Sanjeev Thohan, Senior Research Fellow in Preclinical & Translational Sciences at the Novartis Institutes for BioMedical Research, discusses the most recent challenges and opportunities in the drug discovery industry, and provides insight into how the industry is progressing and its strategies to address demands. He also reviews areas ripe for innovation and disruption.
Drug discovery and development is and always has been the most exciting part of clinical pharmacology. It is my attempt to compile the basic concepts from various books, articles and online journals. Feel free to comment.
In this slide I covered the detailed about hansch analysis, Free-Wilson analysis, and Mixed approach. I also gave a detailed application for each points.
Drug discovery and development is and always has been the most exciting part of clinical pharmacology. It is my attempt to compile the basic concepts from various books, articles and online journals. Feel free to comment.
In this slide I covered the detailed about hansch analysis, Free-Wilson analysis, and Mixed approach. I also gave a detailed application for each points.
Corporate Insight's 2013 Monitor Awards are out! The awards honor financial services firms for excellence in the online user experience they offer prospects, clients and advisors. Throughout the month of February, we will be releasing a series of slide decks highlighting the firms that received Gold Monitor Awards. Each of the nine slide decks will focus on a specific industry within financial services.
The Mutual Fund Monitor Awards recognize leading mutual fund issuers for excellence in the online user experience they offer their prospects and clients.
Evaluating Health Risks in Children Associated with Exposure to Chemicals v2zq
Evaluating Health Risks in Children Associated with Exposure to Chemicals - Resources for Healthy Children www.scribd.com/doc/254613619 - For more information, Please see Organic Edible Schoolyards & Gardening with Children www.scribd.com/doc/254613963 - Gardening with Volcanic Rock Dust www.scribd.com/doc/254613846 - Double Food Production from your School Garden with Organic Tech www.scribd.com/doc/254613765 - Free School Gardening Art Posters www.scribd.com/doc/254613694 - Increase Food Production with Companion Planting in your School Garden www.scribd.com/doc/254609890 - Healthy Foods Dramatically Improves Student Academic Success www.scribd.com/doc/254613619 - City Chickens for your Organic School Garden www.scribd.com/doc/254613553 - Huerto Ecológico, Tecnologías Sostenibles, Agricultura Organica www.scribd.com/doc/254613494 - Simple Square Foot Gardening for Schools - Teacher Guide www.scribd.com/doc/254613410 - Free Organic Gardening Publications www.scribd.com/doc/254609890 ~
Addiction and Motivation; what works?
Presentation at the 2012 Europad conference in Barcelona.
Three main points:
- Evidence base for Motivational Interviewing
- Practitioner competency
- Implementation issues
“Talk to me”: A Self-applied Telepsychology Programme for Treatment of Fear of Public Speaking. Botella C. eHealth week 2010 (Barcelona: CCIB Convention Centre; 2010)
Drug Discovery path
Pharma R & D –overview
Discovery & Development
Preclinical research
Clinical Trial
NDA and FDA Approval
Post marketing data
References
UNHI Creative Works Symposium Session: Deconstructing a Cpyright LicenseUNHInnovation
UNHInnovation Creative Works Symposium session: Deconstructing a Copyright License slide deck
Presenters: Kim A.W. Peaslee, Upton & Hatfield and Tim Benoît-Ledoux, UNHInnovation
Innovating in NH - Innovations Assistance: Negotiation StrategiesUNHInnovation
For many entrepreneurs and business owners, the act of negotiation can be uncomfortable, but the ability to negotiate effectively in a wide range of business contexts, including licensing agreements, deal-making, employment discussions, contracts, and handling disputes is an integral part of any business or start-up. Our speaker, Marc Sedam, is the Managing Director of UNHInnovation and has an extensive background in intellectual asset management, licensing, and start-up formation. In this seminar, he shares the key negotiating skills and strategies he has learned throughout his career. These tactics will help you come to the table prepared to get the best deal possible and avoid common negotiation pitfalls.
Lean Start-up Business Tactics Seminar - HR Issues and Your Start-up UNHInnovation
Inevitably, you will need the services and/or skill sets of other people to get your business running. When you begin to add people to your lean start-up, the initial question will be whether or not each person will be an employee or independent contractor. This seminar will help you understand the pros and cons of each type of relationship, and the legal risks in one vs. the other.
