Dr. Bhaswat S. ChakrabortySr. VP, R&D, Cadila Pharmaceuticals Ltd.Former Senior Reviewer, Health Canada

Pharmacists in Drug Discovery & Development

Presented at the International Conference of Pharmacy (ICP) 2017 at the School of Pharmaceutical Sciences, Lovely Profesional University,

Phagwara, Punjab, India, April 7-8, 2017

Dr. Leslie Benet, PharmacistRemington Honor Medal, 2016

Contents• Global use of medicines

• Drug Discovery & Development (DDD) R&D spending

• DDD models

• Areas of Interest / Expertise

• R&D Pharmacists• Education, training & skills; Adaptation; Teamwork

• DDD Basics

• MNC Pipeline example

• Areas of Drug Discovery & Development for Pharmacists• Molecular biology, immunology, pharmacology; Genomics, proteomics & metabolomics; Preclinical• Pharmacognosy & Chemistry; Pharmaceutics, NDDS• Clinical research

• Conclusions

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Famous Pharmacists

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John Stith Pemberton American pharmacist, Inventor of Coca-Cola

Hubert Humphrey Jr. Pharmacist, 38th Vice President of the USA

Caleb BradhamAmerican pharmacist,

Inventor of Pepsi

Charles WalgreenAmerican pharmacist, Founder of Walgreens

Eugène SoubeiranFrench pharmacist,

Discoverer of Chloroform

M.L. ShroffIndian pharmacist,

Educationist

Jyotish Chandra Ghosh Indian pharmacist,

Pioneer

Bishnu MukherjeeIndian pharmacist,

Pioneer

Indravadan ModiIndian pharmacist,

Industrialist

Pankaj PatelIndian pharmacist,

Industrialist

Global Use of Medicines

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Recent Past: 2012-2016

• New Molecular Entity Launches 160-185

• Global spending Growth CAGR 3-6%

• U.S. Spending Growth CAGR 1-4 %

• Emerging Country Spending Growth CAGR 12-15%

• “Patent Dividend”$ 106Bn 2016 Numbers

• Spending - $ 1.2 Trillion

• Spending on Brands $615-645Bn

• Spending on Generics $400-430Bn

• Developed Country Spending Per Person $609

• Emerging Country Spending Per Person $91

Left chart, EvaluatePharma. Right chart: Genetic Engineering & Biotechnology News, March 2014

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Pharmaceutical R&D Effectiveness & Efficiency

6Paul et al (2010). Nature Reviews/Drg Discovery, 9:203-214

Comprehensive Cost Analysis

7Paul et al (2010). Nature Reviews/Drug Discovery, 9:203-214

Two Models of DDD

8Paul et al (2010). Nature Reviews/Drug Discovery, 9:203-214

Organizational Areas of Interest / Expertise

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Pharmacists’ Areas of Interest / Expertise

Pharmaceutics PharmacologyChemistry

(Medicinal/Organic/Analytical)

Clinical Trials/

Biopharmaceutics

Project/R&D Management

Other areas

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Education, Training and Skills Required to Start with

• Most of the pharmaceutical scientists (pharmacists) have a post graduate training • from a recognized academic institution in their respective fields

• ~10-20% of these individuals are PhD degree holders and rest have a Masters or a Pharm.D. degree

• recently a management plus Masters degree is offered in institutions

• desirable: high IQ, goal setting, problem solving and team playing skills

• also, an eye for details

• writing expressly in technical English or any other vernacular

• being aware of their intellectual and other gifts

11Chakraborty B.S. (2013). PharmaTech, 3:18-20

Adaptation of Fresh Graduates in Functional Roles

• The total number of pharmacy, biotech and medical devices R&D scientists are estimated >400,000 people globally

• Vast majority get a job orientation following their graduation from academia and only after joining their employment

• Get surprised as they get a formal training in on-going projects and SOPs by the minute stepwise descriptions of processes and rigidity of specifications

