CDNM Drug Discovery Handbook by Center for Discovery of New Medicines

University of Michigan

Drug Discovery Handbook

CENTER FOR DISCOVERY OF NEW MEDICINES

The Center for the Discovery of New Medicines (CDNM) is the cross functional science hub of drug discovery at the University of Michigan. The CDNM provides the strategic leadership and the tactical framework to accelerate the discovery and development of novel therapeutic agents. Vince Groppi serves as the Director for CDNM. Groppi was the vice president and chief scientific officer of Essen BioScience, an integrated bioscience company that developed technologies to solve therapeutically important problems in cancer and neuroscience. Previously, he held positions at Upjohn, Pharmacia and Pfizer leading discovery, development and strategy teams. During the course of his career,

he advanced six compounds into clinical development. Groppi holds a doctorate from the Robert Wood Johnson Medical School and was a postdoc and assistant professor at the University of California, San Francisco. He currently serves as a drug discovery consultant for the National Institutes of Health’s National Institute of Neurological Disorders and Stroke and is a standing member of an NIH/NINDS translational study section. Groppi has taught translational pharmacology at U-M and serves on the university's Protein Folding Disease Initiative. He also cofounded Oricula Therapeutics, a biotechnology company that is advancing a clinical candidate to treat hearing loss. 2

TABLE OF CONTENTS

INTRO

Interdisciplinary Innovation

Drug Discovery Process

Mobilizing the Process

+ Keys to Innovation

+ Stages of Drug Discovery

+ Creating a Successful Team

+ Key Decision Points

+ Indicator Background Document + Target Product Profile + Additional tools for drug discovery

SPECTRUM OF RESEARCH Basic and translational research are often seen at odds

Basic Research

Translational Research

Basic research, generally associated with academic research, is dedicated to the advancement of scientific knowledge without the pursuit of practical application. Often focused on the theory of scientific phenomena, basic research contributes new ways of thinking about challenging, unanswered questions.

Translational research, generally associated with research in industry, is dedicated to the advancement of new treatments and therapies for patients in a clinical context. Translational research turns novel inventions into practical solutions for the clinic.

Characteristics Advances scientific knowledge

Advances clinical impact

Oriented around theory

Oriented around application

Centered on core disciplines

Centered on functional teams

Focused on novel invention

Focused on implementation

Funded by grants

Funded based on ROI

Evaluated by publications

Evaluated by commercial success

Organized with formal, tenure-based hierarchies

Organized by formal, functional hierarchy

DRUG DISCOVERY – A PATH FOR ACADEMIA Basic and translational research can be complementary through academic drug discovery

Academic Drug Discovery Academic drug discovery aims to bridge the gap between basic and translational research at large research universities. It fosters the interdisciplinary expertise at universities – connecting biology and chemistry researchers.

Characteristics Advancing novel drug discovery projects Yields new insights on basic research questions Centered on interdisciplinary collaboration Focused on innovation Funded based on milestones Evaluated by publications and clinical impact Organized with informal, interdisciplinary teams

“

Efficiency [in drug discovery] is less about making the system economically viable, than addressing the great unmet medical need.

- Jim Shayman

” 6

DRUG DISCOVERY AS A PATH FOR ACADEMIA Jim Shayman’s reflects on his experience discovering eliglustat at University of Michigan

What are the opportunities for researchers to pursue academic drug discovery? Historically, industry has evaluated the success of drug discovery by economic terms. However, what I’ve found is that academic drug discovery offers many points of success for a basic research lab.

How has your lab benefitted from the eliglustat drug discovery project? Over the past 40 years, we have uncovered a wide range of novel research around lysosomal storage diseases. Specific to Gaucher’s disease, we discovered the biological and physiological mechanisms of the disease. The inhibitor we discovered, PDMP, is not only an effective treatment for Gaucher’s disease, but it is a useful tool in research. It has been the focus for many studies for many

years. It has also become a useful tool for probing pathways to understand other lysosomal storage diseases. Finally, we have had the chance to explore the offtarget effects of the drug, through which we have identified a novel lysosomal enzyme, phospholipase A2. All in all, we have learned and discovered a lot through this process. Meanwhile, we have had success in gaining grants for our research, publishing our discoveries and teaching our students. Through this project, we have meaningfully increased knowledge for society.

What advice would you give other academic researchers interested in pursuing drug discovery? Drug discovery is just one path for discovering something new and interesting. It can catalyze education and funding. Drug discovery is a complement

to basic science activities, rather than a replacement. At the same time, efficiency is important in the process. Efficiency is less about making the healthcare system economically viable, than about addressing the great unmet medical need of patients. Traditional industry leaves a lot of diseases unaddressed. Currently, there are about 7,000 identified diseases. One thousand of these are common, and the remainder are orphan or rare diseases. Of these 6,000 diseases, there are approximately 150 treatments for specific diseases. This is a significant opportunity for academic drug discovery.

DISCOVERING ELIGLUSTAT â&#x20AC;&#x201C; MAJOR MILESTONES ALONG THE PATH Target Identification and Validation

Assay Development

Screening

Hit to Lead

Lead Optimization

Candidate Selection

Preclinical Safety

1972

1987

1995

2000

2000 - 2009

Isolated target enzyme, UDP-GST; Determined optimum activity

Discovered proper conditions for assaying rat brain for glucosyl transferase

Began synthesizing compounds similar structure to ceremide

Inhibited UDPGST with an isomer of PDMP (D-threo-PDMP)

Modified PDMP structure

Lead compound EtDO-P4 licensed to Genzyme

Conducted safety studies of eliglustat tartrate in rat, rabbits and dogs

2000 - 2009

Determined that drug is well tolerated

Ceremide identified as substrate of UDP-GST

1987 Lowered GlcCer with UDP-GST inhibitor

1991 Decreased GlcCer with lead compound

1975 Improved method for isolation of UDPGST from human brain and spleen

1978 Improved assay to determine UDP-GST activity by using short chain ceremides

Tested compounds for inhibition of UDP-GST

1978 Synthesized aromatic versions of ceremide substrate Inhibitor is identified

1987 Tested isomers of PDMP for activity against UDP-GST

1991 Discovered that PDMP is rapidly metabolized and excreted in vivo Tested PDMP homologues for activity against UDP- GST Tested in vivo for biological effects

Determined inhibitory activity against UDP-GST and effect on other biological activity

1998 Continued structural modifications made to phenyl ring of PDMP Identified a more potent inhibitor

Modified EtDO-P4 structure to reduce half life

2009 Selected eliglustat tartrate as best inhibitor with good PK properties

1994 PDMP inhibits cell metastasis in vivo

Abbreviation

Term

GlcCer

Glucosylceremide

UDP-GST

UDP-glucosyltransferase 8

HOW TO USE THIS HANDBOOK

This handbook is intended to provide a general overview of the drug discovery process. It is by no means a comprehensive explanation of the processes involved. However, it should provide the reader with a good starting point for understanding the phases involved. Throughout the handbook, additional references and resources have been included to help find more in depth information. There are additional links that connect to articles with more information. Additionally, each chapter ends with resources for more information.

W ith that… happy discovery!

+ LINK: DRAWN TO SCIENCE + LINK: DRUG DISCOVERY AND DEVELOPMENT PROCESS

Interdisciplinary Innovation + Keys to Innovation + Creating a Successful Team

01 10

â&#x20AC;&#x2039;Innovation is the useful application of novel invention.

+ Keys to Innovation

01 12

INNOVATION IS A PROCESS

Identification

Often pegged as “thinking outside of the box,” effective innovation is a structured process that begins with problem identification. Before embarking on solution seeking, the team must determine whether they are working on an important problem that they can influence with imaginative solutions. Without these ingredients, the team will struggle to develop new ideas.