If you hire even one employee, there are HR legal compliance issues you will need to address. This seminar also discusses the HR issues that are most important as you begin to add employees, such as:
-Your obligations under wage laws and employment verification laws
-Approaching incentive compensation
-Protecting your confidential information and trade secrets
Lean Start-up Business Tactics Seminar - Who Owns Your Company?UNHInnovation
Are you a founder? Do you know how much of your startup you own? What are the ways founders divide up equity? How much ownership do investors usually take? In this seminar we will explore these topics, including tips on bootstrapping, fundraising, and the like, all from the point of view of an evidence-based entrepreneur.
Lean Start-up Business Tactics - Start-up Infrastructure on a BudgetUNHInnovation
Everyone talks about starting a company. Some focus on the idea, others focus on finding customers, and still others on how the world will change when their idea hits the market. But what happens when you start operating your company and need to do everything but don’t have the money? March's Seminar was given by our own Marc Sedam, Executive Director of UNHInnovation and former biotech start-up COO. Marc reviewed his most popular and practical tips for keeping costs low without negatively affecting productivity.
Lean Startup Business Tactics - Identifying Your Minimal Viable ProductUNHInnovation
The minimum viable product (MVP) is that version of a product which allows a team to collect the maximum amount of validating insight about customers' needs with the least amount of product building. It's one of the most important principles of a lean startup.
This deck provides you with insight into the value behind building an MVP, the overall process of achieving the maximum amount of validating learning, why in-depth customer interviews (and not just user testing) are crucial to testing your initial hypotheses about your business or product, and how you might collect or analyze qualitative and quantitative metrics to iterate your MVP.
Josh Cyr, founder of Alpha Loft and web app developer, also shared real lessons learned from one startup while building their MVP.
Innovations in Mobile Applications - Building the UNH Mobile App Suite UNHInnovation
The UNH Mobile App Development Team recently released UNH Mobile App Suite, which features 18 modules within a customizable homescreen enabling users to hide, show, and reorder icons to their preference. In this presentation, the UNH Mobile App Development Team elaborates on their experience building out the suite, which was a collaborative effort between the IT and New & Emerging Media departments.
Innovations in Materials Science: Albany Engineered CompositesUNHInnovation
Brian Coffenberry, Senior Vice President of Strategic Planning & Business Development for Albany Engineered Composites, spoke on Innovations in Materials Science at the October Innovation Catalyst Seminar hosted by UNH's Office for Research Partnerships & Commercialization.
He discussed the challenges and successes Albany Engineered Composites has faced as they've grown and brought their products to market; the current focus of Albany Engineered Composites as they look to the future of materials science; and the most pressing market needs for innovative solutions in materials science.
Innovations in Medical Devices: Medtronic Advanced EnergyUNHInnovation
Suzanne Foster of Medronic Advanced Energy reviews key challenges faced by Salient Surgical Technologies while being acquired by Medtronic Advanced Energy. Also discussed are overall trends for the medical device industry when it comes to sales, marketing, and innovation.
Interoperability Lab at University of New HampshireUNHInnovation
The University of New Hampshire InterOperability Laboratory (UNH-IOL) is an establishment visited by vendors and visitors traveling from all over the world to test their company’s technical equipment, devices and software, or to learn about the services we offer to our customers and others come to learn about opportunities we have for students interested in technology. Some of our guests are here to attend what we call Plugfest events, these events entail multiple technical companies coming together and testing their products with other company’s products. Other vendors come for “in-house testing”, which is a single company of one or more representatives coming in to test their products in our lab.
Intellectual Property 101 - University of New HampshireUNHInnovation
At the core of university-based innovation is intellectual property. Whether it's patents, copyrights, or trademarks, this presentation explains how intellectual property is protected in general and managed at UNH.
This presentation covers the basics of IP and how understanding intellectual property can actually accelerate the advancement of knowledge in your area, whether it be academic, entrepreneurial, creative expression, etc.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
How to Give Better Lectures: Some Tips for Doctors
Innovations in Drug Discovery - Novartis Institutes for BioMedical Research
1. Pharmaceutical Innovation – a personal perspective:
how we got here and now where do we go?
