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Predicting New Uses – Gold mine or Bigger Haystack?

Predicting New Uses – Gold mine or Bigger Haystack?. Numedicus (est. 2008) provides collaborative & consultative services to companies seeking expert advice in the area novel uses for existing drugs www.numedicus.co.uk. Prediction of New Uses. Plenty of known new uses for existing drugs

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Predicting New Uses – Gold mine or Bigger Haystack?

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  1. Predicting New Uses – Gold mine or Bigger Haystack? Numedicus (est. 2008) provides collaborative & consultative services to companies seeking expert advice in the area novel uses for existing drugs www.numedicus.co.uk

  2. Prediction of New Uses • Plenty of known new uses for existing drugs • Drugrepurposing.info contains 1759 repurposing links between mechanism and indication, 159 links between compound and indication and 61 links between compound and mechanism -- so-called "off-target" effects • What about unknown new uses? • Experimental • in silico technologies • screening • retrospective clinical analysis • Ontological • indication hopping • small variation in API • clever IP strategies

  3. Experimental Methods • Molecular modelling • Keiser, 2011; compares ligand topology • Xie, 2011; chemical system biology to deconvolute MoA • Gene profiling • Sirota, 2011; compare mRNA expression & disease: led to topiramate/IBD and cimetidine/lung cancer (not new) • Iorio, 2011; similar strategy led to fasudil/HD (not new) • Screening • Rothstein (Johns Hopkins); ceftriaxone/EAAT2/GLT-1/ALS • Melior; MLR-1023/T2D/lyn kinase • Side effects • Campillos, 2011; phenotypic SE comparison  shared target • Biovista, 2011; pirlindole/MS • Retrospective CT analysis, prescription databases

  4. Ontological approaches Milnacipran Glycopyrrolate BG-12 (dimethyl fumarate)

  5. Anti-TNF therapy for Immunoinflammatory disease Approved indications Also uveitis, vasculitis Cleveland Clin J Med 2006, 73(3), 251

  6. …But no beneficial clinical effect in other TNF-driven diseases …despite efficacy in preclinical models

  7. Comprehensive DRP?

  8. Fractals in DRP – the more we look the more we find Dimethyl fumarate – from fumigant to MS Thalidomide – from mutagen to myeloma Latanaprost – from glaucoma to eyelash growth

  9. Conclusions • There are plenty of drug repurposing opportunities • New ones can derive from knowledge based approaches, or experimental ones • Ontological approaches have led to patented products by linking two known relationships and creating an unknown one • Further repurposing hypotheses via similarity analysis have varying degrees of predictive certainty (should these be quantitated, and how?) • Repurposing possibilities involve multidimensional variation of (at least) API, target, indication & patent: a complete picture may be unachievable

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