Ideation

Once the target has been identified, the team can embark on idea generation, also known as ideation. In this phase, the team engenders diverse and imaginative ideas to address the defined problem.

The team should enlist experts on the problem to provide ideas to address the problem.

Incubation

Next, the team should incubate the solutions devised during the ideation phase. For example, the team might identify 1-2 key experiments that would allow them to test the assumptions of the new ideas solicited. The team should thoroughly evaluate these experiments to understand what is working and what might need to get fixed.

Implementation

Finally, the team should consolidate the learnings from the incubation period to determine how to move forward with the new innovation. Here, the team should identify the key stakeholders in the implementation process – specifically, individuals who will support the process and individuals who might resist the process. Strategies should be developed to work with both of these parties.

Johnstone, C., Pairaudeau, G., & Pettersson, J. A. (2011). Creativity, innovation and lean sigma: a controversial combination?. Drug discovery today, 16(1), 50-57.

INNOVATION PRACTIONERS IN BIOPHARMA Biopharma VCs, such as Flagship and Third Rock, use the innovation process to build new biotech companies.

Team Foundation Interdisciplinary teams Business and Scientific Advisors Network of Experts

Idea Exploration Iterative Refining • Define whitespace • Deep-dive research • Seek feedback from experts • Vet the opportunity • Refine business and scientific model 5-6 project ideas 2-4 project ideas

Industry Partners

Feasibility Test

• Test 1-2 key assumptions • Fail forward

Launch NewCo

1-2 project ideas

2-4 year process 14

TO LEARN MORE ABOUT INNOVATIONâ&#x20AC;Ś

Creative Education Foundation. (2014) Creative Problem Solving Resource Guide. Scituate, MA: Creative Education Foundation. http://www.creativeeducationfoundatio n.org/wpcontent/uploads/2015/06/CPS-Guide6-3-web.pdf [accessed 7/23/2015] Degraff, Jeff. "Certified Professional Innovator." Leading Innovation: How to Make Innovation Happen in Your Organization. University of Michigan. http://mconnex.engin.umich.edu/innov ation/#home_slider [accessed 7/23/2015] Johnstone, C., Pairaudeau, G., & Pettersson, J. A. (2011). Creativity, innovation and lean sigma: a controversial combination?. Drug discovery today, 16(1), 50-57.

+ Creating a Successful Team

01 16

â&#x20AC;&#x153;

â&#x20AC;&#x2039;After mutual respect and understanding are achieved, it is possible to establish real, sincere relationships, which is the foundation of a solid long-term collaboration. - Ron Garan, NASA Astronaut

INTERDISCIPLINARY TEAM DYNAMICS Team dynamics rest on three formative phases: Build, Manage, and Perform

Build

Manage

Perform

Team Inputs

Team Process

Team Effectiveness and Viability

W hen launching a drug discovery program, the team is the most important variable for project success. Without the right expertise areas and team dynamics, a new therapeutic will struggle to overcome the significant hurdles and failures faced in the discovery process. As such, the team must compile the right inputs in order to improve the likelihood of success. The goals in this phase are: • Compose the team • Set goals

Once the team is established, it should develop productive team processes, which will allow the team to overcome team conflict and solve critical issues during the discovery process. In this phase, the goals are to: • Establish effective task processes • Develop positive relational dynamics

Finally, as the team progresses on the project, it should consider its long term effectiveness and viability. Drug discovery project last a very long time. As such, it is critical that participants enjoy a productive and collaborative environment. In this phase, the goals are to: • Evaluate task performance • Assess the Long-term viability and satisfaction • Promote ongoing learning

• Establish Norms

COMPOSING THE TEAM

Build Team Inputs

Drug discovery teams require interdisciplinary expertise in order to evaluate the complex and interdependent components of the drug discovery process. In forming the team, the project leaders should enlist specialists with expertise in specific domains, as well as generalists to manage the team process. Team size is also an important consideration. A group of 5 – 10 is ideal for promoting diverse ideas, while maintaining speed indecision-making.

“I believe in the “two pizza” rule. If you can’t feed the group with two pizzas, it’s too big.”

Biology Project Management

Chemistry

Discovery Team

Commercial

Regulatory

Clinical

Legal

- Jeff Bezos, Amazon 19

SETTING TEAM AND INDIVIDUAL GOALS Overall Goals and Vision

Build Team Inputs

• What is the overall vision for the collaboration? • What are the scientific issues, goals, and anticipated outcomes or products of the collaboration? • When is the collaboration over?

• When is the project over? Who will do what?

Contingencies and Communicating

• What are the expected contributions of each participant? • Who will write any progress reports and final reports?

• What will be your mechanism for routine communications among members of the research team?

• How, and by whom, will personnel decisions be made? How and by whom will personnel be supervised?

• How will you decide about redirecting the research agenda as discoveries are made?

• How and by whom will data be managed? How will access to data be managed?

• How will you negotiate the development of new collaborations and spin-off projects, if any?

• How will you handle long-term storage and access to data after the project is complete?

• Should one of the principals of the research team move to another institution or leave the project, how will you handle, data, specimens, lab books, and authorship and credit?

Authorship, Credit

Conflict of Interest

• What will be the criteria and the process for assigning authorship and credit?

• How will you identify potential conflicts of interest among collaborators?

• How will credit be attributed to each collaborator’s institution for public presentations, abstracts, and written articles?

• Could a collaborator, or any close family members or associates benefit financially from the research?

• How and by whom will public presentations be made?

• Is a collaborator receiving money from someone who could benefit financially from the research?

• How and by whom will media inquiries be handled? • When and how will you handle intellectual property and patent applications?

"Sample Partnering Agreement Template." NIH Office of the Ombudsman. 23 July 2015: http://ombudsman.nih.gov/partnerAgree.html

NORMS OF COLLABORATION: TASK-ORIENTED ROLES

â&#x20AC;&#x2039;W hen working in a team, each individual tends towards certain norms or behaviors. These norms or behaviors can influence how the team makes decisions. On the right, there are five important task-oriented roles for decision making processes. On the drug discovery team, it is important to understand each of the task-oriented roles and ensure each one is represented during the decision making process. These roles help facilitate and coordinate the team as they work towards solving problems and making decisions.

Build Team Inputs

Initiator Offers new ideas for solving group problems or goals

Information Givers

Information Seekers

Offers facts or generalizations about the group problem

Clarifies suggestions and seeks authoritative information and facts

Coordinators

Evaluators

Clarifies relationships among ideas and pulls them together in order to coordinate activities of the group

Assesses the group functioning; May evaluate the practicality, logic or facts of suggestions offered by other team members

â&#x20AC;&#x2039;Benne, K. D., & Sheats, P. (1948). Functional roles of group members.

NORMS OF COLLABORATION: RELATIONSHIP-ORIENTED ROLES

In addition to task-oriented roles, teams should identify and define relationship oriented roles to build cohesion and commitment. These roles help “strengthen, regulate and perpetuate the group as a group.” On the discovery team, it is important to ensure these roles are being filled in order to create a collaborative and enjoyable working group over the course of the many year discovery process.

Build Team Inputs

Encouragers Praise, agree and accept ideas of others; Exudes warmth and solidarity

Standard Setters

Harmonizers

Establishes standards for the group to evaluate group processes, goals and purpose

Mediate intragroup conflict and alleviate tension

Followers

Gatekeepers

Go along passively as friendly team members

Encourages and invites participation from all group members

Group Observers

Benne, K. D., & Sheats, P. (1948). Functional roles of group members.

Tend to stay out of the group process and serve as detached evaluators

NORMS OF COLLABORATION: AVOIDING SELF-ORIENTED ROLES

â&#x20AC;&#x2039;Finally, some people may express selforiented roles, such as the ones listed to the right. These behaviors destroy the team collaboration. When team members exhibit these types of behaviors, it is important to intervene in order to understand the motivations of that individual. If the situation cannot be reconciled, that person should be removed from the team.