Sanjeev Thohan, PhD
March 28, 2013
2. Overview…
Historical perspective
Target prosecution and safety
Leverage
Today and beyond…
Cartoonstock.com
2 Sthohan | March 2013 | Pharma Innovation | Confidential
3. 4000 years of medicine
3 Sthohan | March 2013 | Pharma Innovation | Confidential
4. Serendipity to deliberate drug discovery….
In the past, drugs were at times discovered in a
haphazard, or even accidental way, with
pharmaceutical companies encouraging employees
to take vacations in exotic locations and bring back
dirt, fungus and other organic material, with tests
then done on animals to see what the outcome would
be… Gavin MacBeath, Harvard University, (2003).
Multidisciplinary efforts intersecting at a common
ground of ―target-driven-drugs‖ that are a
consequence of deliberate research and
development…
4 Sthohan | March 2013 | Pharma Innovation | Confidential
5. Historical perspective – influential pharmaceuticals
Medicine year Importance
Morphine 1827 Commercialized by a pharmacy (Merck), pain management (Germany)
Aspirin 1897 Synthetic salicylic acid was commercialized (Germany)
Ether 1842 General anaesthetic, transformed surgery (US)
Arsphenamine 1910 Syphillis Treatment (Hoechst, Germany)
Insulin 1922 1st hormone therapy, transformed diabetes management
Penicillin 1929 Transformed the treatment of microbial diseases
Chlorpromazine and 1950 Transformed management of psyschosis. (France) (Belgium)
Haladol & 1958
Estrogen+ Progestin 1961 Birth Control Pills, deep social impact (USA)
Digoxin 1962 Changed treatment of heart failure and hypertension (Germany)
(France)
Furosemide 1993 Loop diuretic, effective treatment of hypertension
Atorvastatin 1996 Cholesterol lowering medicine (USA)
HAART 1996-7 Transforming effect on AIDS patients
L-Dopa (Sweden); Hydrocortisone; Viagra (1996, USA); Ritalin
5 Sthohan | March 2013 | Pharma Innovation | Confidential
6. New Medicines Increase Longevity
“They can mean an extra three months or five months or a year-
another Christmas with the family, another season to plant a garden,
another passage in the life of a child.”
—Donna St. George on new targeted cancer therapies, The Washington Post, 2004
2.5
40% of Increase in Life Expectancy
Increase in Longevity Due to
New Drug Launches
Number of Years Increased Longevity
Total Increase in Longevity 1.96
2.0
1.65
1.5 1.37
1.07
1.0
0.76 0.79
0.70
0.57 0.62
0.56
0.45
0.5 0.30
0.23
0.12
0.0
1988 1990 1992 1994 1996 1998 2000 Data source: Lichtenberg. National Bureau
of Economic Research Working Paper No.
9754 (Cambridge, MA: NBER, June 2003).
6 Sthohan | March 2013 | Pharma Innovation | Confidential
11
8. Biotech: larger share of innovative approved drugs
Innovativeness of FDA approved drugs (2001 – 2007)
Source: USFDA
8 Sthohan | March 2013 | Pharma Innovation | Confidential
9. Drug Approvals 2012
Mullard, NatRev DD 2013
39 new drugs last year, marking a 15-year high. Most
approvals since 1997 (↑33% over the last 20 years).
20 of 2012 approvals were first-in-class agents
9 Sthohan | March 2013 | Pharma Innovation | Confidential
11. Discovery processes: Target identification strategies
Gene expression profiling
Focused proteomics, e.g. activity-based protein profiling
Pathway analysis – pathway databases, e.g. GeneGo Metacore & Ariadne
Phenotype analysis – phenomic database
Functional screening (siRNAs, shRNAs)
Genetic association
Scientific Literature
11 Sthohan | March 2013 | Pharma Innovation | Confidential
12. Properties of an ideal drug target
Target is disease-modifying and/or has a proven function in the
pathophysiology of a disease.
Modulation of the target is less important under physiological conditions or in
other diseases.
If the druggability is not obvious (e.g. as for kinases) a 3D-structure for the
target protein or a close homolog should be available for a druggability
assessment.
Target has a favorable ‗assayability ‘ enabling high throughput screening.
Target expression is not uniformly distributed throughout the body.
A target/disease-specific biomarker exists to monitor therapeutic efficacy.
Favorable prediction of potential side effects according to phenotype data
(e.g. in k.o. mice or genetic mutation databases).
Target has a favorable IP situation (no competitors on target, freedom to
operate).
