SESSION VISESSION VIResources and Services For Advancing Drug Discovery

Chair — Suzana Petanceska, PhD, National Institute on Aging Session OverviewSuzana Petanceska, PhD, National Institute on Aging An Academic Perspective on Drug Discovery Services: Centers & CROsMarcie Glicksman, PhD, Harvard NeuroDiscovery Center A Drug Discovery Services Perspective on Academic Collaborations Bruce Molino, PhD, Albany Molecular Research, Inc.  Preclinical Therapeutics Development for Neurological Disorders: Funding & Resources Rebecca Farkas, PhD, National Institute of Neurological Disorders and StrokeSuzana Petanceska, PhD, National Institute on Aging

Laboratory for Drug Discovery in Neurodegeneration (LDDN)

Marcie Glicksman6th Annual Drug Discovery Course February 13-14, 2012

“Academic Models of Drug Discovery: Services and Utilizing CROs”

Harvard NeuroDiscovery Center

Outline

> Why outsource?

> Academic Resources

> Contract Research Organizations

Disclaimer: this will in no way be complete!

Harvard NeuroDiscovery Center

Why Outsource?

> Lack of internal resources

> Lack of expertise

> Lack of proper equipment– Chemistry scale up

– Robotics

– Chemical libraries

> Flexibility– Can accommodate needs when you have them

Harvard NeuroDiscovery Center

What resources do you need?

•Bioinformatics•Target ID•Target validation•Assay development•Virtual screening•HTS screening•Reference compounds•Compound libraries•Medicinal Chemistry•secondary assays•In vivo studies•Patent writing

•Pharmacokinetics•ADME studies•Toxicology•Pharmacology•Analytical methods•Route development•Non-GMP scale-up•cGMP scale-up•Pre-formulation

•API supply•Scale-up•Stability trials•Formulation•Patient access•Clinical trials (I-IV)•Drug product

•NDA filing•Approval•Launch•Manufacturing

Discovery PreClinical Clinical Approval

Harvard NeuroDiscovery Center

What to outsource?

> Outsourcing is a HUGE industry, est. $7-8 billion market.

> Every segment of the drug discovery process can be outsourced.

> What are your core competencies?

> What resources do you have?

> Gold standards– HERG channel activity = Chantest

– Preclinical toxicity studies

– GLP studies

– GMP studies

Harvard NeuroDiscovery Center

Academic Resources

> More than 72 Screening centers around the world!– You can find a directory here: http://www.slas.org/screeningFacilities/facilityList.cfm

> Medicinal chemistry centers– Sometimes paired with screening centers– New Directory http://www.slas.org/mcFacilities/facilityList.cfm

> In vivo Pharmacology– Pharmacy schools

> Animal models– Foundations for specific disease area

• e.g. MJ Fox Foundation, ADDF, Families of SMA– Psychogenics– JSW Research– SRI– Academic labs

> GMP Synthesis

Harvard NeuroDiscovery Center

Internet Resources

> Equipment– LabAutopedia

• Topics related to automation, tools and technologies• http://www.labautopedia.com/mw/index.php/Main_Page

– LabMan blog• http://www.slas.org/blog/index.cfm

> Assay technologies– Assay Guidance Manual

• http://spotlite.nih.gov/assay/index.php/Table_of_Contents

> Web courses and forums– Society for Laboratory Automation and Screening (SLAS)

• Webinars, short courses– AAAS

• webinars– Discussion groups (LinkedIn, Facebook, YouTube)

> Local State Biotechnology Council– e.g. MBC sponsors regular programs

Harvard NeuroDiscovery Center

LabAutopedia

> Automation– HTS

– Genomics

> Tools and Technologies

> Data collection and processing

> Conference posters

> Science books

04/08/23

http://www.labautopedia.com/mw/index.php/Portal:Contents

Harvard NeuroDiscovery Center

Assay Guidance Manual

> All types of assays

> Details on strengths and weaknesses

> Options for target types

04/08/23

http://spotlite.nih.gov/assay/index.php/Table_of_Contents

Harvard NeuroDiscovery Center

Example: Harvard ICCB-LongwoodInstitute of Chemistry and Cell Biology

> Core facility for investigator initiated screening

> Mainly for Harvard community

> Small molecules and RNAi libraries

> Collaborators perform their own assay development, perform their own assays, provide all reagents including plates

> Staff maintain and run robotics

> Recharge costs

> Take your compounds with you

> Simple IP

Harvard NeuroDiscovery Center

Model at LDDN: Collaborative Interactions Drive Discovery

> For general academic community

> Small molecule libraries skewed with properties more “drug-like” and likely BBB penetrable (size,PSA, LogP, Lipinski guidelines)

> LDDN or post-doc develops assay and LDDN runs automation

> LDDN provides medicinal chemistry

> Joint grant submission

> Joint IP/ownership

> Joint licensing

LDDN Staff (12)

Collaborating Lab

Harvard NeuroDiscovery Center

Types of Contract Research Organizations

> Fully integrated CRO vs. specialist– Big-box (one-stop-shop) vs. boutique

– Covance, Ricerca

– Cyprotex, Absorption Systems, Wolfe Labs, AMRI

> Location US, Europe, India, China

> High, medium, low cost vendors

> The staff – ratio of PhD-to-MS/BS techs, & years experience– Most important is that they have experience

relevant to your project

– Take advantage of their experience

Harvard NeuroDiscovery Center

Types of CRO Models

> FFS (Fee For Service) – Client drives the science– Competitive RFQs (request for quote)– Protocols worked out or easier chemistry– Intermediates,monomers, templates– Per compound rate

> FTE (Full Time Equivalent) – Client drives the science– With trusted partners– Difficult or speculative chemistry– Reference compounds– Large queues at low cost CROs– Do you have enough work for FTE rate?

