Product Development-Focused Translational Research at the University of Kansas. Scott J. Weir, PharmD, PhD Overland Park, KS 19 October 2012

Transcription

1 Product Development-Focused Translational Research at the University of Kansas Scott J. Weir, PharmD, PhD Overland Park, KS 19 October 2012

2 The New Role of Academia in Drug Discovery and Development

3 Changing Environment for Academia Pharma Industry Undergoing Dramatic Transformation Loss of patent protection for up to $250b (~28%) of current sales by 2015 vs Pricing pressures and increasing focus on comparative effectiveness resulting in reduced product profitability Research productivity is declining and not sustaining sales levels R&D spending declined in 2008 and 2009, for the first time ever as a consequence of declining sales Pharma adopting new approaches to R&D including substantially increased outsourcing of drug discovery and early drug development to academic institutions

4 Changing Environment for Academia Both Pfizer and Merck Expect to Obtain 20-30% of Development Candidates Through Academic Collaborations Emerging model Current model Academic drug discovery centers Major multi-project academicpharma collaborations Academic project consortia Later stage development Partnerships in clinical proof of concept Funded intermediaries, e.g., Biopontis Past pharma-academic model Unrestricted grants Fee-for-service Technology/early product stage licensing

5 Changing Environment for Academia Changes at NIH Supportive of IAMI s Efforts NCATS provides our nation with an opportunity to forge a new paradigm for translational research that involves government, academia, industry, philanthropy, and patient advocacy groups. Through partnerships that capitalize upon our respective strengths, I believe we can work together to achieve our common goal: speeding the movement of scientific discoveries from the lab to patients. F. Collins, 12/23/2011 NIH-FDA Leadership Council to explore strategies and drive progress in regulatory science Therapeutics for Rare and Neglected Diseases (TRND) Program» RAID Program Bridges» Funding early drug development for rare and neglected diseases» TRND Pilot projects» TRND SBIR program to be launched in 2013 Drug Repurposing of Approved and Abandoned Drugs» NIH-Industry Roundtable April 21-22, 2011» Drug Rescue RFA - ~60 abandoned drugs provided by pharma CTSA 2.0 Establish the consortium as a world class environment for high quality, multi-site clinical and translational science

6 Changing Environment for Academia Changes in Disease Philanthropy Organizations Create an Opportunity for Innovative Partnerships Increasingly important source of academic research support for discovery and early development Historically took POC fund approach and provided grants to academic investigators like the NIH» No active management of funded projects» Large number of grants» Limited cross-fertilization of projects» Disappointing results led to re-evaluation of the model Leading funds have shifted funding to institutional investment model» Larger investments possibly including IP assets» Staff includes industry experienced development and project management professionals to actively manage projects» Fund to milestones as defined by development plan Continue/discontinue funding decisions based on results» Obtain success-based returns to supplement philanthropic contributions The Learning Collaborative is an example of the creative approach of IAMI to access philanthropic funding and to structure partnerships to increase patient impact

7 Changing Environment for Academia July 6, 2010 FOCR Town Hall Meeting The New Role of Academia in Drug Discovery and Development New Thinking, New Competencies, New Results HHS Secretary Sebelius presented as keynote speaker Panel discussion with NIH Director Collins and FDA Commissioner Hamburg moderated by Richard Gephart Four panels representing academia, government, industry and disease philanthropy Held at Kauffman Foundation

8 Our Strategy

9 Our Strategy Cancer Center Vision circa 2005 Excel in the discovery and advancement of new cancer therapies to the clinic, Provide state-of-the-art cancer research, prevention and healthcare programs, Enhance care at both the community and national level; and Measurably reduce the burden of cancer in our region. Resulting in The University of Kansas Cancer Center being designated as a NCI Comprehensive Cancer Center Goal established in 2005

10 Our Strategy Opportunities circa 2005 KU School of Pharmacy ranked in top 5 based on NIH funding Significant pieces of drug development capabilities tied to Marion legacy not linked across campus Strength of cancer biology research conducted at the Stowers Institute for Medical Research Strength of Children s Mercy Clinical Pharmacology, also linked to Marion legacy Regional drug development assets linked to Marion legacy Need unique niche capability to support designated Cancer Center approval