12 Sthohan | March 2013 | Pharma Innovation | Confidential
13. Therapeutic approaches: target modulation
Traditional Novel – Good IP position
Small Molecules Antibody drug conjugates
• Enzymes, receptors, transcription Stapled or stabilized
factors, ion channels, transport
proteins, protein-protein interfaces proteins
Biologics Nanotechnology
• Extracellular proteins, trans- Repurposed/repositioned
membrane receptors, cell surface drugs
receptors, substrates and
metabolites
Patent extension
Nucleic Acids
• RNAi
13 Sthohan | March 2013 | Pharma Innovation | Confidential
15. Drug Failures in Ph II-III
Phase II failures 2008-2010 Phase III failures 2007-2010
Nature Reviews Drug Discovery 10, 328-329 (May 2011) Nature Reviews Drug Discovery 10, 87 (February 2011)
Leading reasons for adverse events:
• cardiovascular toxicity
• hepatotoxicity
15 Sthohan | March 2013 | Pharma Innovation | Confidential
16. Population Responses
What we use in research models
Intrinsic variability
• Drug-target or metabolite target interaction
• Type of target transduction
• Access at the biophase
• Delivery and input rate
• Metabolism and pheno/genotype
• Disease and homeostasis
What is • Placebo response
Extrinsic Variability
• Drug-drug interactions
• Interactions with endogenous substances
16 Sthohan | March 2013 | Pharma Innovation | Confidential
17. Elements of early safety assessment
• In vitro Safety Pharmacology:
– Human target based: associated with clinical adverse reactions
• GPCRs
• Nuclear hormone receptors
• Ion channels Risk Assessment and Mitigation
• Transporters
• Kinases
- Integration with ADME and PK data
- Computer-assisted Drug Design (SAR)
• Proteases
-Clinical annotation
• Other enzymes
-Bioinformatics and network prosecution
• Phenotypic and Organ-toxicity
– Cell- & tissue-based
• Cardiomyocyte-based assays
• Hepatotoxicity
• Hematotoxicity
• Neurotoxicity
• Genotoxicity
17 Sthohan | March 2013 | Pharma Innovation | Confidential
18. How to identify targets for safety profiling?
Reverse translation
Therapeutic effect A
Relevance to EFPC
Common ADR Molecular target Cmax
AC50
General application
Therapeutic effect B
Define coverage
EFPC: effective free plasma concentration
AC50: concentration necessary to achieve
50% activity @ off-target, in vitro
18 Sthohan | March 2013 | Pharma Innovation | Confidential
19. Predicting targets based on ADRs
Requirements
• Large-scale computational effort to predict the activity of marketed drugs against
adverse drug reaction (ADR) targets
• In vitro profile of marketed drugs
• Biomarker for the off-target related ADRs a d
• Extrapolation to drug candidates to predict ADRs in silico
a
Side effect profile of
d Side effect profile of Pr
chlorotrianisene synthetic estrogens
Prenylamine
Chlorotrianisene
Chlorotrianisene
e
e
Domperidone
Lounkine et al. Nature (2012)
b
19 Sthohan | March 2013 | Pharma Innovation | Confidential
b
20. Prescription drug cocktails?
There is a chance to enhance side effects by taking several promiscuous compounds
Do we take this into account?
20 Sthohan | March 2013 | Pharma Innovation | Confidential
21. Proof of Target – ADR link: 5HT2b agonism - VHD
Common feature: 5HT2b agonism
Clinical landscape of VHD
Restrictions
Withdrawn Withdrawn
30
Fen- Phen
Dose dependent effect! Kvernmo, 2006
Specifics of 5HT2b-related VHD
Long latency development, but irreversible*
Hard to detect/diagnose in the clinic
No signal in short regulatory animal studies
Needs special in vivo experimental design to
confirm manifestation
21 Sthohan | March 2013 | Pharma Innovation | Confidential
22. Combination therapy profiles
Look for caution signals and common pathways
Pimozide Risperidone Zolpidem Alprazolam Fluphenazine Haloperidol
22 Sthohan | March 2013 | Pharma Innovation | Confidential
23. Type 2 Diabetes mellitus treatment landscape
Monotherapy add add
Obese metformin sulfonylurea exenatide or Insulin or
glitazone
Non-obese Sulfonylurea exenatide or Insulin or
or metformin glitazone
elderly Low dose secretagogue Switch to simple insulin ---
regimen
Asian glitazone metformin Sulfonylurea or
Insulin or Exenatide*
(*not approved w glitazone)
Multidrug regimen for diabetes can become more complex with atherogenic
dyslipidemia, hypertension, and prothorombotic/proinflammatory states
• Cholesterol management (simvastatin)
• ACE inhibitors (enalapril)
• Low dose aspirin
23 Sthohan | March 2013 | Pharma Innovation | Confidential
25. Drug Innovation – ―the new‖
New tools to do things
• reagents to explore biological phenomena or new types of drugs, such as aptamers,
chimeric proteins, peptidomimetics, multi-valent antibodies, etc.
