Corresponding author: Porkodi Ayyar ( porkodi.ayyar17@gmail.com ) Academic editor: Georgi Momekov
© 2022 Porkodi Ayyar, Umamaheswari Subramanian.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Ayyar P, Subramanian U (2022) Repurposing – second life for drugs. Pharmacia 69(1): 51-59. https://doi.org/10.3897/pharmacia.69.e72548
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Drug repurposing refers to finding new indications for existing drugs. The paradigm shift from traditional drug discovery to drug repurposing is driven by the fact that new drug pipelines are getting dried up because of mounting Research & Development (R&D) costs, long timeline for new drug development, low success rate for new molecular entities, regulatory hurdles coupled with revenue loss from patent expiry and competition from generics. Anaemic drug pipelines along with increasing demand for newer effective, cheaper, safer drugs and unmet medical needs call for new strategies of drug discovery and, drug repurposing seems to be a promising avenue for such endeavours. Drug repurposing strategies have progressed over years from simple serendipitous observations to more complex computational methods in parallel with our ever-growing knowledge on drugs, diseases, protein targets and signalling pathways but still the knowledge is far from complete. Repurposed drugs too have to face many obstacles, although lesser than new drugs, before being successful.
Indication switch, In silico method, Use patent, Re-profiling
“The real voyage of discovery consists not in seeking new landscapes but in having new eyes”
Marcel Proust
In brief, drug repurposing refers to finding new indications for existing drugs which may be either approved and marketed or in clinical trials or shelved due to reasons other than safety. A repurposed drug may also include new dosage, new formulation, and new method of use or new patient population. Drug re-profiling, drug re-tasking, drug rescue, indication expansion or indication switching are other terms used for drug repurposing(
From the medical community-patient perspective, drug repurposing has the ability to meet unmet medical needs- neglected diseases and, rare and orphan diseases(
Drug repurposing strategies could be either drug oriented or disease oriented(
Drug oriented repurposing could be either on-target or off-target repurposing (Fig.
Drug repurposing methods can be broadly classified into either activity based or in silico methods. Activity based methods include in vivo (living organisms) and in vitro high-throughput screening methods where the drug/chemical of interest is used for screening(
Phenotypic screening using in vivo and in vitro cell based assays have been central to the discovery of new drugs where chemical libraries are screened to identify ‘hits’(
Novel hypotheses can be generated by linking seemingly unrelated scientific facts or indirect associations between them by analysing extensive volumes of data to identify correlations. Based on Swanson’s ABC model-two islands of knowledge A and C may be related to each other if they share a common intermediate link B(
A) Swanson’s ABC model B) Signature similarity approach – Drug B has inverse signature similarity with the disease against which it is effective and drug A with similar signature to drug B can be potentially repurposed for the same disease C) Side effect similarity approach D) Associative indication transfer approach.
Similar property principle i.e., similar drugs with similar structures lead to similar biological effects, forms the base for this approach (
Administration of a pharmacologically active compound into a biological system causes perturbation of the biological system owing to the drug’s action and it is possible to construct a ‘signature’ of the molecular activity of the drug using high throughput molecular measurement techniques, such as gene expression microarrays even though the precise mechanism of action is not known. The molecular ‘signatures’ of a drug can then be compared with that of the disease to establish drug-disease relationship by anti-correlational transcriptional effects or inverse signature method(
Connectivity map (CMap) project contains gene expression profiles for 1309 compounds by exposing these compounds to a few cancer cell lines and measuring the genome wide transcriptional response. Based on similarities in molecular activity shown in their CMap profiles, drugs can be connected to either drugs or diseases through pattern matching algorithms. If a disease is used as a query signature then drugs with inverse similarity signature can be used as treatment. In case of drug effect used as a query, the drug effect signatures stored in CMap Project similar to the query will have similar effects (Fig.
Molecular docking involves simulation and modelling of drug-target interactions, as most small molecules exert their effect by binding to proteins or targets. A drug can be repurposed for a new disease if it is shown to interact with a protein target known to be involved in the pathogenesis of the disease. Inverse docking refers to the investigation of binding of a drug against a panel of known therapeutic targets to identify ‘off-target’ binding of the drug in question allowing for repurposing opportunities(
Genome-Wide Association Study (GWAS), a database developed by the National Human Genome Research Institute (NHGRI) consist of reported Single Nucleotide Polymorphisms (SNP) and their associated genetic trait expressions(
Drugs with similar target binding profiles cause similar side-effects - this provides the basis to relate drugs to other drugs or diseases by side effect profiles, even in cases where the precise pharmacological mechanism facilitating the side effect is unknown (Fig.
‘Guilt by association’ – diseases are considered similar if they shared significant number of drugs. A drug can be repurposed, if it is indicated for only one disease of a pair, for the other disease of the pair (Fig.