• The hierarchy of reporting and the reality of owning the responsibilities are also strikingly novel for entry level scientists

• A suitable mentor can hold the hands of a fresh graduate during these bewildering times

12Chakraborty B.S. (2013). PharmaTech, 3:18-20

Teamwork

• Pharma R&D teams: management, operational and expertise

• management teams: leading and co-ordinating

• operational teams: actual delivery of projects and problem solving

• expert teams: critical input and depth expertise wherever needed

• Mentoring process should establish an equal dignity and importance of all roles such that there is no artificial competition and dissatisfaction

• Clear SOPs should be written up for the development of team playing skills

• myth: soft skills (mentoring included or implied) cannot be written as procedures. This is not true. Mentoring objectives and essentials of the processes must be written down to enhance clarity

• e.g., leadership role: use authority in a positive way; implementer role: delivering projects on time and building quality in projects

• both utilizing the skills for a common larger team

13Chakraborty B.S. (2013). PharmaTech, 3:18-20

Learning Teamwork in Large Multidisciplinary Setting

• A large company (MNC) engages in R&D of many therapeutic areas

• may or may not be candidate’s preference

• may have to adjust rather than express her talent

• Scholarly oriented PhD scientists in pharmacy face challenges of

• general co-ordination

• time, scope and budget bound focus on R&D projects

• Emphasis on eventual commercial success and profit

• Leadership roles in pharma R&D are complex

• Team playing roles and expectations may not be transparent

14Chakraborty B.S. (2013). PharmaTech, 3:18-20

Drug Discovery & Development (DDD) Basics

15Chakraborty B.S. (2012). PharmaTech, 3:22-26

Drug Discovery & Development (DDD) Basics..

16Chakraborty B.S. (2012). PharmaTech, 3:22-26

R&D Pipeline of an MNC (Pfizer)

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Areas of Drug Discovery & Development for Pharmacists

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Era of Molecular Knowledge & MoA

19Eder et al (2014). Nature Reviews Drug Discovery, 13: 577–587

• Target: A validated biological entity, which is characterized, efficacious, safe, meet clinical and commercial needs & ‘druggable’• e.g., proteins, receptors, genes and

RNA• certain targets are more amenable to

small molecule, eg, G-protein-coupled receptors

• others to large molecules: antibodies are good at blocking protein/protein interactions

• Chemocentric: systems-based approaches originate from a known compound or compound class

Drug Discovery Screening Assays

20Hughes et al (2011). British Journal of Pharmacology, 162:1239–1249

Genomics, Proteomics & Metabolomics

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• Genomics, proteomics and metabolomics are recent advances in DDD

• Genomics use novel and next-generation sequencing techniques and discovers normal and diseased-state tissues, transcription and/or expression profiling, side-effect profiling, pharmacogenomics and biomarkers

• Proteomics carry out target and lead identification, compound optimization, throughout the clinical trials process and after market analysis

• isotope coded affinity tags, stable isotopic labeling by amino acids in cell culture, isobaric tags for relative and absolute quantification, multidirectional protein identification technology, activity-based probes, protein/peptide arrays, phage displays and two-hybrid systems etc.

• Metabolomics use systems biology approaches

• characterization of metabolites and metabolism in biological systems

• diagnose disease, understand disease mechanisms, identify novel drug targets, customize drug treatments and monitor therapeutic outcomes

Genomics and Proteomics

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• Most genes code for proteins, which interact to form pathways

• Pathways interact with sub-cellular mechanisms to generate function at cellular and higher levels

• The upward pointing arrow is the usual way in which these interactions are viewed

• There is downward causation too

• Higher-level properties determine which sub-cellular pathways are activated and which genes are expressed

Noble D. (2003). TRENDS in Biotechnology, 21: 333-337

Genomics and Proteomics

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Preclinical Studies: Drug Candidate Confirmation

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Preclinical Studies: Preclinical Drug Characterization

Pharmacology

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Pharmacognosy & Chemistry

• Drug discovery from medicinal plants: lengthier and more complicated than other drug discovery methods

