Drug repurposing for quicker, cheaper, less risky R&D in rare diseases

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Gerald Campbell
5 years ago
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1 Drug repurposing for quicker, cheaper, less risky R&D in rare diseases = Drug repositioning = Drug reprofiling = Therapeutic switching A technology company with a social mission, focused on drug repurposing for rare diseases

2 HUGE UNMET THERAPEUTIC NEED 350M people affect by rare diseases world wide rare diseases, less than 5% with a treatment New initiatives NIH NCATS: focus on repurposing in rare diseases E-rare: EU funding for rare disease repurposing Cures within Reach: CureAccelerator Findacure Drug repurposing is becoming increasingly popular in rare disease R&D

3 RISK IN PHARMACEUTICAL DEVELOPMENT Research NME=New Molecular Entity NCE=New Chemical Entity years Bunnage, Nat Chem Biol 2011

4 COST IN PHARMACEUTICAL R&D

5 BASIC STRATEGY OF DRUG REPURPOSING New biology Old data Clinical trials New medicine Reduces time: traditional discovery 4-9yr; repurposing discovery 1-3.5yr Reduces risk Traditional developmental probability 10%; repurposing 25% Safety risk much reduced Efficacy risk mostly maintained Reduces cost: Traditional cost $1.8bn; repurposing cost $0.3bn Offers Method of Use patents Additional marketing exclusivity advantages in rare or orphan diseases

6 Alternative R&D Routes Compound identification Compound acquisition Preclinical development A. Repurposing discovery years Phase I-III Clinical trials Regulatory approval C. Pharmaceutical development 2-7 years Target discovery Lead discovery Lead optimisation In vitro ADME Preclinical development B. Conventional NCE discovery 4-9 years

7 TAKE HOME MESSAGES Most drugs (90%) have secondary uses, same or different mechanism Vastly underexploited area, can be very beneficial for rare diseases Dose, route of administration, duration of treatment and safety can all be different Repurposing still risky for efficacy failure in development Defining a commercial impetus is not easy but can be hugely advantageous, if not essential Orphan drug exclusivity is a major advantage for repurposing in rare diseases Repurposing hypotheses can arise from computer predictions or retrospective analyses

8 COMMERCIAL IMPETUS Many repurposing projects not commercially attractive Without commercial impetus, drug companies will not take it on Without company investment development will be slow; and/or quality of data proving efficacy and safety will be poorer

9 ACETYL SALICYLIC ACID, 2000 YEARS AFTER HERODOTUS Aspirin first marketed by Bayer in 1899, for pain In 1970s, John Vane shows it disrupts platelet aggregation; effective for MI & stroke In 2010, shown to prevent GI and other cancers (25,000 pts) [Rothwell, 2010] Hazard ratio for pancreatic cancer = 0.25 No commercial impetus, no regulatory approval for use of aspirin to prevent reoccurrence of cancer Identifying new uses can take a long time and developing them even longer

10 SUCCESSFUL EXAMPLES OF REPURPOSING Drug Old use New use Thalidomide Nausea Leprosy, myeloma Sildenafil Erectile dysfunction Pulmonary hypertension Finasteride Prostate hypertrophy Male pattern baldness Glycopyrronium Gastric ulcers Chronic obstructive pulmonary disease 94 examples at

11 ORPHAN DRUG EXCLUSIVITY Legislation date Prevalence Market exclusivity United States Japan Australia European Union / Fewer than 200,000 (6.25 per 10,000) Fewer than 50,000 (4 per 10,000) 7 years Reexamination period extended from 4 to 10 years Fewer than 2,000 (1.1 per 10,000) None Fewer than 5 per 10, years Fee waiver Yes No Yes At least partial Over 300 products FDA approved since 1983 (fewer than ten ) Even with orphan exclusivity, off-label prescriptions can erode commercial impetus

12 MISCONCEPTIONS Repurposing does not identify ground-breaking drugs Alemtuzumab (formerly CamPATH for CLL; now MS) Pirfenidone (formerly anthelmintic for IPF) Ketamine (from anaesthesia to severe depression) Espindolol (hypertension to cachexia) Big pharma is not interested Access to failed assets and data from pharma companies (MRC, NCATS) Repurposing is a major new strategy for drug rescue in pharmaceutical R&D

13 MODEL Big data & omics Drug repositioning Patient charities

14 APPROACHES Gene expression: compare drug and disease profiles Treatment allocation: responders vs nonresponders Big data Retrospective trial analysis: find nonpredicted effects

15 reverting the genotype to revert the phenotype First published in 2007 and replicated/improved by leading investigators worldwide