â&#x20AC;&#x2039;Benne, K. D., & Sheats, P. (1948). Functional roles of group members.

Build Team Inputs

Blockers

Recognition Seekers

Negative, stubborn and unreasoningly resistant

Call attention to themselves; Avoid being placed in an inferior position

Dominators

Avoiders

Assert authority by manipulating the group or certain individuals in the group

Passive resisters try to remain insulated from interaction

DECISION MAKING: DIVERGENT AND CONVERGENT THINKING

Ideal decision making processes have two phases: • Divergent Thinking: Generating lots of ideas and options

• Convergent Thinking: Evaluating ideas and options, and making decisions. During the divergent phase, team members share their thoughts and opinions on a topic. At start, familiar opinions are shared, but over time, more diverse, and thus more creative, perspectives are shared.

Manage Team Process

New Idea

Diversity of Ideas

New Topic

Decision Point

Familiar Opinions

Next, the team should consolidate the best ideas and begin to refine them towards reaching a decision.

Refinements

Diverse Perspectives

Consolidated Thinking

Time

Kaner, S., et al. (2014). Facilitator's Guide to Participatory Decision-making. 3rd ed. San Francisco: Jossey-Bass.

SOLUTION

CHALLENGE

DECISION MAKING: SET BACKS IN THE PROCESS

Manage Team Process

Jumping to Decisions

Ineffective feedback

Fear of Judgment

Confrontational

Team leaders eager to end meetings and avoid conflict may make a decision in the midst of the divergent thinking phase. This quickly disengages the team that can slip into cynicism.

W hen discussing complex challenges, team members will have differing opinions. Often, feedback on new ideas is not productive because it shuts down the conversation. For example, “That won’t work because…”

During the divergent thinking phase, it is important for the team to be open to a wide range of ideas in order to find the best possible solution. Judgment prevents this idea flow, and thus suboptimizes the process.

In a rapid-paced conversation, it can be easy to lose track of word choice. “No, but” phrasing instantly shuts down the conversation because it comes across as confrontational.

Divergent and convergent thinking must be balanced

Ask problems as questions

Defer or suspend judgment

Focus on “Yes, and…” rather than “No, but.”

Ideas need time to fully form and develop. Instead of shutting down the idea, frame feedback as an open-ended question that invites a solution. For example, “How might this idea work in XXX context?”

Save judgment for the convergent thinking phase in order to avoid shutting down idea generation.

“Yes, and…” allows the continuation and expansion of ideas. Whereas “But” closes down the conversation. This subtle word choice will dramatically shift the conversation flow.

The team leader should communicate clearly to the group (e.g., on the agenda) the timing for divergent and convergent thinking, so that all participants are aware of the process.

Creative Education Foundation. (2014) Creative Problem Solving Resource Guide. Scituate, MA: Creative Education Foundation.

GIVING EFFECTIVE FEEDBACK

Perform Team Effectiveness and Viability

When providing feedback on ideas, it is important to begin with the positives in order to promote idea generation. Criticisms are best provided in question format to prompt solution seeking. Pluses

Potentials

Concerns

Overcome Concerns

To begin the feedback process on an idea, begin by stating the pluses. What is good or unique about the idea as it stands?

Next, offer potential opportunities, benefits or impact that could result from the idea. What are speculations, spinoffs, or possible future gains from the idea? What are the ultimate potentials of this idea/what it could eventually lead to? What opportunities might result if the idea was implemented?

Shifting to concerns about the idea, position them as questions rather than statements. It can be effective to use the language stem “How might…?” or “In what ways might…?” For example if an idea is too expensive, a concern would be positioned as “How might we make this idea more affordable? This invites improvement to the idea.

Finally, prioritize the key concerns of the idea. Then, generate solutions for overcoming the concerns one at a time. For the example about cost, the team might come up with the idea to outsource or to remove a couple steps from the process. These ideas are then incorporated into the original concept, thereby making it better.

Creative Education Foundation. (2014) Creative Problem Solving Resource Guide. Scituate, MA: Creative Education Foundation.

TO LEARN MORE ABOUT TEAM DYNAMICSâ&#x20AC;Ś

Bennett, L.M., Gadlin, H., and LevineFinley, S. (2010). Collaboration & Team Science: A Field Guide. National Institutes of Health: August 2010. Hackman, J.R. (2002). Leading Teams: Setting the stage for great performances. Boston, MA: Harvard Business School Press Kaner, S., et al. (2014). Facilitator's Guide to Participatory Decisionmaking. 3rd ed. San Francisco: Jossey-Bass. Benne, K. D., & Sheats, P. (1948). Functional roles of group members.

Drug Discovery Process + Stages of Drug Discovery + Key Decision Points

02 28

+ Stages of Drug Discovery

02 29

TWO PATHS TO TARGET DISCOVERY

Drug discovery projects typically stem from two different, though overlapping paths: 1. Target-based approach: Broadly viewed as the “molecular approach”, whereby researchers discover the specific cellular mechanisms that cause the disease. Once the disease pathway has been determined, researchers can begin to identify critical intervention points in the pathway, as a promising therapeutic target. 2. Phenotypic approach: In this process, researchers likely do not know the exact pathway or mechanism of action for a drug target. Instead, researchers may have discovered a desired phenotypic response in an animal model or cell-based assay. Once the phenotypic response has been identified, researchers can begin the screening process. Further target identification and validation may or may not be completed in the future.

Target-Based Approach Clinical Samples

Disease tissue expression Genomics, proteomics, genetic association

Cell Models

Forward genetics

Modulation in cell models (mRNA knockout)

Drug Discovery

Phenotypic Approach Patients

Clinical sciences

Animal models

Forward or reverse genetics

Modulation in animal models

Disease model Target identification

+ LINK: TARGET DISCOVERY + LINK: HOW WERE NEW MEDICINES DISCOVERED? + LINK: TARGET-BASED DRUG DISCOVERY: IS SOMETHING WRONG? Lindsay, M.A. (2003) Target discovery. Nature Reviews Drug Discovery 2, 831-838.

Target validation

MOLECULAR TARGET IDENTIFICATION In target identification, researchers aim to identify receptors, proteins, enzymes, DNA, RNA or ribosomal targets that can be modulated to inhibit or reverse the disease process. Targets can be identified via three strategies: Genomics: Identifies disease targets by comparing normal and diseased tissues. Proteomics: Measures protein expression, activity and interaction with other biological macromolecules. Genetic association: Identifies gene mutations that can help determine the disease mechanism.

Lindsay, M.A. (2003) Target discovery. Nature Reviews Drug Discovery 2, 831-838.

VALIDATING TARGETS Previously Unknown Target Once a target has been identified, it must be validated.

To validate a target, researchers must demonstrate that the target is both involved in the disease process, and when modulated, it has a therapeutic effect.

•

Screen compound collections to identify desired phenotypes

• Knockout animal models where the target gene is removed • Knock-in or gain of function models where gene expression is reactivated • Antisense DNA/RNA and RNAi inhibit normal function of DNA/RNA

Chemical

Target validation can be accomplished by evaluating the criteria to the right. The process can be typically completed in 12 months.

