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Repurposing approved drugs on the pathway to novel therapies

https://onlinelibrary.wiley.com/doi/full/10.1002/med.21627

Repurposing approved drugs on the pathway to novel therapies

Table 2. Examples of drugs tested for indications quite different from their original use

CompoundInitial useRepurposed for:MechanismClinical stage/comments

Atorvastatin (generic Lipitor)	Hypercholesterolaemia	Cavernous angioma	Blunts lesion development and hemorrhage through inhibiting RhoA kinase (ROCK)	Exploratory; proof of concept40
Statins	Hypercholesterolaemia	Oncology	Inhibits production of mevalonate and isoprenoids involved in Ras and other small GTPase oncogenes pathways	Clinical failures may be due to bad clinical trial design41
Losartan	Blood pressure reduction	Alzheimer disease	Angiotensin 1 receptor antagonist; high blood pressure may exacerbate AD	Preclinical trials42
Fenofibrate	Reduces, triglyceride-rich particles (LDL) in plasma	Reduces macrophage recruitment in abdominal aortic aneurysm	Activates lipoprotein lipase, to remove LDL; reduces the proinflammatory protein osteopontin	Ongoing randomized controlled trials43
Telmisartan	Blood pressure reduction	Abdominal aortic aneurysm	PPAR-ɣ agonist, reduces TGF-β, MMP-9 and other biomarkers associated with progression	Ongoing randomized controlled trials43
Amiloride	Acid-sensing ion channel antagonist	Secondary progressive multiple sclerosis (SPMS)	These three drugs were selected from seven candidates for clinical testing for repurposing as neuroprotective therapies in MS	Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm, phase IIb randomized, double-blind, placebo-controlled clinical trial.44
Fluoxetine	Serotonin selective reuptake inhibitor (SSRI)
Riluzol	Glutamate antagonist
Edaravone	Neuroprotective agent in acute ischemic stroke and ALS	Multiple sclerosis	Aids in remyelination and neuroprotection	Possible candidate for clinical testing45
Dexpramipexole	ALS and other neurological diseases: phase 3 trials did not meet endpoint	Hypereosinophilic syndromes	Serendipitous observation that patients in the ALS studies had reduced eosinophils.	12 Wk/10 patient phase II trial showed glucocorticoid doses, paving the way for phase III46; NCT02101138
Disulfiram (antabuse)	Reduces ethanol tolerance in alcoholism	Metastatic breast cancer & Alzheimer disease	Blocks acetaldehyde dehydrogenase; modulates ADAM10, an α-secretase in neurons which cleaves amyloid progenitor protein to sAPP-α	In testing, with copper, for breast cancer: NCT03323346 basis for testing in AD.47
Metformin	Diabetes	Anti-nonsmall cell lung cancer, & Augmented resistance in aging	Decreases hepatic glucose production and enhances insulin sensitivity. The effects in other diseases were observed in many users	Phase II for NSCL, trial48; safe but not effective. However, only 14 of 50 patients were enrolled resistance in aging trial (MASTER)49
ɣ-Secretase inhibitors (GSI)	Alzheimer disease: prevent amyloid precursor cleavage	Several inhibitors are being testing against a variety of cancers	GSIs can inhibit NOTCH1 signaling by inhibiting the secretase, some also inhibit signal peptide peptidases50	Ongoing clinical trials (NCT01981551, NCT03785964, NCT03691207), as well as in combination with other cancer drugs or Car T-cell therapy (NCT 03502577)
Saracatinib (AZD-0530)	Cancer therapy	Mild to moderate Alzheimer disease	Inhibits SRC, Bcr-Abl and Fyn Kinase, the latter may contribute to synapto-toxicity in AD	Phase Ib-II trials for AD indicated the drug was safe but efficacy was unclear51
Mibefradil (Posicor)	Antihypertensive, calcium channel blocker	Short term use as an adjuvant in cancer therapy	Enhances action of anticancer agents and radiation, tested especially for glioblastoma	Several trials for use in combination therapies52
Nelfinavir	HIV protease inhibitor	Solid tumors	Inhibits endogenous Akt activity in cancer cells	Phase I53 NCT01445106
Human Albumin	Blood additive	Immunorestoration	Binds and inactivates prostaglandins.	ATTIRE study ongoing in England54 to restore serum albumin to >30 g/L by concentrated infusions
Ebselen	Antioxidant, (mimics glutathione peroxidase)	Bipolar disorder	Ebselen and lithium both inhibit IMPase and reduce glutamate and inositol levels in brain areas	Tests in healthy volunteers using up to 3600 mg dose55
Loxapine	Antipsychotic and antischizophrenia	Irritability associated with autism	Rebalances dopamine and serotonin levels; increase brain-derived neurotrophic factor (BDNF)	12 Wk open trial56
Nitazoxanide	Antiprotozoal agent	Influenza	First-in-class broad-spectrum thiazolide antiviral inhibits strains resistant to neuraminidase inhibitors57	Phase III: NCT03336619

• Note: Numbers beginning with NCT are ClinicalTrials.gov ID's for related studies. See13 for antibiotics and other drugs that have been repurposed for cancer therapy.
• Abbreviation: TNF, tumor necrosis factor.