Drug Repurposing. John P. Overington Stratified

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1 Drug Repurposing John P. Overington Stratified

2 Stratified Medical Deep Learning in Drug Discovery ~1,500 drugs ~1,000,000,000,000,000,000,000 drug-like molecules Drug Disease ~5,000 treated diseases ~14,400 diseases (~7,000 rare diseases) Target ~400 drug targets ~19,000 genes in human genome

3 T. Oprea & J.P. Overington (2015) Computational and Practical Aspects of Drug Repositioning Drug Repositioning, Repurposing and Reuse, 1, DOI: /drrr also published in ASSAY and Drug Development Technologies (2015) DOI: /adt tio drrr PMID:

4 DREL

5 Drug Repurposing Drug Repurposing Finding a new clinical use for an approved drug Drug Rescue Finding a clinical use for a stalled clinical development stage compound Phase 2 or beyond established PK and tolerability, maybe safety and usually a known chemical structure

6 Drug Repurposing

7 Some Will Pay For What Others Pay To Avoid Bimatoprost

8 Lumigan TM Latisse TM

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10 What Drugs Are Already Used For There is no consistent description of disease and drug linkage Several classification schemes exist but it is in the physicians, regulators and manufacturers interest to stay silent on the precise diseases The Drug Label is the best guide to allowed use The best useful scheme though is probably the WHO ATC Side effects are usually negative ones Manufacturers need to be very careful about off-label promotion

11 The WHO ATC ATC Anatomical Therapeutic Chemical Classification Updates for new drugs and drugs in registration phase Contains combinations, and some odd things Often coupled with DDD DDD is the defined daily dose typical daily dose for an adult being treated with the drug

12 ATC Level 1 First level The first level of the code indicates the anatomical main group and consists of one letter. Code Contents A Alimentary tract and metabolism B Blood and blood forming organs C Cardiovascular system D Dermatologicals G Genito-urinary system and sex hormones H Systemic hormonal preparations, excluding sex hormones and insulins J Antiinfectives for systemic use L Antineoplastic and immunomodulating agents M Musculo-skeletal system N Nervous system P Antiparasitic products, insecticides and repellents R Respiratory system S Sensory organs V Various

13 ATC Levels 2 to 5 Second level The second level of the code indicates the therapeutic main group and consists of two digits. Example: C03 Diuretics Third level The third level of the code indicates the therapeutic/pharmacological subgroup and consists of one letter. Example: C03C High-ceiling diuretics Fourth level The fourth level of the code indicates the chemical/therapeutic/pharmacological subgroup and consists of one letter. Example: C03CA Sulfonamides Fifth level The fifth level of the code indicates the chemical substance and consists of two digits. Example: C03CA01 Furosemide

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15 Selection of Drugs for Repositioning Product profile can/should be used to restrict set E.g. Known oral dosing, no safety warnings, low DDI potential, non-irreversible, no controlled substances, no cytotoxics.. Use a filtered USAN/INN set Annotated with a few in silico models E.g. HERG, BBB ~3,000 high priority compounds

16 Prodrugs Are Problematic

17 Other Structural Complexities Tautomers Epimerization Covalent/reactive Active metabolites Hydration Enumeration of stereoisomers

18 Built dataset of clinical stage small molecule protein kinase inhibitors 33 approved (3 Japan only, 1 China only) 488 in total 2-D structures for 68% many errors in structure assignment in literature Patents (claimed) Targets Implemented a systems pharmacology pipeline to investigate repositioning and resistance profiling Protein Kinases

19 Drug Repurposing On Target Finding new uses of a drug acting through the originally known target Literature, omics experiments.. Positive feature is that it is likely to be compatible with dosing of original drug Off Target Finding new uses of a drug acting through a novel or unanticipated target Docking, fingerprint methods,. Drug was not originally optimised for that target, so need to be watchful of dosing

20 Drug Repurposing Simplest case is to take a library of drugs and screen them in a model assay We will look at two papers that did just this, both working on neglected diseases

21 Plasma concentration C p (mg/l) Drug Action % effect 100 XC 50 efficacy target Master headline Time (hr)

22 Plasma concentration C p (mg/l) Acute ADRs Primarily C max Linked XC 50 off target C max can vary greatly due to drug dose and a wide range of environmental and genetic factors Occurrence and duration of sideeffects appears stochastic Examples QT prolongation/herg effects for cisapride potentially fatal Blue vision side effect for sildenafil an inconvenience % effect Master headline Time (hr)

23 Plasma concentration C p (mg/l) Pharmacology Spectrum of a Drug XC 50 ADR target As concentration increases, an ever larger number of targets are affected XC 50 off target Higher dosing - more pharmacology, both positive and negative XC 50 efficacy target Master headline Time (hr)

24 Drug Repurposing On Target Finding new uses of a drug acting through the originally known target Literature, transcriptomics/gwas experiments.. Positive feature is that it is likely to be compatible with dosing of original drug Big exception of privileged compartments occular, brain Off Target Finding new uses of a drug acting through a novel or unanticipated target Docking, fingerprint methods,. Drug was not originally optimized for that target, so need to be very critical of dosing

25 Plasma concentration C p (mg/l) Off Target Effects Not Optimised Affinity for novel beneficial target is likely to be lower than for on-target Almost certainly non-optimal dosage/pharmacokinetics for new target Dependent on disease XC 50 off target Master headline Time (hr)

26 How to Find Out About Drugs The Prescribing Information (PI)/Summary of Product Characteristics (SPC) is a good place to start Let s look at one.. Wikipedia is good but confirm things Abiraterone, Lemborexant,.

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29 Drug Repurposing Practical John Overington Stratified Medical 3 rd November 2015

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31 Product Profile The pharmaceutical requirements of a drug Delivery route Oral, parenteral, topical, inhaled. Drug Drug interactions Differentiation from current therapies Safety, Cost, Efficacy Dosing frequency Every eight hours, every day, every week, every month Cost of goods Risk of Misuse/Controlled substances Tolerable side effects Safety in pregnant/breastfeeding populations Dose adjustment in pediatric patients Monitoring specialist use, liver function tests,

32 Task 5 minutes - As a class: Develop a prototypical product profile for a novel antimalarial Consider dosing, safety, cost of goods, patient population. 30 minutes - As small teams: Examine hits from the Yuan paper Classify dosing, safety, and approval status Triage drugs to most likely repurposing candidates 10 minutes As a class: Select realistic drug repositioning prospects

33 What The Results Should Look Like Aspirin would be..

34 Some Homework