Biological •

Repurposed molecule

• Previously known target/pathway (e.g., GCPR, ion channel, nuclear receptor, transcription factor, cell cycle, enzyme, etc.) • Repurposed molecule

Previously Known Target + LINK: TARGET SELECTION IN DRUG DISCOVERY 32

TARGET VALIDATION

Target Identification and Validation

Assay Development

Screening

Scientific Criteria

Commercial Criteria

• Key molecules to modulate target

• Intellectual property of target

• Type of target has a history of success

• Determine marketability of target

Hit to Lead

Lead Optimization

Candidate Selection

Preclinical Safety

• Genetic confirmation • Availability of known animal models • Low-throughput target validation assay that represents biology

Hughes M, Inglese J, Kurtz A, et al. Early Drug Discovery and Development Guidelines: For Academic Researchers, Collaborators, and Start-up Companies. 2012 May 1 [Updated 2012 Oct 1]. In: Sittampalam GS, Coussens NP, Nelson H, et al., editors. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004-. Available from: http://www.ncbi.nlm.nih.gov/books/NBK92015/

DEVELOPING AN ASSAY FOR EFFECTIVE SCREENING

Quality of assay determines the quality of the data

A useful assay must have the following criteria: Relevance: Does the readout unequivocally relate to the target? Reliability/Robustness: Are results reproducible and statistically significant? Practicality: Do time, reagents, and effort correlate with quality and quantity of results?

Feasibility: Can assay be run with resources at hand? Automation: In order to screen large numbers of compound, can assay be automated and run in highly parallel format + LINK: ASSAY GUIDANCE MANUAL + LINK: CELL DEATH ASSAYS

Cost: Does cost of the assay permit scale-up for high-throughput screening?

Eckstein, Jens. ISO/ARF Drug Development Tutorial. http://www.alzforum.org/sites/default/files/legacy/drg/tut/ISOATutorial.pdf

Assay Development • Produce reagents • Pick compound library to screen • High sensitivity • High Z’-factor

Assay Optimization • Optimize reproducibility, sensitivity and cost • Determine linear range • Measure signal stability over time

Pilot Screen • Triplicate run of test plates • Estimate the amount of systemic error using ANOVA test • Rough idea of hit rate

IDENTIFICATION OF ACTIVES

Target Identification and Validation

Assay Development

Screening

Clinical Criteria

Commercial Criteria

• Acquisition of screening agents

• Intellectual property of target

• Primary HTS assay development and validation

• Determine marketability of target

Hit to Lead

Lead Optimization

Candidate Selection

Preclinical Safety

• Compound library available to screen • Actives criteria defined

HIGH THROUGHPUT SCREENING

High throughput screening is a rapid Estimated attrition rates from screen to hit process to identify hits from a compound library. It is an ongoing Screening library narrowing process where the team analyzes screening results in a handful Primary screen of conditions in order separate false Same conditions positives from promising hits. and collection Repeat primary screen sample Specifically, the primary screen will be run twice to reduce the number of false Dose response positives. Next, the team will run a dose response of the “confirmed actives.” Next the team will acquire new samples of the 100 – 150 compounds that appear active. A secondary set of screens are performed to identify 5 – 30 hits. + LINK: DESIGNING SCREENS + LINK: HTS IN ACADEMIA + LINK: NOVEL TRENDS IN HTS + LINK: SOURCES OF ASSAY INTERFERENCE

Obtain new sample Same conditions Different conditions

Repeat dose response

Selectivity Screens

150,000 samples 0.1-2% actives 1500 compounds ~30% repeat 500 compounds ~50% titrate 250 compounds ~50% available 125 compounds 50% titrate 60-70 compounds 10-40% hits 5 - 30 compounds

CONFIRMATION OF HITS

Target Identification and Validation

Assay Development

Screening

Hit to Lead

Scientific Criteria

Commercial Criteria

• Perform highthroughput screen

• Composition of Matter Invention Disclosure

• Confirmation of repeat assay • Secondary assays for specificity, selectivity, and mechanisms

Lead Optimization

Candidate Selection

Preclinical Safety

• Chemical Intellectual Property

• Confirmed identity and purity • Cell-based assay confirmation of biochemical assay when appropriate • Druggability of chemical class Hughes M, Inglese J, Kurtz A, et al. Early Drug Discovery and Development Guidelines: For Academic Researchers, Collaborators, and Start-up Companies. 2012 May 1 [Updated 2012 Oct 1]. In: Sittampalam GS, Coussens NP, Nelson H, et al., editors. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004-. Available from: http://www.ncbi.nlm.nih.gov/books/NBK92015/

HIT-TO-LEAD Hit-to-lead is the process of culling the list of confirmed hits to prioritize chemical series for further optimization. Decision criteria typically includes potency, selectivity, chemical tractability, binding mechanism, pharmacokinetic properties and patentability. Once a chemical series is selected, researchers will embark on a number of optimization strategies, including hit evolution, (bio)isosteric replacements and hit fragmentation. In hit fragmentation, there are three additional paths for optimization, including expansion, linking/merging and/or self-assembly.

+ LINK: HIT DISCOVERY AND HIT-TO-LEAD APPROACHES + LINK: BEYOND HIGH THROUGHPUT SCREENING + LINK: IMPROVING THE HIT-TO-LEAD PROCESS + LINK: ROLE OF NUTURE AND NATURE IN MEDICINAL CHEMISTRY Keserű, G., Makara, G. (2006) Hit discovery and hit-to-lead approaches. Drug Discovery Today 11 (15–16), 741-748.

IDENTIFICATION OF CHEMICAL LEAD

Target Identification and Validation

Assay Development

Screening

Hit to Lead

Lead Optimization

Candidate Selection

Scientific Criteria

Commercial Criteria

• Structure Activity Relationship defined

• Eligible for Phase I SBIR

Preclinical Safety

• Select mechanistic assays • In vitro assessment of drug resistance and efflux potential • Evidence of in vivo efficacy of chemical class • PK/Toxicity of chemical class known based on preliminary toxicity insilico Hughes M, Inglese J, Kurtz A, et al. Early Drug Discovery and Development Guidelines: For Academic Researchers, Collaborators, and Start-up Companies. 2012 May 1 [Updated 2012 Oct 1]. In: Sittampalam GS, Coussens NP, Nelson H, et al., editors. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004-. Available from: http://www.ncbi.nlm.nih.gov/books/NBK92015/

LEAD OPTIMIZATION Lead optimization is an iterative, non-linear process of transforming a promising hit into a preclinical drug candidate.

A D M E Affinity

Selectivity

Physiochemical

Pharmacological

Toxicity

Improved affinity typically results in improved potency. Using structure-based drug design, chemists can improve how the small molecule binds to the desired target.

Improving selectivity ensures that the drug is only active with the desired target, rather than all proteins. The molecule is tested with other proteins to ensure there is no interaction.

Solubility and lipophilicity are important criteria for drugs in order to cross membranes throughout the body.

Absorption, distribution, metabolism and excretion (ADME) properties are critical to ensure that the molecule stays in the body long enough to interact with the target.

W hile all drugs have off-target effects, chemists must ensure that none of these effects are toxic. Many important considerations are hERG, liver damage and drug-drug interactions.

+ LINK: MAKING MEDICINAL CHEMISTRY MORE EFFECTIVE + LINK: LEAD OPTIMIZATION IN 12 MONTHS? + LINK: ROLE OF THE MEDICINAL CHEMIST Mochly-Rosen, Daria, and Kevin Grimes. A Practical Guide to Drug Development in Academia: The SPARK Approach. New York: Springer, 2014.

DETERMINING IN VIVO EFFICACY

In vivo studies can be an effective, though not conclusive, path towards understanding the efficacy of a drug and identifying the desired drug-like properties. A short in vivo efficacy study is recommended even before lead optimization begins in order to gain some insight into the behavior of the molecule.

Which animal model? Each indication typically has an accepted animal model. As such, it is important to discuss with disease experts and research literature in order to determine the appropriate animal model. How to deliver the drug? In the first efficacy study in animals, intraperitoneal (ip) injection is the recommended method. Alternatively, the drug can be delivered with a solvent, such as ethanol, DMSO, or polyethylene.