11 KU School of Pharmacy Currently ranked #2 based on NIH funding, consistently ranked in top five Dr. Takaru Higuchi» The Father of Physical Pharmacy Dr. Higuchi Dr. Valentino Stella» KU s most successful entrepreneur» NCI Experimental Therapeutics (NExT) Program Dr. Stella National Leadership in Medicinal Chemistry» Dr. Jeffrey Aube National Specialized Chemistry Center ($20M) Center for Chemical Methodologies and Library Development ($20M) Dr. Aube» Center for Cancer Experimental Therapeutics

12 The Institute for Advancing Medical Innovation An Academic Proof of Concept Center Established in January, 2009 $16.1M over 5 years» Largest single grant awarded by Kauffman Foundation» Match provided by KU Endowment Association Supports regional (and KU) translational research priorities» Frontiers» University of Kansas Cancer Center Home to pharmaceutical industry expertise spanning target validation through clinical proof of concept» Focus on drugs and supporting diagnostics» Milestone based investments NOT grants! Investment decisions» Hire subject domain expert consultants» Prepare Investment Memo» Input from IAMI Advisory Board» Final decision by KU upper management Three types of projects» Faculty» IAMI» Partnerships

13 Guiding Vision, Mission & Approach Vision» Change the standard of care for patients suffering from cancer, neurologic, rare and neglected diseases Mission» Discover and develop drug products and companion diagnostics with a clear path to market

14 Guiding Vision, Mission & Approach Approach to Achieve Function as sustainable translational research engine for the Kansas City region Develop innovative T1 translational research projects and programs with a clear path to market Define and execute project plans that enhance the probability of success and increase the value of licensing transactions Partner with industry, academia, government, and disease philanthropy collaborators to fully leverage the strengths and capabilities of each partner, and accelerate new treatments to patients Maintain therapeutic focus, while opportunistically pursuing other product and therapeutic areas when strategic

15 Organizational Structure Proposed Organization Proposed Positions P. Terranova (KUMC) S. Warren (KUL) (Vice Chancellors for Research) S. Carani KU Endowment * S. Weir Director, IAMI External Advisory Board R. Stein Deputy, Drug Discovery TBN Chief Operating Officer M. Baltezor Deputy, Drug Delivery M. Hughes Director, OPPM L. Yeager Administration M. Koenig KUCTC * R. Wood Project Director M. Broward Project Director TBN Entrepreneur-In- Residence External Consultants K. Meyer SOM Finance * L. Hoebelheinrich KUMC General Counsel * C. Janovy Communications * T. Bruns Project Director K. Schorno Project Director COO will manage operational based collaborations with key university functions

16 The Institute for Advancing Medical Innovation Strategic Challenge: Aligning IAMI s Academic and Commercial Missions Product development focused translational research to sustainably spur regional innovation Regional Growth Academic Research Mission Entrepreneurial /Commercial Mission Sustainability

17 KU Drug Discovery and Development Strategy Two-Pronged Strategy Discovery and development of new drugs Repurposing approved and abandoned drugs Particular focus on rare and neglected diseases Drug discovery and development are key differentiators for CTSA Cancer Center seeking NCI designation Established industry best practices including project and program management Leverage strengths Top five ranked School of Pharmacy (i.e., medicinal and pharmaceutical chemistry) Translational research competencies and capabilities Regional contract drug development assets Established high performance public-private partnerships to bridge the valley of death

18 KU Drug Discovery and Development Strategy Biology Target Validation Generate Leads Optimize Leads Clinical Enabling Activities Clinical Proof of Concept Target Assay Development HTS Combinatorial Chemistry Probe Development Chemical Lead Development In Vitro eadmet Preclinical Formulation In Vivo DMPK API Synthesis Off-Target Pharmacology In Vivo non-glp Toxicology GMP API Synthesis GLP Toxicology GLP Safety Pharmacology GMP Clinical Formulation Protein (Vaccine) Characterization Stabilization Formulation In Vitro Drug Metabolism KU Clinical Research Center Early Stage Clinical Trials Investigator-Initiated Phase I Safety, DT, PK Clinical Proof of Concept PK/PD and BA Clinical PK/PD Analysis Pharmacogenomics Biostatistics and Data Management Regulatory Science Project and Program Management KU External Partners

19 Our Collaborators

20 Empowered Teams Define Project Plans

21 Project and Portfolio Management Project Progression Requires Greater Capacity Biology Drug Discovery Animal Efficacy Clinical Proof of Concept Drug Development Registration and Launch Earliest Exit OPPM FTE Demand Latest Exit Increased management of multidisciplinary project activities across organizations