A network is constructed with drugs, diseases and targets as nodes and edges on the basis of connectivity established through known relationship (experimental data) or through predicted associations from data derived from cheminformatics, bioinformatics, literature-based connections and other data. In short, data from almost all methods are combined holistically, and drug repurposing is done by constructing new edges based on the topology of the network. Extensive knowledge on the drug, disease, target proteins and mode of action is necessary for construction of a network and to draw inferences from it(
A repurposed drug’s commercial success depends on attaining effective market exclusivity through a combination of intellectual property protection and regulatory exclusivity(
A repurposed drug can be protected by composition of matter and/or use patent. A comparison between the modes of patent protection is shown in Table
Comparison between composition of matter patent and method of use patent.
Feature | Composition of matter patent | Method of use patent |
---|---|---|
Applies to | New patentable API or formulation or delivery mechanism or combination of API | New method of dosing or use for a specific indication |
Level of protection | Strong | Weak |
This can be used for product protection in the absence of patent protection. Regulatory exclusivity differs between new chemical entities and new use/formulation (Table
Comparison between new chemical entity exclusivity and new use/formulation exclusivity in drugs that are being repurposed.
Feature | New chemical entity exclusivity | New use/formulation exclusivity | |
---|---|---|---|
Applies to | API not approved as marketed drug product | Addition of new indication, dose, formulation, delivery method or patient population | |
Duration | 5 years from approval | 3 years from approval | |
ANDA for generic version or 505(b)(2) new drug application for a modified version of the reference drug | Waiting period to file application | First 4 years of exclusivity period | None |
Approval | Not before exclusivity period | Not before exclusivity period | |
Patent challenge from ANDA or 505(b)(2) to be filed along with application | After the waiting period – 4 years | None | |
Patent infringement suit from the owner of reference listed drug | Additional 30 month stay | Additional 30 month stay |
The Covid-19 pandemic undoubtedly brought the world to a standstill but set the wheels in motion for the research community in search for a drug effective against the dreaded severe acute respiratory syndrome-coronovirus-2 (SARS-CoV2). While, conducting methodical drug trials was fraught with logistic and scientific challenges and with no vaccine in sight in the near future during the initial phase of the raging pandemic, drug repurposing offered probably the only hope of finding ‘hits’ potentially useful against Covid-19(
Therapeutic effect | Drug | Proposed mechanism of action |
---|---|---|
Viral entry inhibitors | Estradiol | ACE2 receptor downregulation preventing interaction of spike protein with cellular ACE2 receptor |
Spironolactone | ||
Isotretinoin/retinoic acid | ||
Bicalutamide | TMPRSS2 inhibition | |
Nafamostat | ||
Camostat mesilate | ||
Umifenovir | Inhibit spike glycoprotein trimerisation | |
Nelfinavir | Interferes with membrane fusion | |
Chloroquine/hydroxychloroquine | ACE2 receptor glycosylation; reducing pH of endosomes | |
Amiodarone | Reducing pH of endosomes | |
Chlorpromazine | Inhibit clathrin mediated endocytosis | |
Verapamil | Blocking ion channels | |
Linagliptin, sitagliptin | DPP4 inhibitor | |
Baricitinib | Reduces endocytosis by affinity for AP2 associated protein kinase 1 | |
Imatinib | Lysosomal accumulation | |
Arbidol | Hemagglutinin fusion machinery, spike glycoprotein | |
Bictegravir | Interferes with viral protein dimer formation | |
Viral replication inhibitors | Remdesivir | Inhibit RdRp |
Favipiravir | ||
Galidesivir | ||
Tenofovir alefanamide | ||
Clevudine | ||
Ribavirin | Reduces intracellular GTP inhibiting RdRp indirectly | |
Elbasvir | Inhibit RdRp, papain like proteinase and helicase | |
Famotidine | Inhibit papain like proteinase | |
Emtricitabine | RNA synthesis nucleoside analogue | |
Lopinavir-ritonavir | Inhibit main protease | |
Darunavir | ||
Atazanavir | ||
Danoprevir | ||
Tegobuvir | ||
Cepharanthine | Inhibit RdRp, main protease | |
Sofosbuvir | RdRp chain termination | |
Oseltamivir | Inhibit viral replication | |
Plitidepsin | ||
Selinexor | ||
Atorvastatin | ||
Dampen cytokine release/inflammation | Dexamethasone | Inhibit various cytokine synthesis and effect |
Methyl prednisolone/prednisolone | ||
Doxycycline | IL-6 inhibition; interference with cell fusion and viral replication through MMP chelation | |
Tocilizumab | Anti-IL-6 receptor mab | |
Sarilumab | ||
Clazakizumab | Anti-IL-6 mab | |
Olokizumab | ||
Canakinumab | Anti-IL-1β mab | |
Ravulizumab | Anti-C5 mab | |
Anakinra | Recombinant IL-1 receptor antagonist | |