+ LINK: ANIMAL MODELS FOR RARE DISEASES + LINK: PLASMA PROTEIN BINDING IN IN VIVO EFFICACY + LINK: DISCOVERY TOXICOLOGY AND PATHOLOGY + LINK: DRUG-TARGET RESIDENCE TIME

During lead optimization, in vivo studies are important for answering the following questions: • Which parameters of in vitro pharmacology best predict disease efficacy? • Which parameter(s) of drug exposure best predict disease efficacy in vivo? • Does the drug reach the appropriate compartment to drive disease efficacy? • Do metabolites show pharmacological activity? • What is the projected human dose? • How safe are the compounds and what is the therapeutic index?

Mochly-Rosen, Daria, and Kevin Grimes. A Practical Guide to Drug Development in Academia: The SPARK Approach. New York: Springer, 2014.

PHARMACOKINETICS

Pharmacokinetics is the study of what the body does to the drug. Specifically, it evaluates the ADME characteristics. The specific metrics it measures includes: Bioavailability. Measures the percentage of an administered dose reaches the systemic circulation. Volume of distribution. Measures the volume required to dissolve the administered dose at the drug concentration in the plasma.

Drug administration

Absorption Enteric transport Enteric metabolism

Distribution Intravascular space Extravascular space Protein binding

Metabolism Hepatic influx transport Phase I metabolism Phase II metabolism

Clearance. Measures the amount of time to completely purify the drug from blood or plasma. Half-life. Measure the time required for the drug concentration to fall by 50% of earlier measurement. Area under the curve. Measures the integral under a plot of plasma drug concentration versus time.

Biliary excretion Efflux transport

Intestinal excretion

First pass effect. Measures the metabolism that occurs before an orally administered drug enter the systemic circulation.

Renal excretion Efflux transport

+ LINK: ADME/PK AS RATIONAL APPROACH TO DRUG DISCOVERY + LINK: ADME AND PK PROPERTIES Undevia, S. Gomez-Abuin, G. & Ratain, M. (2005) Pharmacokinetic variability of anticancer agents. Nature Reviews Cancer 5, 447-458. 42 Mochly-Rosen, Daria, and Kevin Grimes. A Practical Guide to Drug Development in Academia: The SPARK Approach. New York: Springer, 2014.

SELECTION OF OPTIMIZED CHEMICAL LEAD

Target Identification and Validation

Assay Development

Screening

Hit to Lead

Lead Optimization

Candidate Selection

Preclinical Safety

Scientific Criteria

Commercial Criteria

• Acceptable in vivo PK and toxicity

• Eligible for Phase II SBIR

• In vivo preclinical efficacy

• Feasible formulation

• Dose range finding pilot toxicology • Process chemical assessment of scale up feasibility

CANDIDATE SELECTION Key information is required prior to candidate selection

Efficacy data

Metabolism

Safety

Chemistry

• Enzyme activity: IC50/Ki and selectivity against enzyme/receptor/target.

• In vitro metabolism: rate with mouse, rat, dog and human microsomes, major metabolite identification. Drug–drug interaction potential. Absorption potential (for example, CACO-2 cells).

• In vitro selectivity: broad toxicity-related receptor/enzyme profiling. Cytotoxicity.

• Physical form: compound characterized (log D, pKa, solubility, stability). Preliminary analytical method developed. Salt form decided. Preliminary formulation.

• Whole organism activity: IC50/IC90 versus laboratory strains (sensitive, resistant), comparison against standard drugs, interactions with existing agents, mechanism of action (cidal or static). • Animal models: ED50/ED90 with appropriate formulations. Parenteral and oral activity. Other more detailed animal testing as appropriate. Postulate curative dosing regimen.

• In vivo pharmacokinetics: po/iv pharmacokinetics in rodent species over therapeutic dose range. Plasma half-life, Cmax, clearance and volume of distribution in rodent. Oral bioavailability in rodent. Major circulating/active metabolites. Human doserange projection

• In vitro mutagenicity: structural alerts (for example, DEREK). Ames test (micronucleus test if Ames is positive). • In vitro cardiac: hERG binding (dog Purkinje fibre test if hERG is positive). • Animal toxicology: Exploratory single-dose and multiple-dose range finding to demonstrate lack of overt toxicology concerns in major organs.

• Manufacture related: economic scale-up assessed. Preliminary cost of good estimate. • Back-up strategy. • Objectives: potential shortcomings of candidate identified. Potential and time frame for improvement assessed.

+ LINK: DECISION GATES Nwaka, S. and Ridley, R. (2003) Virtual drug discovery and development for neglected diseases through public–private partnerships. Nature Reviews Drug Discovery, 2, 919-928.

DRUG CANDIDATE SELECTION: KEY QUESTIONS AND PIVOTAL STUDIES

Questions

Studies that provide answers

Can the drug candidate be measured and is it stable in biological matrices?

Bioanalytical assay development

Does the drug candidate have reasonable metabolic stability? What are the metabolites and are they active, possibly even a better drug candidate? Are there species differences in metabolism?

In vitro metabolism studies using animals and human hepatocytes, microsomes or human expressed enzyme systems and analysis of incubates using LC/MS/MS or LC/NMR/MS. Synthesis and pharmacology testing of metabolites.

Does the drug have sufficient bioavailability and persistence in the bodies of animal models?

Pharmacokinetic studies in rodent and non-rodent species after oral verses intravenous administration.

Is the drug mutagenic or cytotoxic in vitro?

Ames bacterial mutagenicity assay. Mammalian cell (for example, mouse lymphoma) mutagenicity assay.

What is the maximum tolerated dose (MTD) and dose-limiting toxicity?

Rising single and repeat dose escalation toxicology study in rodent and non-rodent species until limiting toxicity is observed.

Can active pharmaceutical ingredient (API) be synthesized at a reasonable cost? Is the API stable after synthesis?

Chemical synthesis process assessment. Assay development for API purity. Chemical stability assessment. Geneation of API certificate of analysis.

Can the drug be formulated for use in animal toxicology studies and early human studies?

Pre-formulation development testing. Assay development for purity and content formulated product.

â&#x20AC;&#x2039;Pritchard, J.F. Jurima-Romet, M., Reimer, M., Mortimer, E., Rolfe, B. & Cayen, M. Making Better Drugs: Decision Gates in Non-Clinical Drug Development. Nature Reviews Drug Discovery, 2, 542-553

Legend

IS A LEAD DEVELOPABLE?

Toxicology studies

Pharmaceutical development

Bioanalysis

Safety pharmacology

Metabolism Lead identified

Ames bacterial mutation

Mouse lymphoma assay

In vitro metabolism, metabolic stability in hepatocytes

Bioanalytical method validation

Inhibition of CYP450 enzymes

MDCK and/or Caco-2 cell permeability

Cross validation – rat plasma

Single intravenous/oral dose pharmacokinetics in rat

Cross validation – dog plasma

Single intravenous/oral dose pharmacokinetics in dog

Identify new lead compound

hERG-K+ conductance

Single (acute) dose intravenous in mouse(MTD)

Repeat intravenous dose range finder and toxicokinetics in rat

Single (acute) dose intravenous in rat (MTD)

Repeat intravenous dose range finder and toxicokinetics in dog

Pharmaceutical development assessment: solubility, stability, and synthesis

Pritchard, J.F. Jurima-Romet, M., Reimer, M., Mortimer, E., Rolfe, B. & Cayen, M. Making Better Drugs: Decision Gates in Non-Clinical Drug Development. Nature Reviews Drug Discovery, 2, 542-553

Is lead developable?