22 Product Investment Strategy Integrated Product Development and Commercialization Process Invest. Memo Based on Target Product Profile (4) IAMI Advisory Board Review (5) Identify Opportunity (1) Domain Expert Assessment (3) Technical Feasibility and Creation of IP (2) Value Proposition, Assessment & Reassessment Investigator Agreement (6) KUCTC Markets Technology (9) KUCTC Licenses Technology (10) Results Versus Target Product Profile (8) Product Development- Focused Translational Research to De-Risk (7)

23 Product Investment Strategy Integrated Product Development and Commercialization Process (1) Identify opportunity resulting from federally or philanthropically funded project and/or unmet medical need (2) Initial Go/No Go decision based on evaluation of technical feasibility (e.g., target validation, formulation prototype) (3) Assessment by external domain expert consultant(s) and industry contacts (4) Investment Memo based on potential to address unmet need in target patients (5) IAMI Advisory Board review of investment opportunity and input (6) IAMI investment agreement established with KU faculty and staff to define development plan, budget, criteria for success, and deliverables (7) IAMI investment (money, expertise, project management) supporting product development-focused translational research to de-risk (8) Comparison of results to pre-defined criteria and Target Product Profile (9) Candidate marketed by KUCTC (10) License negotiated and executed by KUCTC

24 Product Investment Strategy Differing Development Paths $250,000 Novel Drugs Biology Drug Discovery Animal Efficacy Clinical Proof of Concept Drug Development Registration and Launch CBI IAMI Commercial Partner Repurposed Drugs $250,000 $2,000,000 Biology Drug Discovery Animal Efficacy Clinical Proof of Concept Drug Development Registration and Launch IAMI External Partners Commercial Partner

25 Drug Discovery and Drug Repurposing

26 Managing the Chemistry Biology Interface Biology to Target Assay Cancer Biology Target Validation Generate Leads HTS Assay Development Stein Dedicated laboratory Philanthropic support to create and advance cancer projects Reduce cycle time from target to probe HTS Assay Validation, Cassette, Full Library FDA approved drugs routinely screened R01, RO3, R21 support Leveraging Cancer Center Pilot Funding COBRE funding biology-chemistry interface CTSA Cancer Center

27 Managing the Chemistry Biology Interface Biology Drug Targets Medicinal Chemistry Dr. Aubé KU recognized as a leader in chemical biology Extremely rare capability found in academia Two NIH-funded national centers in chemical biology led by Dr. Jeff Aube Significant contribution to #2 ranking of School of Pharmacy $40M in NIH funding Home to pharmaceutical industry veterans from GSK, Pfizer and Amgen Most productive center within NIH network Leadership role within new NIH, NCATS Excel in high impact, high visibility national level collaborations

28 Drug Repurposing

29 Drug Repurposing news release For immediate release Contacts: LLS: Andrea Greif, (914) , KU: Erica Brown, (913) , The Leukemia & Lymphoma Society and The University of Kansas Cancer Center Advance Novel Drug to Clinic in 13 Months White Plains, NY And Kansas City, KS In only 13 months, a team of researchers and drug developers at The University of Kansas Cancer Center, Ontario Cancer Institute, The Leukemia & Lymphoma Society (LLS), and Beckloff Associates Inc. have advanced a promising new therapy for leukemia into a Phase I clinical trial.

30 Drug Repurposing 30 Repurposing Ciclopirox Olamine 13 Months $1.5M First clinical trial in relapsed and refractory acute myeloid leukemia patients First trial approved by Health Canada (Canadian FDA ) Capitalized on existing data generated by innovator company 29 patients have received ciclopirox olamine to date Discovery licensed to biotechnology company

31 Public-Private Partnerships

32 Public-Private Partnerships Blood Cancers: a Broad Spectrum of Diseases With Diverse Outcomes Comparison of Diseases by Survival Rate, Age of Onset & Incidence AML MM NHL CLL CML Average Age of Onset Incidence 58,000 MDS HL MPD 4,300 ALL SEER database, scientific literature Median 5-year Survival Rate 32

33 * 3-yr overall survival reported Public-Private Partnerships Alignment of Research Spend with Disease Severity & Incidence Lower Need Less Spend Needed Higher Need More Spend Needed