New ways to measure things
• techniques of scientific observation and measurement, including new visualization
methods, multiplexed assays, real-time biological kinetics measurements and others.
New ‗things‘ themselves
• devices, including the use of new materials with novel properties.
New ways to handle and extract insights from experimental
observations
• advances in bioinformatics, data integration, knowledge management, artificial
intelligence and others.
25 Sthohan | March 2013 | Pharma Innovation | Confidential
27. Repositioning
"New technologies however enable the systematic evaluation of any drug or mechanism of
action against any disease."
Aris Persidis of Biovista is in the process of filing for novel use patents for 12 drugs with
potential in Parkinson's, Alzheimer's, epilepsy, depression and sleep disorders.
Clive Morris, head of the new opportunities division at AstraZeneca, existing medicines
that have already been in clinical trials can skip the early phase of drug development
and go straight into phase two (mid-stage) trials, which can save three to five years.
AstraZeneca is now testing a failed diabetes and obesity drug for use as a glaucoma
treatment.
AstraZeneca (October 2012) made 22 failed medicines available to academics through
a partnership with the Medical Research Council and it also struck a £180m partnership
with its bigger rival GlaxoSmithKline in May to boost the faltering development of new
antibiotics, dubbed NewDrugs4BadBugs.
"Typically, repositioning is done by accident, or in a limited way,―
-between 2007 and 2009, 30% of all newly marketed medicines
were either existing drugs or new formulations of old drugs.
- - Aris Persidis (Biovista - 2012).
27 Sthohan | March 2013 | Pharma Innovation | Confidential
28. Repositioning
The safety advantage.
• Existing drugs that are either approved or have been shown to be safe in late-stage trials, but have failed to meet
end points of their originally-targeted indications, can leverage their inherently reduced development risk into
potentially new indications. Since safety accounts for approximately 30% of drug failures in clinical trials, this is a
significant development advantage that repositioned drugs enjoy.
The money savings advantage.
• Relaunching a repositioned drug averages $8.4 million, whereas to relaunch a new formulation of an existing drug
in its original indication costs an average $41.3 million. NCE/NME development averages more than $1.3 billion
(160 million times less investment). Repositioning is in a completely different league of investment needed to
create a new drug product in the market.
The market potential advantage.
• Potential for market success depends on numerous factors, including market need, competition, differentiation, an
excellent product, IP barriers, payer acceptance, compliance and a successful market strategy. These factors
apply for repositioned drugs in the same way as they do for NCE/NME drugs as well.
The return on investment potential.
• Portfolio strategy: it is prudent to have a reasonable stable of repositioned drugs under development as a portfolio,
to allow for attrition due to potential lack of efficacy (but not safety), when any drug is tested in clinical trials.
The out-licensing potential.
• Pharmaceutical companies are said to be exploring new models to out-license some of their clinical drug
candidates that may have been shelved for whatever reason. Benefits: met end points and have proven
themselves to be safe. Repositioning grants a pharmaceutical company specific and novel business development
possibilities for out-licensing.
28 Sthohan | March 2013 | Pharma Innovation | Confidential
29. Repositioning
Original Use Repurposed
Aspirin (Bayer) - 1897 Inflammation and pain antiplatelet drug for treating and
preventing heart attacks and strokes
Ibuprofen (Boots) -1960 Anti-inflammatory Hangovers, rheumatoid arthritis, and
Parkinson's disease prevention?
