Download - Drug Repurposing Anlaytics
Role of Big Data & Pharma Analytics in Rescuing Failed or Shelved Compounds
Nandu Gattu, PhD Vice President, GVK Biosciences
December 21, 2015 GVK BIO Confidential 2
Pharma Business Analytics
Data + Science + Business = Pharma Business Analytics
24%41%
24%
11%
Source: Everest group
December 21, 2015 GVK BIO Confidential 3
Pharma Business Analytics
Research & Development
Sales & Marketing
Strategy
Patient & Care Giver
Identification of new drugs
Patient Stratification
Better Clinical trial Design
Rescue the failed drugs
Recycle current drugs
Supply Chain & Distribution
Manufacturing Operations
Effective Pre-clinical exp
Pharma Analytics
Research & Development Analytics
December 21, 2015 GVK BIO Confidential 4
Drug Discovery & Development Process
Major Challenges:
• Soaring R&D Cost
• Longer duration
• High Attrition Rate or Lower Success Rate
• Failures due to efficacy
• Failures are mostly in the clinical phase only
$ 1.5 Billion 14 years
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Pharma R&D Spend vs. Approvals
25 X
2 X
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Pharma Strategy – The Number Game
Drug Discovery & Development Cost
$ 5 Billion & 14 YearsPer Drug
Forbes 2013
Company Global Rank # of Drugs 10 Y R&D ($ M) R&D per Drug ($ M)J&J 8 13 67624 5202GSK 6 11 57595 5236Pfizer 1 10 77786 7779Novartis 3 10 60727 6073Merck & Co 4 9 49133 5459BMS 12 9 30352 3372Roche 5 8 70928 8866Sanofi 2 6 60768 10128Bayer 16 5 33118 6624Amgen 14 5 21350 4270Genzyme 2 5 4814 963AstraZeneca 7 4 38245 9561Eli Lilly 10 4 26710 6678Takeda 13 4 24132 6033Eisai 24 4 11534 2884Biogen Idec 33 4 9470 2368Genetech 5 4 6277 1569Forest 38 4 5184 1296Shire 32 4 3827 957Wyeth 1 3 22702 7567Schering-Plough 4 3 18845 6282Astellas 18 3 12582 4194Gilead 21 3 5527 1842Baxter 22 3 4627 1542Novo Nordisk 17 2 9251 4626Celgene 27 2 7193 3597Teva 11 2 6763 3382Lundbeck 42 2 3527 1764Abbott 9 1 13183 13183UCB 33 1 4325 4325Yamanouchi 18 1 4321 4321Fujisawa 18 1 4286 4286Shionogi 36 1 3854 3854
Global rank <50; 10 Y R&D spend; > $ 2B;
http://www.forbes.com/sites/matthewherper/2013/08/11/the-cost-of-inventing-a-new-drug-98-companies-ranked/
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http://www.phrma-jp.org/archives/pdf/profile/Profile_2010_FINAL.pdf
http://www.discoverymanagementsolutions.com/the-organization-of-biopharmaceutical-rd/common-goals-between-discovery-and-development/innovation/nme-output-versus-rd-expense-perhaps-there-is-an-explanation/
Drug Discovery & Development
# of Projects for One Launch
December 21, 2015 GVK BIO Confidential 8
Percent R&D Budget Spent
Decreased Pre-clinical Cost
Increased Clinical Cost
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Pharma Innovation – Root cause for Failures
Forbes 2013
December 21, 2015 GVK BIO Confidential 10
Nature Reviews in DD, 2011, 10(5), 328
Nature Reviews in DD, 2011, 10(2), 87
Pharma Innovation – Root cause for Failures
Retrospective Analysis
Phase II Failures (2008-2010)(108 Failures)
Retrospective Analysis
Phase III Failures (2007-2010)(83 Failures)
December 21, 2015 GVK BIO Confidential 11
Pharma Innovation – Strategic step for Success
Identify New Indications
Steep increase in R&D Cost
Repurpose the Failed Candidate
Drug Discovery & Development Cost
$ 5 Billion & 14 Years ?
Big ticket & long duration
High Odds 57:1 >50% Clinical Costs
Low success rate in Clinical Phase
Efficacy is the main culprit
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December 21, 2015 GVK BIO Confidential 12
Drug Repurposing is real
http://thomsonreuters.com/products/ip-science/04_038/drug-repositioning-cwp-en.pdf J Clin Pharmacol. Nov 2007; 64(5): 563–565; Journal of Market Access & Health Policy 2014, 2: 22813.
