronic health records and real-world evidence gained popularity in drug repurposing, for instance for COVID 19.[15] Computational drug repurposing is expected to reduce drug development costs and time.[16] 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.[17]

Drug repositioning evidence level (DREL) assessment of repositioning studies[18] !Drug repositioning evidence level !Quality of scientific evidence
0No evidence; includes in silico predictions without confirmation
1In vitro studies with limited value for predicting in vivo/human situation
2Animal studies with hypothetical relevance in humans
3Incomplete studies in humans at the appropriate dose e.g. proof of concept; few cases from medical records; some clinical effects observed
4Well-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. 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. 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.

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.[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. 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. 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.

See also

Further reading

Notes and References

  1. Bartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, Carrà G . 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 . November 2021 . 34509090 . 10.1016/j.jpsychires.2021.09.018 . 237485915 .
  2. Sleigh SH, Barton CL . 25267555 . Repurposing Strategies for Therapeutics. Pharmaceutical Medicine. 23 August 2012. 24. 3. 151–159. 10.1007/BF03256811.
  3. Kesselheim AS, Tan YT, Avorn J . The roles of academia, rare diseases, and repurposing in the development of the most transformative drugs . Health Affairs . 34 . 2 . 286–293 . February 2015 . 25646109 . 10.1377/hlthaff.2014.1038 .
  4. Ashburn TT, Thor KB . Institute of Medicine; Board on Health Sciences Policy; Roundtable on Translating Genomic-Based Research for Health . Drug repositioning: identifying and developing new uses for existing drugs . Nature Reviews. Drug Discovery . 3 . 8 . 673–683 . August 2004 . 15286734 . 10.1038/nrd1468 . 205475073 .
  5. Book: Beachy SH, Johnson SG, Olson S, Berger AC . Drug Repurposing and Repositioning: Workshop Summary. 2014. National Academies Press. 10.17226/18731 . 24872991 . 978-0-309-30204-3.
  6. Porta EO, Kalesh K, Steel PG . Navigating drug repurposing for Chagas disease: advances, challenges, and opportunities . Frontiers in Pharmacology . 14 . 1233253 . 27 July 2023 . 37576826 . 10416112 . 10.3389/fphar.2023.1233253 . free .
  7. Book: Gambino D, Otero L . Essential Metals in Medicine: Therapeutic Use and Toxicity of Metal Ions in the Clinic . 13. Metal Compounds in the Development of Antiparasitic Agents: Rational Design from Basic Chemistry to the Clinic . Sigel A, Freisinger E, Sigel RK, Carver PL . 19 . 2019 . de Gruyter GmbH . Berlin . 978-3-11-052691-2 . 10.1515/9783110527872-019 . 30855114 . 331–357 . 73728129 . Section 2.2.2. "Repositioning of Drugs"
  8. Rosa SG, Santos WC . Clinical trials on drug repositioning for COVID-19 treatment . Revista Panamericana de Salud Pública . 44 . e40 . 2020 . 32256547 . 7105280 . 10.26633/RPSP.2020.40 .
  9. Oprea TI, Bauman JE, Bologa CG, Buranda T, Chigaev A, Edwards BS, Jarvik JW, Gresham HD, Haynes MK, Hjelle B, Hromas R, Hudson L, Mackenzie DA, Muller CY, Reed JC, Simons PC, Smagley Y, Strouse J, Surviladze Z, Thompson T, Ursu O, Waller A, Wandinger-Ness A, Winter SS, Wu Y, Young SM, Larson RS, Willman C, Sklar LA . Drug Repurposing from an Academic Perspective . Drug Discovery Today: Therapeutic Strategies . 8 . 3–4 . 61–69 . 2011 . 22368688 . 3285382 . 10.1016/j.ddstr.2011.10.002 .
  10. Nabirotchkin S, Peluffo AE, Rinaudo P, Yu J, Hajj R, Cohen D . Next-generation drug repurposing using human genetics and network biology . Current Opinion in Pharmacology . 51 . 78–92 . April 2020 . 31982325 . 10.1016/j.coph.2019.12.004 . free .
  11. King EA, Davis JW, Degner JF . 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 . December 2019 . 31830040 . 10.1371/journal.pgen.1008489 . 6907751 . free .
  12. Kale VP, Habib H, Chitren R, Patel M, Pramanik KC, Jonnalagadda SC, Challagundla K, Pandey MK . Old drugs, new uses: Drug repurposing in hematological malignancies . Seminars in Cancer Biology . 68 . 242–248 . January 2021 . 32151704 . 10.1016/j.semcancer.2020.03.005 . free .
  13. Kale VP, Amin SG, Pandey MK . Targeting ion channels for cancer therapy by repurposing the approved drugs . Biochimica et Biophysica Acta (BBA) - Biomembranes . 1848 . 10 Pt B . 2747–2755 . October 2015 . 25843679 . 10.1016/j.bbamem.2015.03.034 . free .
  14. Paranjpe MD, Taubes A, Sirota M . Insights into Computational Drug Repurposing for Neurodegenerative Disease . Trends in Pharmacological Sciences . 40 . 8 . 565–576 . August 2019 . 31326236 . 6771436 . 10.1016/j.tips.2019.06.003 .
  15. Zong N, Wen A, Moon S, Fu S, Wang L, Zhao Y, Yu Y, Huang M, Wang Y, Zheng G, Mielke MM, Cerhan JR, Liu H . Computational drug repurposing based on electronic health records: a scoping review . npj Digital Medicine . 5 . 1 . 77 . June 2022 . 35701544 . 9198008 . 10.1038/s41746-022-00617-6 .
  16. Park K . A review of computational drug repurposing . Translational and Clinical Pharmacology . 27 . 2 . 59–63 . June 2019 . 32055582 . 6989243 . 10.12793/tcp.2019.27.2.59 .
  17. Allegretti M, Cesta MC, Zippoli M, Beccari A, Talarico C, Mantelli F, Bucci EM, Scorzolini L, Nicastri E . Repurposing the estrogen receptor modulator raloxifene to treat SARS-CoV-2 infection . Cell Death and Differentiation . 29 . 1 . 156–166 . January 2022 . 34404919 . 8370058 . 10.1038/s41418-021-00844-6 .
  18. Firth A, Prathapan P. 1 January 2021. Broad-spectrum therapeutics: A new antimicrobial class. Current Research in Pharmacology and Drug Discovery. en. 2. 100011. 10.1016/j.crphar.2020.100011. 34870144 . 8035643 . 2590-2571. free.
  19. Krishnamurthy N, Grimshaw AA, Axson SA, Choe SH, Miller JE . Drug repurposing: a systematic review on root causes, barriers and facilitators . BMC Health Services Research . 22 . 1 . 970 . July 2022 . 35906687 . 9336118 . 10.1186/s12913-022-08272-z . free .
  20. 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 . en . 52 . 7 . 825–851 . 10.1007/s40319-021-01088-0 . 237717052 . 2195-0237. free .
  21. Breckenridge A, Jacob R . Overcoming the legal and regulatory barriers to drug repurposing . Nature Reviews. Drug Discovery . 18 . 1 . 1–2 . January 2019 . 29880920 . 10.1038/nrd.2018.92 .
  22. Fava M . The promise and challenges of drug repurposing in psychiatry . World Psychiatry . 17 . 1 . 28–29 . February 2018 . 29352538 . 10.1002/wps.20481 . 5775121 .

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