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

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 B AC

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

Molecular modelling Gene profiling In vitro screening In vivo phenotypic screening Human experience analysis Hit compound Lead compound Clinical development Increasing confidence in result Increasing scale of analysis

Ontological approaches SNRI Depre ssion FMS Milnacipran Glycopyrrolate BG-12 (dimethyl fumarate)

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

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

Comprehensive DRP? Compound Metabolite Isomer Target Subtype Pathw ay Polypharmacology Canonical vs non-canonical COM patent MOU Formulation Route Combination Parent indication Genotype Phenotype Disease resistant

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

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