DRUG ORIGINAL INDICATION NEW INDICATION
Amphotericin B Fungal infections Leishmaniasis
Aspirin Inflammation, pain Antiplatelet, Colorectal Cancer
Bromocriptine Parkinson’s disease Diabetes mellitus
Finasteride Prostate hyperplasia Hair loss
Gemcitabine Viral infections Cancer
Methotrexate Cancer Psoriasis, Rheumatoid arthritis
Raloxifene Cancer Osteoporosis
Duloxetine Depression Detrusor Instability
Miltefosine Breast Cancer Visceral Leishmaniasis
Retinoic acid/Tretinoin Severe acne Acute promyelocytic leukemia
Thioridazine Schizophrenia QTc prolongation, Antimicrobial agent
Imatinib Chronic Myeloid Leukemia Gastrointestinal stromal tumor,
Propranolol Angina, Hypertension Migraine
Botulinum Toxin A Blepharospasm, Cervical dystonia Axillary hyperhidrosis
Bosentan Monohydrate CHF PAH
Crizotinib Anaplastic large-cell lymphoma NSCLC
Galantamine Pot-polio paralysis and Neuro Pain Alzheimer’s
Plerixafor HIV Mobilization of hematopoietic stem cell
Rituximab Non-Hodgkin’s Lymphoma RA
December 21, 2015 GVK BIO Confidential 13
Drug Re-purposing
• Drug Re-Purposing: Identification of additional therapeutics indications for existing marketed drugs or clinical candidates
• It is a strategic approach to drug development to extract added value from prior Research and Development investments
• The Drug Re-positioning concept is not new; So far more than 300 FDA approved repurposed drugs are in the market
• Repurposed drugs generated approximately $20 Billion annual sales in year 2012
• All major pharmaceutical companies are interested and invested in drug repurposing program
• Drug Repurposing science is moving from serendipitous discovery to data driven approach.
Recycle
Reinvent
December 21, 2015 GVK BIO Confidential 14
Why Drug Re-purposing ?
Drug Development Drug Repurposing
Cost $1.5 B to develop $300- $400 M to develop
Time for R&D 12-14 years 2-6 years
Experiments Complete set Significantly less
Cost Vs benefit Lower Higher
Success rate Low Relatively better
Complexity High Relatively less
Ph II to Market 10% 25%
Ph III to Market 50% 65%
• Approximately 200 Drug candidates per year are placed in the shelve for variety of reasons
• Majority of the Phase III compound are failing due to efficacy only
• Pharma companies looking for novel strategic ways to build or strengthen the portfolio
Time and Money matters…
Repurposed Drugs
December 21, 2015 GVK BIO Confidential 15
Sildenafil (Viagra) – A Billion Dollar Repurposed Drug
The little blue pill
Pfizer discovered Sildenafil in 1992 for cardiovascular diseases
Pfizer tried this drug for Hypertension and Ischemic heart diseases
Drug had little effect on angina
REPURPOSED
In 1998, FDA approved Sildenafil for Erectile Dysfunction
BECAME A BILLION DOLLAR DRUG
REPURPOSED AGAIN
In 2006, FDA approved this drug for Pulmonary Arterial Hypertension
Revolutionized the lives of Millions of people
December 21, 2015 GVK BIO Confidential 16
Thalidomide – A Billion Dollar Repurposed Drug
Thalidomide was synthesized in 1954 Hailed as “wonder drug” that provides “safe,
sound sleep” Given to pregnant women to treat symptoms
associated with morning sickness Thalidomide was a “catastrophic drug” with
tragic side effects When thalidomide was taken during pregnancy
it caused birth defects – short extremities
After 44 years
In 1998, Thalidomide was approved as “repurposed drug” for Leprosy by FDA
After 52 years
In 2006, Thalidomide was approved as “repurposed drug” for Multiple Myeloma by FDA
A Billion Dollar Drug