Galantamine (Sopharma) Plio paralysis/ Alzheimers
1960’s - USSR anesthesia
Zidovudine (GSK) 1964 Oncology HIV/ AIDS
Rogaine (Pfizer) - 1976 High blood pressure hair loss
Mifepristone (RU486) - 1980 Pregnancy termination Antipsychotic, major depression
Gemzar (Lilly) - 1980s Antiviral cancer drug
Cymbalta (Lilly) - 1990 Antidepressant fibromyalgia
Finasteride (Merck) -1993 Benign prostatic Hair loss
hyperplasia
Topiramate (JNJ) - 1996 Epilepsy Obesity
Viagra (Pfizer) -1996 Heart disease Erectile dysfunction
Pulmonary Arterial Hypertension
29 Sthohan | March 2013 | Pharma Innovation | Confidential
31. Repositioning: explore alternative indications for existing drugs
Bioinformatics-based approaches have the potential to offer systematic
insights into the complex relationships among drugs, targets and
diseases necessary for successful repositioning.
Network modeling links repositioning objects in a
network format.
The network biological relevance is measured by the
purity of identified modules and topological parameters
such as ―betweenness centrality and closeness.‖
The network can be used to predict novel repositioning
opportunities.
Liu, et.al., DDT 2012
31 Sthohan | March 2013 | Pharma Innovation | Confidential
32. Biologics: 907 medicines and vaccines in development - 2013
338 cancer therapeutics that target
several different types of solid tumors,
leukemia and lymphoma. Monoclonal
antibodies account for 170 of the 338
products in development.
176 candidates in development for an
array of infectious diseases, including 134
PhRMA Productivity report 2013
vaccines.
71 medicines for autoimmune diseases, such as lupus, multiple sclerosis
and rheumatoid arthritis.
58 treatments for cardiovascular diseases, such as congestive heart
failure and stroke.
Other diseases include diabetes, digestive disorders, genetic disorders,
neurologic and respiratory disorders
32 Sthohan | March 2013 | Pharma Innovation | Confidential
33. Protein-protein interactions
Today:
high-quality interaction
networks of reasonable
coverage are available
for only a small number
of interaction types and
model organisms, thus
limiting the evolutionary
trajectories. Limiting our
understanding.
Yama and Burk. Nat rev mol cell biol 2009
Future opportunities: shift from static 2D to comparative spatiotemporal
network.
Higher density data with greater resolution means more opportunity.
33 Sthohan | March 2013 | Pharma Innovation | Confidential
35. Stapled peptides
Can stapled peptides solve the ―undruggable
space?‖
Historical perspective:
• Not orally available in active form
• Lack the ability to enter cells
• Inactivated by proteases, filtered from the blood by the
kidneys within minutes.
A stabilized α-helix (pink) binds to a
key portion of the HIV capsid (blue),
as shown in an NMR structure. A
hydrocarbon side-chain cross-link
(yellow) helps this helix enter cells.
Drahl, CEN. Volume 86 Issue 22 (2008)
http://www.aileronrx.com
35 Sthohan | March 2013 | Pharma Innovation | Confidential
36. New Technology: Histopathology imaging
Whole slide images of histology sections resolved into
distinct patches (e.g., viable tumor, necrosis) so that
each patch can be linked with the outcome.
Computed code, from the learned representation, is
then utilized to classify patches from a curated library of
images.
Evaluation over 1400 and 2500 samples of glioblastoma
multiforme and clear cell kidney carcinoma indicates a
performance of 84% and 81%, respectively.
Color coding is black
(tumor), pink (necrosis),
and green (transition to Processes are computationally demanding
necrosis). Solutions may be in High Perfomance
Computing – AI learning.
36 Sthohan | March 2013 | Pharma Innovation | Confidential
37. Opportunities for innovation
FIPNet (fully integrated pharmaceutical network) model of drug development,
in which the core capabilities of different stakeholders in the development
process are leveraged. CRO, contract research organization
Katin, Clin Pharmacol Ther. 2010 March; 87(3): 356–361.
37 Sthohan | March 2013 | Pharma Innovation | Confidential
38. Sharing?
Securely profile every compound
ever synthesized against every
assay with multiple computational
models in a collaborative manner,
using standard technologies
without structural disclosure.
There is a need for a universal
platform for collaborative drug
discovery and development that
will allow researchers to
collaborate, while retaining refined
IP rights.
Bunin & Ekins, DDT 2011
―Integrated specialization‖
Operate within natural workflows or with minimal interruption to research individuals/teams.
Securely and selectively collaborate with anyone or any organization with truly
complementary and best in class capabilities… Bunn and Ekins DDT 2011
38 Sthohan | March 2013 | Pharma Innovation | Confidential