• Many pharmaceutical companies have eliminated or scaled down their natural product research

• Department of AYUSH in India, however, provide financial support and necessary skill, expertise, knowledge and resources for pharmacognosy based drugs

• In USA, National Center for Natural Products Research at the University of Mississippi and NIH Botanical Centers at the University of Illinois at Chicago are recent positive developments

• `New high throughput screening techniques and faster characterization of plant based drugs are available

28Balunas & Kinghorn (2005). Life Sciences, 78:431–441

29Source: Mike Sumner, internet

Pharmaceutics

Lipinski's Rule of Five

(most medication drugs are relatively small and lipophilic molecules)

• Lipinski’s rule states that, in general, an orally active drug has no more than one violation of the following criteria:

• Not more than 5 hydrogen bond donors (expressed s as the sum of OHs and NHs)

• Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms)

• A molecular mass less than 500 D

• An octanol-water partition coefficient log P not >5

• Compound classes that are substrates for biological transporters are exceptions to the rule

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• Structural Characterization

• Impurity Identification

• Solubility assessment

• Prototype formulation

• Stability testing

• NDDS

• IVIVC

New Drug Delivery Systems (NDDS)

31Allen and Cullis (2004). Science, 303:1818-1822

Problem Implication Effect of DDS

Poor Solubility

Hydrophobic drugs may precipitate in aqueous

media

Toxicities are associated with use of excipients

DDS like liposomes provide both

hydrophobic and hydrophilic

environments, enhancing drug solubility

Tissue Damage on Extravasation Leads to tissue damage Regulated drug release from DDS can

reduce/eliminate tissue damage

Rapid breakdown of the drug in vivo Loss of activity of drug follows administration DDS protects drug from premature

degradation and functions as a sustained

release system

Unfavourable pharmacokinetics Drug is cleared too rapidly, requiring high doses or

continuous infusion

DDS can substantially alter PK of drug,

reducing clearance

Poor Biodistribution Widespread distribution can affect normal tissues,

resulting in dose-limiting side effects

DDS lowers the volume of distribution,

and helps to reduce side effects in

sensitive, nontarget tissues

Lack of selectivity for target tissues Distribution of drug to normal tissues leads to side

effects

Low concentrations of drugs in target tissues will

result in suboptimal effects

DDS can increase drug concentrations in

diseased tissues by the EPR effect

Ligand-mediated targeting of DDS also

increases selectivity

New Drug Delivery Systems (NDDS)

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(A) Liposomes containing an anticancer drug extravasate in in tumor tissue (dark green), but not in normal tissue (light green)

(B) Drug is released from the liposomes in the vicinity of the tumor cells and taken up into the cells

(C) Liposomes containing anticancer drugs (or plasmid DNA or antisense oligonucleotides) bind to cell surface receptors (dark green triangles), which triggers internalization of the DDS into endosomes

Allen and Cullis (2004). Science, 303:1818-1822

Clinical Research

33Chakraborty B.S. (2012). PharmaTech, 3:22-26

Well Designed Ph II RCT

34Belani, Chakraborty, Modi & Khamar (2016) Annals of Oncology

Concluding Remarks• The discovery or isolation of the drug, whether small or large molecule is a complex

process of studying its structure (along with 1000s of related compounds), mechanism of action, and proof of concept of efficacy and safety

• The preclinical phase actually decides which few candidates will go further to be tested clinically in humans – healthy and patients

• Research & Development Pharmacists can dedicate themselves in any one or more than one areas of specialty in DDD

• Clinical studies test the drug to see whether it should be approved for wider use in the relevant patient population

• outcome measures in clinical trials describe and quantitate the benefits (and risks) of the drug

• I am highly optimistic about the current and future glory of Indian pharma R&D scientists. Approximately one out of six pharma scientists in the US is of Indian origin!

• Along with domain expertise, team playing skills are now essential for pharmaceutical DD scientists

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Thank You Very Much