December 21, 2015 GVK BIO Confidential 17
Big Data Analytics in Pharma World
Big Data Analytics is crucial for Repurposing – Data driven Science
December 21, 2015 GVK BIO Confidential 18
GVKBIO Repurposing Integrated Platform - GRIP
Repurposing Algorithms
Analytic s Engine
Visualization Tools
GRIDGVKBIO Repurposing Integrated Database
Novel Repurposing Ideas
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GVKBIO Repurposing Integrated Database (GRID)
Proprietary DatabasesGOSTAR (SAR Database with 6 M compounds)
GOBIOM (Biomarker database)CTOD (Clinical Trial Outcome Database)
Public DatabasesMore than 40+ Public database
GVKBIO Repurposing Integrated Database (GRID)
Target Drug
Disease
Understanding the relationship among Drug – Disease – Target is key to identify new alternative Indications
December 21, 2015 GVK BIO Confidential 20
Drug Repurposing Integrated Database
Target Disease
Drug
GenePathwayDiseasesBiomarkersTarget/EC50, IC50 etc..Gene expressionTranscription factorClinical trial infoMarketed drugsAdverse eventsDrug-protein interactions
GenePathwayDrugsBiomarkersGene expressionClinical trial infoDisease –gene relationship
DrugsPathwayDiseasesBiomarkersTarget/EC50, IC50 etc..Tissue specific expressionGene expression drugs, diseaseTranscription factorClinical trial infoMarketed drugsTarget-Target interactions
December 21, 2015 GVK BIO Confidential 21
Drug Repurposing Algorithms
Drug Repurposing Algorithms
Structural similarity
Adverse Events
Gene Expression
Clinical Trials
Pathways
Interactome
Genome Wide
Association
Literature Mining
December 21, 2015 GVK BIO Confidential 22
Drug Repurposing Modalities
December 21, 2015 GVK BIO Confidential 23
Drug Repurposing Flow Chart
List of Drug –Disease Associations
(17040)
Drugs /Targets/Disease
Drug –Disease Associations
(888)
Relevancy check at vertical levels and removing duplicates
Drug –Disease Associations
(447)
Standardization with MESH termsRemoving general indicationsUnifying synonyms/alias
145 indications
MESH tree MESH term Unique list of indications (442) Adverse EventsClinical trialsInteractomeLiterature MiningPathwaysStructure Similarity
CARDIOVASCULAR DISEASES ACUTE CORONARY SYNDROME ACUTE CORONARY SYNDROME Y Y
CARDIOVASCULAR DISEASES ACUTE ISCHEMIC STROKE ACUTE ISCHEMIC STROKE Y Y Y Y Y Y
CARDIOVASCULAR DISEASES HEART FAILURE HEART FAILURE Y Y Y Y Y Y
PHYSIOLOGICAL PHENOMENA AGING AGING Y Y Y Y
ENDOCRINE SYSTEM DISEASES HYPERALDOSTERONISM ALDOSTERONISM PRIMARY Y Y
CARDIOVASCULAR DISEASES HYPERTENSION HYPERTENSION Y Y Y Y Y Y
UROGENITAL ABNORMALITIES NEPHRITIS, HEREDITARY ALPORT SYNDROME Y
RESPIRATORY TRACT DISEASES ALVEOLITIS, EXTRINSIC ALLERGIC ALVEOLITIS Y
LIVER DISEASES NONALCOHOLIC STEATOHEPATITIS NONALCOHOLIC STEATOHEPATITIS Y Y Y Y Y Y
HEMIC AND LYMPHATIC DISEASES ANEMIA ANEMIA Y Y
CARDIOVASCULAR DISEASES ANGINA PECTORIS ANGINA PECTORIS Y Y
CARDIOVASCULAR DISEASES AORTIC VALVE STENOSIS AORTIC VALVE STENOSIS Y
NERVOUS SYSTEM DISEASES ALZHEIMER DISEASE ALZHEIMER'S DISEASE Y Y Y Y Y
CARDIOVASCULAR DISEASES ATHEROSCLEROSIS ATHEROSCLEROSIS Y Y Y Y Y
CARDIOVASCULAR DISEASES CARDIOMYOPATHIES CARDIOMYOPATHY Y Y Y Y Y
CARDIOVASCULAR DISEASES CORONARY ARTERY DISEASE CORONARY ARTERY DISEASE Y Y Y Y Y
NUTRITIONAL AND METABOLIC DISEASESDIABETES MELLITUS DIABETES MELLITUS Y Y Y Y Y Y
UROLOGIC DISEASES DIABETIC NEPHROPATHIES DIABETIC NEPHROPATHY Y Y Y Y Y
EYE DISEASES DIABETIC RETINOPATHY DIABETIC RETINOPATHY Y Y Y Y Y
NERVOUS SYSTEM DISEASES BIPOLAR DISORDER BIPOLAR DISORDER Y Y