> Collaborations – CRO helps drive part or all of the science– May be FTE based– May include risk sharing

> Reduced fee> Equity> Milestone payments

Harvard NeuroDiscovery Center

What LDDN Outsources

> Protein purification (e.g. Blue Sky)

> In vitro ADME (e.g. Cyprotex)– Microsomal stability

– solubility

> Pharmacokinetics (e.g. Absorption Systems)

> Profiling – Kinome (e.g. Carna Biosciences, Nanosyn)

– Side effect profiling (e.g. MDS Pharma, Cerep, Caliper)

– mechanism

> Supplemental chemistry (e.g. Aberjona)

> In vivo efficacy models– Academic labs

Harvard NeuroDiscovery Center

Recommendations

> Develop a list of CROs with overlapping capabilities> Give a small pilot project to a CRO before more commitment.

– Some go as far as sending the same project to more than one CRO.

> Make sure you get updates> Make sure you get reports that are satisfactory and you have

agreed ahead of time on what these reports will look like.– Contain supporting documentation– Contain raw values

> Confidentiality agreements are standard– Is the CRO covered by US/WTO patent laws?– Proprietary process and product needs to be defined

> Establish a relationship with CROs

Harvard NeuroDiscovery Center

04/08/23

Equipment/Technology Partnerships

> What academics can offer vendors– As a central facility, many scientists gain exposure to the

instrument and technology– Act as a “Demo” site– Novel applications– Collaborations– Data sharing (no proprietary targets, no long approval process)– Publications

> What vendors can offer academics– Price discounts– Collaborations– Access to new technology early

Harvard NeuroDiscovery Center

Summary

> Lots of resources out there!

> Use resources that are outside of your expertise

> Talk with others for recommendations

> Try a pilot project with a new outsourcing partner

> Establish a relationship

> Make sure you discuss what your expectations are

Thank YOU, for your attention!

A Drug Discovery Services Perspective on Academic Collaborations

6th Drug Discovery For Neurodegeneration Conference: An Intensive Course on Translating Research into Drugs

February 12-14, 2012

Bruce Molino, Ph.D.Senior Director, AMRI Medicinal Chemistry

As a global leader in drug discovery, AMRI provides valuable contract discovery, development, and manufacturing services to advance our clients’ goals.

AMRI advantages include:

• Comprehensive in vitro biology, in vitro ADMET and chemistry capability from lead generation to advanced development to manufacturing

• Substantial capacity located at multiple facilities throughout the world • Integrated services providing a seamless product to the client• Cost effective outsourcing solutions with flexible business models

AMRI Global Integrated Drug Discovery, Development & Manufacturing Services

Overview

•What are the R&D outsourcing needs of Academic laboratories?

•What Drug Discovery Services are available from CROs?

•How do you identify the best CRO to meet your needs?

•Outsourcing cost?

Role of US Academia in Drug Discovery• “Academic institutions and their investigators traditionally play a key role in identifying

novel potential targets but do not participate in later stages of the drug discovery process”

• Survey of ~80 academic drug discovery centers indicated that on average 49% of targets being investigated are based on unique discoveries that had little validation in the literature

• “Drug companies cannot afford the risk of investing on a novel approach without strong validation that the new approach is viable”

• Need to do a better job of translation of these early innovations to the proof of concept and into human clinical trials

P. Jeffrey Conn, “Translation of Research Across Disciplines to Impact Patient Care” Vanderbilt Center for Neuroscience Drug Discovery, http://www.vcndd.com/presentations/

S. Frye, M. Crosby, T. Edwards, R. Juliano Nature Rev Drug Discov. 10, 409, 2011

Albany, NY (August 18, 2011) – AMRI (NASDAQ: AMRI) today announced it received a federal contract award from the National Institutes of Health (NIH) / National Institute of Neurological Disorders and Stroke (NINDS) to provide chemistry and other drug discovery technologies in support of NINDS Medicinal Chemistry for Neurotherapeutics Program (MCNP), part of the NIH Blueprint Neurotherapeutics Network. AMRI has been collaborating with NINDS since 2005 on novel treatments for spinal muscular atrophy, a degenerative neuromuscular disease.

CROs work with Non-Profits & Government Agencies to ‘Bridge the Gap’

Areas that AD can Benefit from Outsourcing

Many academic programs are in early stages of Drug Discovery,Hit Generation

• Validated ‘Hits’ identified from biological screening

Lead Generation

• Progress through ‘Hit-to-Lead’ stage to Lead Compound Series

Lead Optimization

• Progress Lead Series to Pre-Clinical Development Candidate

and seek to translate innovative approaches to useful therapies.

Prerequisites•Target-based or phenotypic-based screen•Validated screening assay•Screening strategy – assay format/compounds for testing

Hit Generation/Exploratory

Output/Goal of this stage:•Hit finding•Hit validation•Hit selection•Determine which screening hits have the best chance of becoming a Lead Chemical Series

Hit Validation – Important ConsiderationsPay attention to the basics in hit validation•Confirm bioassay results•Low cytotoxicity•Confirm integrity of test compounds, purity, chemical structure•CADD – similarity searches, cheminformatic clustering, virtual screening, SBDD docking studies/pharmacophore model/virtual screen•Apply relevant filters – MW, clogP, tPSA, HBD, HBA, solubility•Identify frequent hitters, compounds with reactive functionality

Hit Selection•Emerging S.A.R. from structurally similar analogues•Cellular proof-of-concept – functional activity•Freedom to operate in chemical space•Synthetic feasibility •DMPK properties

Artwork

What can be outsourced?

In Vitro Biology Services