Progress preclinical development

SELECTION OF DEVELOPMENT CANDIDATE

Target Identification and Validation

Assay Development

Screening

Hit to Lead

Lead Optimization

Candidate Selection

Preclinical Safety

Scientific Criteria

Commercial Criteria

• Acceptable PK (with a validated bioanalytical method)

• Prepare pre-IND meeting package, which includes adequate information for FDA to address the specific questions

• Demonstrated in vivo efficacy/activity • Acceptable safety margin (toxicity in rodents or dogs when appropriate) • Feasibility of GMP manufacture

• Conduct Pre-IND meeting with FDA • Adjust project plan to address FDA comments

• Acceptable drug interaction profile

PRECLINICAL SAFETY

During preclinical safety, the research team strives to gain both proof of principle and proof of concept with the drug candidate. That is, the team aims to demonstrate that the clinical candidate is a safe and effective therapeutic viable for treatment in humans. Additionally, the research team brings on a process R&D team to scale up the synthesis of the compound to ensure that the required quantity can be made at the requisite quality.

Timeline for Preclinical Safety Development Proof of Proof of Principle Concept

Candidate drug selection (6 – 9 months)

Concept testing (2 – 3 years)

Filing for Registration

Development for launch (2 years)

Launch phase (one year)

Synthesis Process freeze freeze

Medicinal chemistry synthesis

Early

Advanced

Scalable synthesis (first generation)

Scalable synthesis (second generation)

+ LINK: LOGISTICS OF PROCESS R&D + LINK: DECISION GATES Federsel, H.J. (2003). Logistics of process R&D: transforming laboratory methods to manufacturing scale. Nature Reviews Drug Discovery 2, 654-664 (August 2003)

PRECLINICAL SAFETY: KEY QUESTIONS AND PIVOTAL STUDIES

Questions

Studies that provide answers

Can the drug be reliably prepared and formulated according to good manufacturing practices (GMP) guidelines that regulate drug material prepared for human use?

Formulation development. Define release GMP testing criteria for content and purity. Define formulation stability.

What is the maximum no-effect dose following repeated dosing? Is there dose related exposure? What organs are affected by repeated dosing?

Fourteen-day to three-month toxicology studies in a rodent and non-rodent species with toxicokinetics.

What is the safety margin?

Ratio of maximum no-effect dose or exposure over expected pharmacological no-efect dose or exposure

What enzymes are involved in the drugâ&#x20AC;&#x2122;s metobolism?

In vitro drug metabolism studies using human microsomes and or cytochrome protein expression systems.

How long and by what routes is parent drug eliminated?

Pharmacokinetics in rodent and non-rodent species. Radiolabelled drug-excretion balance studies.

Does the drug produce any cardiovascular effects or cardiovascular conductance?

In vivo telemetry studies in animals evaluating alterations in cardiac electrophysiology and cardiovascular vital signs. Action potential duration using isolated rabbit Purkinje fibers.

Are there any effects on behavior or pulmonary function?

Irwin behavior tests in rats. Rat pulmonary function evaluation.

IS A LEAD DEVELOPABLE? Legend

Is lead developable?

Plasma protein binding

Toxicology studies

Formulation

Metabolism

Safety pharmacology

Irwin test of Formulation Toxicity Cardiobehavior Excretion Toxicity development Excretion assessment in vascular and body In vivo bone balance and Identify assessment and stabilitybalance and dogs or safety – marrow Reproductive temperature metabolite cytochrome in rats after establish metabolite monkeys after telemetry in microtoxicology identification P450 four weeks of clinical trial identification four weeks of conscious nucleus test studies Normal – dog or enzymes exposure and material – rat exposure and animal and pulmonary in rodents monkey toxicokinetics release toxicokinetics PK/PD function – specifications rat

Quantitative tissue distribution

STOP

Is it safe to give candidate to humans?

Initiate early clinical program

Pritchard, J.F. Jurima-Romet, M., Reimer, M., Mortimer, E., Rolfe, B. & Cayen, M. Making Better Drugs: Decision Gates in Non-Clinical Drug Development. Nature Reviews Drug Discovery, 2, 542-553

SUBMISSION OF IND APPLICATION

Target Identification and Validation

Assay Development

Screening

Hit to Lead

Lead Optimization

Candidate Selection

Preclinical Safety

Scientific Criteria

Commercial Criteria

• Acceptable clinical dosage form

• Clear IND regulatory path

• Acceptable • Human Proof of preclinical drug safety Concept(HPOC)/Clini profile cal Proof of Concept (CPOC) plan is acceptable to regulatory agency (Pre-IND meeting)

TO LEARN MORE ABOUT DRUG DISCOVERY

A Guide to Drug Discovery. Nature Reviews Drug Discovery. http://www.nature.com/nrd/series/drug discovery/index.html#d201103 Eckstein, Jens. ISO/ARF Drug Development Tutorial. http://www.alzforum.org/sites/default/fil es/legacy/drg/tut/ISOATutorial.pdf Hughes M, Inglese J, Kurtz A, et al. Early Drug Discovery and Development Guidelines: For Academic Researchers, Collaborators, and Start-up Companies. 2012 May 1 [Updated 2012 Oct 1]. In: Sittampalam GS, Coussens NP, Nelson H, et al., editors. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004-. Available from: http://www.ncbi.nlm.nih.gov/books/NB K92015/

Lindsay, M.A. (2003) Target discovery. Nature Reviews Drug Discovery 2, 831-838. Mochly-Rosen, Daria, and Kevin Grimes. A Practical Guide to Drug Development in Academia: The SPARK Approach. New York: Springer, 2014. Rydzewski, R. (2010). Real world drug discovery: a chemist’s guide to biotech and pharmaceutical research. Elsvier Science, Oxford. Sams-Dodd, F. Target-based drug discovery: is something wrong? Drug Discovery Today 10(2), 139-147. Swinney, D.C. and Anthony, J. How were new medicines discovered? Nature Reviews Drug Discovery 10, 507-519

Mobilizing the Process + Indicator Background Document + Target Product Profile + Risk Management and Assessment + Prioritization Matrix

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+ Indicator Background Document

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“

By failing to prepare, you are preparing to fail - Benjamin Franklin

”

INTRODUCING THE INDICATOR BACKGROUND DOCUMENT

An Indicator Background Document (IBD) helps the discovery team to understand the context of the disease indication, for which the new therapeutic is being developed. It is akin to a business planning document other organizations might use for launching a new product. The IBD analyzes the current state of the disease, as well as the clinical and commercial potential of a new therapeutic in the disease area. To understand the current state of the disease, the team should evaluate the etiology and epidemiology of the disease. Additionally, the team should evaluate the current standard of care, as well as any gaps in the current care offering, or unmet medical need.

Assuming there is an unmet medical need, the team should evaluate how the proposed therapeutic might address the unmet need, as well as the clinical and commercial considerations for developing the new therapeutic. Once the team has collected the information for the IBD, they should assess whether the project should move forward to develop a Target Product Profile, an even more specific project planning document.

INDICATOR BACKGROUND DOCUMENT: TEN BUILDING BLOCKS Establishing a shared understanding for the disease indication of a new therapeutic

Disease Description

Epidemiology

Scientific Rationale

Future Standard of Care

Market Dynamics

Which disease is the drug intended to treat?

What are the causes of the disease?

How is the disease characterized?

What are the consequences of the disease?

What is the mechanism of action for the proposed therapeutic?

What are the new and/or upcoming therapeutic approaches for treating the disease?

What is the size and growth of this market in terms of current drug sales?

How is the disease diagnosed?

How prevalent is the disease?

Standard of Care

Competitive Landscape

Commercial Opportunity

How is the disease currently being treated?

Are there other drug What is the forecasted discovery programs pursuing revenue for this project? the same target?

Why will it fulfill the unmet need?

How do they compare with this project?

Unmet Medical Need

Key Clinical and Commercial Issues

What are the existing problems or gaps in addressing this disease?

What are the key risks in pursuing this drug discovery project from a commercial and clinical perspective?

UNDERSTANDING THE CONTEXT OF THE DISEASE

Disease Description

Epidemiology

Current State of the Disease On the left side of the IBD, the research team evaluates the current state of the disease. The team will identify the specific disease at hand, its epidemiology, the current standard of care, and any unmet needs of patients dealing with this disease.