NEOPLASMS URINARY BLADDER NEOPLASMS BLADDER CANCER Y Y
CARDIOVASCULAR DISEASES BRADYCARDIA BRADYCARDIA Y Y
NERVOUS SYSTEM DISEASES BRAIN EDEMA BRAIN EDEMA Y Y
NERVOUS SYSTEM DISEASES BRAIN INFARCTION BRAIN INFARCTION Y Y Y
CARDIOVASCULAR DISEASES HYPERTROPHY, LEFT VENTRICULAR HYPERTROPHY, VENTRICULAR Y Y Y Y Y
NEOPLASMS CARCINOMA, ENDOMETRIOID CARCINOMA ENDOMETRIOID Y
UROLOGIC DISEASES KIDNEY FAILURE, CHRONIC KIDNEY FAILURE, CHRONIC Y Y Y Y Y Y
CARDIOVASCULAR DISEASES MYOCARDIAL INFARCTION MYOCARDIAL INFARCTION Y Y Y Y Y
NUTRITIONAL AND METABOLIC DISEASESOBESITY OBESITY Y Y Y Y Y
CARDIOVASCULAR DISEASES ATRIAL FIBRILLATION ATRIAL FIBRILLATION Y Y Y Y
NERVOUS SYSTEM DISEASES BRAIN ISCHEMIA BRAIN ISCHEMIA Y Y Y Y
NEOPLASMS BREAST NEOPLASMS BREAST NEOPLASMS Y Y Y Y
UROLOGIC DISEASES CARDIO-RENAL SYNDROME CARDIORENAL SYNDROME Y
CARDIOVASCULAR DISEASES CAROTID STENOSIS CAROTID ARTERY STENOSIS Y Y
NERVOUS SYSTEM DISEASES CEREBRAL HEMORRHAGE CEREBRAL HEMORRHAGE Y
Binning and Profiling
Frequency table
Indications with Preclinical evidence
Indications with clinical
evidence
Indication with no evidence
Priority indications(10 indications)
•Ignored all kinds of hypertensions•Ignored CNS indications•Focused on partner interest•Based on target mechanism
December 21, 2015 GVK BIO Confidential 24
6 Stalled Compounds from
Major Pharma
Drug Repurposing – Live Case Study with Major Japanese Global Pharma
GRIP Initiated Pre-clinical Proof of concept experiments
6 months
Provided leads to Improve the pipeline!
Patent new use cases!! Rescue the failed compounds!!!
Possible additional revenue of millions of dollars !!!!
5 out of 6
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Failed Compound Case Study
December 21, 2015 GVK BIO Confidential 26
Drug Repurposing Case Study – In-silico Predictions
Compound is shelved due to lack of efficacy (safety profile is good)Like to repurpose..
Compound with focus on __________ disease
Structural Similarity
Literature Mining
Clinical trial mining
Received the following:Compound InfoTarget InfoOriginal therapeutic focusReceived certain Internal data
GRID & Well trained MS/PhD level scientists
with drug discovery experience
Proposed for TB
New Mechanism of Action
Possible first in class treatment
Proposed for Pulmonary
Hypertension
New Mechanism of Actions
Possible first in class treatment
3 independent MOA to intervene the patho-
physiology
Current StatusPre-clinical
Stage
Interactome
GWAS
Gene Express
Adverse Events
Pathways
Internal Data
GVKBIO Repurposing Integrated Platform (GRIP)
Identify novel Therapeutic utility
& create IP
December 21, 2015 GVK BIO Confidential 27
Repurposing of Client Compound for PAH – Pre-clinical Exp
Hemodynamic parameters
• Validation of monocortaline (MCT) induced
pulmonary arterial hypertension (PAH) model in
SD rats with marketed drugs
• Repurposing of Client compounds for PAH
Protocol
Cpd – Client Compound
December 21, 2015 GVK BIO Confidential 28
Repurposing of Client Compound for PAH – Pre-clinical Exp
Hemodynamic parameters
Vehicle MCT MCT+cpd 10mg/kg45.00000
seconds
0.000000
25.000000
50.000000
75.000000
mm
Hg
RV
P
5.00000 10.00000seconds
0.000000
25.000000
50.000000
75.000000
mm
Hg
RV
P
20.00000seconds
0.000000
25.000000
50.000000
75.000000
mm
Hg
RV
P
Systemic blood pressure
Cpd – Client Compound
December 21, 2015 GVK BIO Confidential 29
Drug Repurposing Portal
http://www.drugrepurposingportal.com
Sponsored & Maintained by GVKBIO
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