16 EXAMPLES: RARE AND ULTRA RARE NGLY1 Medulloblastoma Frequency 1/180,000,000 1/1,000,000 Patients worldwide 39 7,000 Patient groups 2 31 Publications ( ) Datasets Samples in dataset <

17 REPURPOSING TOOLS Omics data In silico algorithms DrugRepurposing.Info Literature Mining Accurate, insightful, protectable DRP Validation

18 RETROSPECTIVE EVIDENCE IN CANCER Cancer type Breast Colorectal Liver Lung Melanoma Oesophageal Ovarian Pancreatic Prostate Stomach Drug type Beta-blockers Calcium-channel blockers HMG CoA inhibitor Na + /K + ATPase inhibitor Metformin NSAIDs PPAR agonists Quinolone antibiotic TNF antagonists but sometimes not repeated prospectively (metformin in pancreatic cancer)

19 OTHER INDICATIONS Age related macular degeneration Depression Pneumonia Alzheimer disease Diabetes (type II) Psoriasis Asthma Epilepsy Rheumatoid arthritis Autism Glaucoma Sepsis Burn injury Influenza Stroke Cachexia Myocardial infarction Systemic vasculitis Cataracts Osteoporosis Transplant rejection Chronic renal failure COPD Parkinson disease Periodontitis

Over 9 million patients An independent risk factor for mortality, poor quality of life & hospitalization 20% to 40% of all

20 CACHEXIA: A DEVASTATING DISEASE AND A NEW MARKET OPPORTUNITY Weight loss of chronic disease Cancer, heart failure, chronic lung disease, HIV/AIDS, liver and kidney disease, rheumatoid arthritis, severe burn injury etc. Over 9 million patients An independent risk factor for mortality, poor quality of life & hospitalization 20% to 40% of all cancer patient deaths are directly attributed to cachexia * No widely approved agents Substantial unmet medical need * US National Cancer Institute: Nutrition in Cancer Care

21 CARVEDILOL TREATMENT REDUCES WEIGHT LOSS IN HEART FAILURE (COPERNICUS) Event: loss of >6% weight on follow up (n=2262) Anker SD et al (2002) Eur Heart J. 23:

22 ONE β-blocker APPEARS TO HAVE PARTICULARLY BENEFICIAL EFFECTS In the Yoshida hepatoma model of cancer cachexia: Many β-blockers affect some aspects but not others Many β-blockers have no effect at all Only espindolol, of the many β-blockers studied, had significant effects on all aspects and had the greatest impact upon survival Effects concluded to derive from combination of: β1 blocker: reduced catabolism β2 partial agonist: enhanced anabolism 5-HT1a receptor activity: decreased fatigue and increased appetite Espindolol produced better effects than racemic pindolol on a dose for dose basis

23 ESPINDOLOL HAS SUPERIOR EFFECTS Δ Body mass over 16d (g) Overall Survival

24 ACT-ONE TRIAL 87 patients recruited; lung, colon and rectal cancer Randomised 3:2:1 High Dose Espindolol (10mg bd) Placebo (bd) Low Dose Espindolol (2.5mg bd) Primary endpoint: effect of high dose espindolol in comparison to placebo on the rate of weight change over a 16 week period Slope of weight change in kg/4 weeks (CI): Placebo = (-0.62, -0.11) High-dose espindolol = 0.42 (0.20, 0.64) LS means difference between the groups = 1.14 p <

25 MEAN ABSOLUTE WEIGHT CHANGE (ITT)

26 MEAN BODY COMPOSITION CHANGE (ITT) Δ Lean Mass by DEXA (kg) Δ Fat Mass by DEXA (kg)

27 FUNCTIONAL DATA (ITT) Hand-grip strength: slopes of change Slope of absolute change / 4 weeks. LS Mean (SD) p-value vs placebo (Adjusted Bonferroni) Placebo (0.72) - Low-dose espindolol 0.49 (0.96) High-dose espindolol (0.69) No effect on blood pressure!

28 CONCLUSIONS Drug repurposing offers a radical way of reducing cost, time and risk in R&D; and particularly useful for rare diseases Dose, safety, route of administration in secondary indication not necessarily same as in primary indication Commercial incentives are important to get companies involved, to the advantage of patients Espindolol is the most effective developmental drug currently known for the treatment of cancer cachexia

Professor Karl Claxton, Centre for Health Economics, University of York

Welcome to the InstEAD Annual Lecture 2014 Professor Karl Claxton, Centre for Health Economics, University of York Health (and ethics) Needs Economics: Which Health Technologies, at What Price and for