Standard of Care

Unmet Medical Need

By assessing the current state of the disease, the project team should gauge what is the clinical opportunity for pursuing a drug project for this disease. In particular, the project team should evaluate how well does the current standard of care address this disease. Is the first line of treatment effective for all patients? Or is there an opportunity for a better treatment for a specific subset? In turn, what are the known unmet medical needs? Does the drug discovery project address these needs? More often than not, clinicians have a strong sense for the current state of the disease. Successful drug discovery projects will enlist a clinician with a specialty related to the disease indication to provide context for clinical impact and outcomes.

EXAMINING OPPORTUNITIES FOR A NEW THERAPEUTIC

Opportunity for Drug Discovery On the right side of the IBD, the research team evaluates the clinical and commercial opportunity for a new therapeutic in this disease area. From a scientific perspective, the team should evaluate the scientific rationale for the new therapeutic. Then the team should examine future therapeutics being developed for the disease indication across all mechanisms of action. Next, the team should explore the competitive landscape among therapeutics in the given mechanism of action. From a commercial perspective, the team should assess the market dynamics for drugs for this disease. Next, the team should analyze the commercial opportunity. Finally, the team should explore the remaining clinical and commercial issues in pursuing this drug discovery project

Scientific Rationale

Future Standard of Care

Market Dynamics

Competitive Landscape

Commercial Opportunity

Key Clinical and Commercial Issues

Disease Description Which disease is the drug intended to treat? How is the disease characterized? How is the disease diagnosed?

Some therapeutics can be prescribed for multiple indications. For example, Bevacizumab (trade name Avastin) is prescribed for colorectal, lung, renal cervical and ovarian cancers. Additionally, it has been prescribed by opthamologists for off-label use in age-related macular degeneration (AMD) and diabetic retinopathy. Yet when embarking on a new drug discovery program. It is important to focus on a specific indication when moving the project forward. Thus, the project team should specify for which

disease is the new therapeutic intended to treat. If the project team believes that the drug should treat multiple diseases, then the team should create a separate Indicator Background Documents for each disease. For the Disease Description, the team should capture the perspective of a clinician who might be diagnosing a patient with this disease. That is, how is the disease characterized? How does the disease present itself? Finally, the team should evaluate how

the disease is currently diagnosed? As the team collects this information, they should begin to consider how the new therapeutic fits in with the current context of the disease. For example, are there key biomarkers associated with the disease that can be used later in the Proof of Concept stage of the project?

Epidemiology What are the causes of the disease? What are the consequences of the disease? How prevalent is the disease?

The discovery team should understand the epidemiology of the disease because this information will be valuable both for performing financial projections, as well as designing clinical trials. As a starting point, the team should describe the causes of the disease – though this information is often unknown for rare diseases. The team should elucidate both the micro level causes (i.e., molecular pathways of the disease), as well as the macro level (i.e., the symptoms associated with the disease).

Further, the team should explain the consequences of the disease. What happens to the patient when the disease is left untreated? What is the burden of the disease on the patients? On society? These questions can help identify how and when intervention options should be introduced for the disease. Finally, the team should analyze the disease prevalence. That is, how many patients suffer from this disease each year? This information will help estimate annual revenues.

In turn, are the patients regionally concentrated or are they evenly distributed across the country and around the world? This information will factor into clinical trial design – particularly for rare diseases. For example, the University of Michigan Comprehensive Cancer Center treats more adrenal cancer patients than any other hospital in the world. As a result, it is significantly easier and cost effective to launch one clinical trial site than multiple disaggregated around the world.

Standard of Care How is the disease currently being treated? What are the first line drugs to treat the disease? What are the liabilities of these first line drugs?

W hen a clinician encounters a patient with a certain disease, how will he or she proceed? Given this decision making process, how will the new therapeutic integrate into the existing treatment algorithm? The discovery team should assess the current standard of care for a disease. That is, the team should identify all of the current treatments for the disease. What are the first line drugs offered to patients? What might be their liabilities? How and why are the second and third tier drugs introduced to the treatment regimen?

In addition to the other drugs being offered, the drug discovery team should understand the current patient experience with the current standard of care. Is treatment offered in a hospital or clinical setting or can patients treat themselves at home? Similarly, how well do patients adhere to the current therapy protocol?

valuable to interview patients to understand their perception and experience with the current treatment options. By assessing the current standard of care, the discovery team will begin to identify the unmet needs, which will be more thoroughly enumerated in the following section.

To fully understand the current standard of care, the discovery team should speak with multiple clinicians in the disease area to understand the positives and negatives of the current treatment options. Similarly, it would be 62

Unmet Medical Need What are the existing problems or gaps in addressing the disease? Why are these gaps important to patient care and clinical outcomes? Why have these gaps been unaddressed?

Before cisplatin was discovered, patients with testicular cancer had few treatment options. Today, cisplatin with other chemotherapies cures more than 90% of testicular cancer patients. While there are several side effects to cisplatin, the high cure rate presents a high bar for a new therapeutic for testicular cancer to be introduced. The discovery team should consider the unmet medical need of a disease indication before embarking on a drug discovery project. When assessing clinical need, there are four categories for the discovery team to assess:

1. No Therapies Currently Available W hen no therapies exist for a given disease indication, the unmet medical need is obvious. 2. Need to Reverse or Arrest Disease Process Many diseases have treatments that provide palliative care, but do not reverse or arrest the disease process. This is a critical area of unmet need. 3. Severe/Unacceptable Side Effects Some diseases may have very curative therapies available, yet the side effects dramatically compromise

"Use of Cisplatin for Cancer Treatment." National Cancer Institute. Web. 21 July 2015.

the patient’s quality of life. Here, new therapies that can provide the same level of curative treatment with ameliorated side effects would address an important unmet need. 4. Patient Preference/Convenience Cost Oral drugs taken daily are more preferable than injection based treatments. For example, substrate replacement therapy is vastly preferable to enzyme replacement therapy for patients with Gaucher’s disease.

Scientific Rationale What is the mechanism of action for the new therapeutic? Why will it fulfill the unmet need? What target validation has been completed for the new therapeutic?

The scientific rationale should establish the value proposition of the new therapeutic. The discovery team should elucidate the mechanism of action for the new therapeutic. For drugs that have been discovered through phenotypic studies, the discovery team should explain the desired phenotypic activity and how that relates to the current understanding of the disease.

medical need of the disease. In this section, target validation studies will be useful for clarifying the scientific rationale.

Moreover, the discovery team should explain how the new therapeutic will address the afore stated unmet

Future Standard of Care What are the upcoming therapeutic approaches for treating the disease? Could these new therapeutics become first line of care? What are the liabilities of these new therapeutics?

Well-researched disease often have multiple disease pathways, and thus multiple drugs with different mechanisms of action. When developing a new drug – even if it tackles a novel target – it is important to understand how other treatments are tackling this disease. As such, the discovery team should explore all of the other treatments in the pipeline for this disease. In particular, the team should consider treatments beyond small molecule oral therapeutics. For example, are there new biologics being developed? Or is there a surgical or

device-based therapy for the disease? Are some of these therapies more effective than the current standard of care? If so, how might the new therapeutic compare to the team’s discovery project? The team should enumerate all of the existing and upcoming drug classes to compare and evaluate the safety and effectiveness of each class. Based on this analysis, the team should gain a strong sense for how the new therapeutic will fit in the existing context of therapies.

To collect information about the future standard of care, the discovery team should solicit information from industry experts and venture capitalists with a specialty in the disease area. These individuals have a strong pulse on new developments in a specific disease domain.

Competitive Landscape Are there other drug discovery programs pursuing the same mechanism of action? How do they compare with this project? What liabilities have been unveiled in addressing this mechanism of action?