Infliximab | Anti-TNF-α mab | |
Baricitinib | JAK 1/2 inhibitor | |
Ruxolitinib | ||
Abivertinib | EGFR kinase inhibitor | |
Acalabrutinib | Bruton tyrosine kinase inhibitor | |
Ibrutinib | ||
Zanubrutinib | ||
Dampen cytokine release/inflammation | Ozanimod | Sphingosine-1-phosphate receptor modulator |
Leronlimab | Anti-CCR5 receptor mab | |
Emapalumab | Anti-IFN-γ mab | |
Duvelisib | Inhibits PI3K | |
Conestat alpha | Inhibit complement activation | |
Crizanlizumab | Anti-P-selectin mab | |
Dornase alpha | Degrades DNA of NET | |
Montelukast | Inhibit NF-κB signalling | |
Pentoxifylline | Inhibit proinflammatory cytokine synthesis | |
Fluoxetine | ||
Fluvoxamine | ||
Pyridostigmine | ||
Etoposide | ||
Melphalan | ||
Thalidomide | ||
Fingolimod | ||
Methotrexate | ||
Colchicine | ||
Cholecalciferol | ||
Naltrexone | ||
N-acetyl cysteine | ||
Ulinastatin | ||
Prazosin | ||
Miscellaneous | Ivermectin | Inhibit nuclear transport |
Pegylated IFN α-2b | Enhanced antiviral host response through IFNAR1 signalling | |
Nitazoxanide | Increase phosphorylated factor 2-α | |
Calcineurin inhibitors | Inhibit viral replication and cytokine transcription | |
Sirolimus | ||
Daclatasvir | Target different viral proteins | |
Dapagliflozin | Reduces lactate and tissue oxygen consumption | |
Aspirin | Antiplatelet and inhibit viral replication | |
Isoflurane/sevoflurane | Decrease ARDS severity | |
Alteplase/rtPA | Fibrinolytic | |
Bevacizumab | Anti-VEGF mab | |
Iloprost | PGI2 analogue | |
Ibudilast | PDE4 inhibitor | |
Lucinactant/poractant α | Surfactant | |
Aviptadil | Synthetic VIP | |
Sargramostim | Recombinant GM-CSF | |
Sildenafil citrate | Inhibit nitric oxide synthase | |
Pirfenidone | Inhibit apoptosis, reduce ACE2 receptor expression, antioxidant | |
ARB/ACE inhibitors | Increase lung ACE2 receptor expression | |
2-deoxy-D-glucose | Inhibit glycolysis in virus-infected human cells, reduces inflammation and interferes with viral replication |
Drugs repurposed for reasons in addition to novel indication such as new dosage, new formulation or new patient population have to undergo clinical trials to demonstrate safety and efficacy which is almost similar to de novo drug discovery process. Even for drugs entering late phase clinical trials, the cost involved in bringing the drug to market is still in millions and the drug can still fail during clinical trials or post-marketing, though the failure rate is low compared to new drug discovery(
Selected drugs which had a big bang, thanks to drug repurposing are cited in Table
Drug | Original indication | New indication (year) |
---|---|---|
Gemcitabine | Anti-viral | Various Cancers (Various) |
Raloxifene | Osteoporosis | Invasive Breast Cancer (2007) |
Finasteride | Hypertension | Benign prostatic hyperplasia (1992) |
Male Pattern Baldness (1997) | ||
Thalidomide | Anti-Nausea | Erythema Nodosum Leprosum (1998) |
Multiple Myeloma (2006) | ||
Sildenafil | Angina | Erectile Dysfunction (1998) |
Pulmonary artery Hypertension (2005) | ||
Rituximab | Various Cancers | Rheumatoid Arthritis (2004) |
Dimethyl fumarate | Psoriasis | Multiple Sclerosis (2013) |
Though repurposing appears to be an attractive strategy, several challenges exist for the drugs identified to be repurposed before making it to the market. These include, but not limited to, low potency, dose adjustments, new safety signals and route of administration(
Chloroquine/hydroxychloroquine touted to be the game changer in the battle against Covid-19 fizzled out in a matter of few months. The Food and Drug Administration (FDA) agency revoked emergency use authorisation (EUA) granted to these antimalarials for lack of efficacy and cardiac adverse events within 3 months of initial approval(
Bupropion, a norepinephrine and dopamine reuptake inhibitor in combination with naltrexone, a pure opioid antagonist was approved as an adjunct for weight management in adults by FDA in December 2010(
Bevacizumab, a humanised anti-VEGF monoclonal IgG1 antibody has been approved for treatment of advanced colorectal carcinoma, advanced non-small cell lung carcinoma, metastatic breast carcinoma and advanced renal cell carcinoma in addition to chemotherapy(
Drug repurposing – a second life for failed drugs and drug candidates, and expanding successful ones, appears to offer some real solution to the problem the pharmaceutical industry is facing by turning the tables on pipeline erosion and also offers the prospect of identifying treatment for unmet medical needs, finding safer, efficacious and cheaper drugs to the community. Drug repurposing strategies have their own pros and cons and selection of a combination of strategies tailored to the need is essential for a repurposed drug to make it to the market and be successful.
“Although a bit of an exaggeration, there is a lot of truth in the saying that we do not need to find new drugs; rather we need to find the patients who can benefit from existing drugs” - Christopher Lipinski.