Narrowing down from the broader group of future therapies, the discovery team should examine whether there are other drug discovery projects developing a drug targeting the same mechanism of action. If there are other drug discovery or development programs pursuing the same drug strategy, the project is not doomed. By way of example, Lipitor was expected to be a fifth line therapeutic when it was being developed. Moreover, the marketing team expected the drug to generate $300M in revenue per year. Instead,

when it was approved, Lipitor turned out to be far more effective than the competing drugs, and soon generated $5B in revenue per year. Miracles can happen. That said, if there are many other drugs completing with the drug strategy, the discovery team must thoroughly analyze why their therapeutic will be the preferred drug on the market.

Market Dynamics What is the size and growth of this market in terms of current drug sales? What is the payer/provider context for other drugs with this disease indication? How have other drugs succeeded in launching in this market?

Market sizing should not be a key criteria for moving forward an academic drug discovery project. In fact, academic drug discovery is wellpositioned to take on projects that may not be economically viable for industry. However, the discovery team should understand the market dynamics for the disease indication in order to evaluate the pharmacoeconomics of the discovery project. There are many stakeholders in the prescription drug industry, and understanding their interests and concerns is important for the success of the project.

Reimbursement Agency • Sets reimbursement pricing for the drug reflecting perceived costeffectiveness

Managed Care Organizations/Health Insurance Companies • Want substantive real world outcome data

Office Physicians • Increasingly cost conscious • Concerned with long-term patient outcomes • Motivated by efficiency

Kennedy, T. (1997). Managing the Drug Discovery/Development Interface. Drug Discovery Today, 2 (10), 436-444.

Pharmaceutical Industry • Assesses economic opportunity/viability • Fear exclusion of drugs from pharmacies or HMOs

Pharmacists • Decide which drugs are used in a hospital setting

Patients • Increasingly well informed and organized to influence companies and policy 67

Commercial Opportunity What is the forecasted revenue for this new therapeutic? What are the prospects for venture capital in this disease area? Who might be potential exit partners for a drug in this disease area?

The discovery team should evaluate the commercial opportunity in order to identify key development partners. Unlike industry, academic drug discovery projects are not beholden to creating shareholder value. Quite to the contrary, academic drug discovery projects should be focused on addressing unmet medical needs and expanding scientific knowledge. Nevertheless, the team benefits from understanding the commercial opportunity of a drug discovery project. For example, if a drug discovery project is focused on an orphan

indication, then there are numerous venture capitalists and/or accelerators that specifically focus on orphan disease projects. As such, the team can save time by targeting these organizations for partnerships, rather than taking a buckshot approach.

drug discovery project. Likewise, the Department of Justice has funding for translational research. The discovery team should be able to identify a promising set of potential partners by determining the commercial opportunity.

Similarly, patient advocacy groups have engaged earlier in preclinical drug discovery projects. These groups can be promising sources of funding, as Tomasz Cierpicki and Jolanta Grembecka discovered when working with the Lymphoma and Leukemia Society on their menin-MLL leukemia 68

Key Clinical and Commercial Issues What are the key risks in pursuing this drug discovery project from a commercial and clinical perspective? Does the FDA have any additional guidance for new drugs for this disease indication? Can patients be identified to participate in a clinical trial?

No two drug discovery projects are alike. Each indication will have its own clinical and commercial requirements. In turn, each therapeutic will have its own quirks in the discovery and development process. It is impossible to know all of the risks of a drug discovery project. Yet it is important for the drug discovery team to thoroughly enumerate the possible risks in the project.

these individuals can provide guidance for how to overcome certain risks. Similarly, the team should meet with disease experts, who can provide feedback on the project throughout the process.

The team can gain this information through conversations with veteran drug discovery scientists. Having gone through the process a handful of times, 69

+ Target Product Profile

03 70

“

Our goals can only be reached through a vehicle of a plan, in which we must fervently believe, and upon which we must vigorously act. There is no other route to success.

- Pablo Picasso

” 71

INTRODUCING THE TARGET PRODUCT PROFILE (TPP)

The Target Product Profile (TPP) is an invaluable document for defining the clinical and commercial criteria for discovering and developing a successful drug. It defines the minimum and optimum criteria for the drug discovery project. Moreover, the TPP is a useful document for the team to establish a shared vision and plan for the drug discovery project. Knowing the interdisciplinary nature of drug discovery, it is vital for the team to collaboratively create and work towards a plan.

+ LINK: TARGET PRODUCT PROFILE

To develop the TCP, the team should envision how the drug is intended to be used in the clinic. That is, how does the disease present itself, how is it

diagnosed, and what treatment options currently exist. In turn, the team should define the drug efficacy and safety criteria. Finally, the team should evaluate the regulatory, legal and financial criteria of the project. The TPP should guide the go/no-go decisions throughout the project. The team should reference the TPP after each experiment to examine how the results align with the plan set forth by the TPP. It is important to remember that the TPP is a living, evolving document. It should be developed as early as the Target Validation phase. The TPP will become more specific as the project moves forward and more data is collected. 72

KEY CRITERIA FOR DRUG DISCOVERY GOALS The Target Product Profile enables the team to define and strive towards the drug discovery goals. It captures both the clinical and commercial development criteria.

DEFINE

DISCOVER

DEVELOP

Product Description

Preclinical Work

Development Candidate

Safety and toxicity in humans

Intellectual property

Indication and Usage

Pharmacokinetics

Dosage and Regulatory Financial Administration Considerations Considerations

DEFINING THE TARGET DEFINE Product Description

Indication and Usage

For the Define section of the TPP, the team can utilize much of the information developed in the Indicator Background Document. Along these lines, Tony Kennedy in Managing the Drug Discovery/Development Interface recommends that teams follow the “disease flow” to understand “how the disease is detected and how the disease progresses acutely and chronically.”

Product Description

The team should define the purpose of the treatment and its mechanism of action. Specifically, the team should define characteristics for: • Proposed target • Type of agent

Indication and Usage The team should define the clinical indication and target patients for the drug. In this section, the team should define characteristics for: • Clinical indication • Target patient population • Current available treatment options

Kennedy, T. (1997). Managing the Drug Discovery/Development Interface. Drug Discovery Today, 2 (10), 436-444.

CRITERIA FOR DRUG DISCOVERY DISCOVER Preclinical Work

Development Candidate

Preclinical Work

Development Candidate

The team should define the minimum and optimum safety profile and which animal models to demonstrate these measures. Key criteria would include:

The team should define the minimum and optimum efficacy requirements, as well as specificity. Key criteria include:

• Animal model(s) of disease

• Efficacy (in vitro and in vivo)

• Specificity

• Safety/toxicity profiles

Pharmacokinetics

Dosage and Administration

Dosage and Administration Pharmacokinetics

The team should define the required Similarly, the team should define the dosing regimen and commercial minimum and optimum form of the drug. Key criteria pharmacokinetics criteria for the include: drug: • Dosing amount and frequency • ADME characteristics

• Route of administration

• Half-life in plasma or serum

• Formulation (excipients)

• Pharmacodynamics

• Estimated shelf life, required storage conditions, etc.

• Protein binding

CRITERIA FOR DRUG DEVELOPMENT DEVELOP

Safety and toxicity in humans

Intellectual property

Safety and toxicity in humans

Intellectual property

• Known on-target or off-target predicted safety concerns

• No freedom to operate issues and potential right to exclude

• Therapeutic window

• Desired licensing outcomes

Regulatory considerations

Financial considerations

• Presumed clinical path forward

Regulatory Financial Considerations Considerations

• Eligibility for Orphan drug status, Fast Track, etc. • Precedents set by previous trials in indication/patient population

• Cost of goods • Projected pricing compared to current options • Cost to develop • Estimated return on investment

Thank you!