34 Public-Private Partnerships Discovering and developing drugs for the treatment of rare hematological malignancies Bench to bedside translation in drug repurposing National leadership in medicinal and pharmaceutical chemistry Pharma experience The Learning Collaborative Focus on rare and neglected diseases Industrial scale HTS, medicinal chemistry, and bioinformatics capabilities Pharma experience ~ 400 active research projects World-wide network of blood cancer experts Track record of commercial partnerships Pharma experience

35 The Learning Collaborative NIH TRND Pilot Project Management Committee Austin (NIH) DeGennaro (LLS) Weir (KU-IAMI) AML Auranofin Leflunomide Drug Discovery Systematic HTS Screen of the NPC Collection in Difficult to Treat and genetically engineered AML cell lines Drug Repurposing for Rare Blood Cancers Multiple Myeloma Targeting Novel Blood Cancer Pathway 3

36 Public-Private Partnerships Translational Research Strategy Basic Research Drug Discovery Drug Discovery Early Stage Development Late Stage Development FDA Approval The Valley of Death The Learning Collaborative Industry Partner The Bridge of Life Bridging the valley: Multi-disciplinary, multi-organizational teams Translational research best practices Seek and engage industry partners Advance new therapies to patients 36

37 Public-Private Partnerships Fast into Patients Ridaura (Auranofin) 11/5/2010 Auranofin Selected as First TLC Project 3/22/2011 Cooperative Research and Development Agreement Signed 8/5/2011 Clearance from FDA to Proceed to Clinical Proof of Concept in CLL 10/7/2011 First CLL Patient Dosed with Auranofin 37

38 Public-Private Partnerships Repurposing Auranofin % increase in ROS Auranofin Effects demonstrated in: Primary Inhibits thioredoxin and del17p CLL reductase cells and increases reactive oxygen species CLL Increases patient lethal cells ER treated stress ex vivo CLL Induces patient apoptosis cells on drug treatment Human Induces Mantle misfolded Cell protein Lymphoma response cells % decrease in TRR activity Drug Repurposing Primary CD19+ CLL cells nm, AF NRF2 HMOX1 ZAP70 c-raf HDAC6 AKT β-actin Funding Source: NIH-TRND RFP S11-229, LLS Drug Development Grant #472, Philanthropy Shared Resource Usage: Lead Development & Optimization, Biospecimen, Biostatistics & Informatics, and Clinical Trials Management Cancer Center Member Collaborators: Aljitawi (CB), Bhalla, Godwin, Kambhampati, & Weir (all D3ET)

39 Benchmarking

40 Initiated in 2009 Nanotax Phase I Trial in Peritoneal Cancers SR Phase 0 Trial Ciclopirox Olamine Phase I Trial in AML Initiated in 2010 Captisol-Enabled Melphalan Phase IIa Trial in BMT Initiated in 2011 Benchmarking Achieving Bench-to-Bedside Translation Oral Pediatric Anticancer Drug PK/PG Trial Auranofin Clinical POC Trial in CLL Oral Pediatric Cardiorenal Drug Pivotal Bioavailability Trial (Conducted at CRO) Oral Pediatric Drug in Sickle Cell Anemia (Conducted through the Pediatric Trial Network) IV Tigecycline Phase I Trial in AML Planned for 2012 Oral Pediatric Anticancer Drug Pivotal Bioavailability Trial Repurposed Drug Clinical POC Trial in Rare Blood Cancer Repurposed Drug Clinical POC Trial in Sarcoma

41 Stevens et al 1» 125 medical schools studied» Study spans 40 years» Medical school research conducted led to registration of 153 drug products» Forty of the 153 drug products were hematology and oncology products University of Kansas Benchmarking» Eight hematology and oncology products advanced to clinical trials over » An additional two drug products entering clinical trials in NEJM (6):

42 Public-Private Partnerships

43 Next?

44 Next The Sarcoma Learning Collaborative Replicating the TLC model! Sarcomas Two-pronged strategy Discovery of novel drugs Drug repurposing Innovative clinical proof of concept trials Children, adolescents and adults Pediatric Oncology Experimental Therapeutics Investigators Consortium (POETIC) Funding to date NIH CTSA Supplement $500K, Drug Repurposing for GIST Philanthropic gift $250K, Ewing s Sarcoma Potential to leverage MCA Partners Advisory Board funding Neville Perez ) Godwin Leeder Iwakuma Stein Weir Baltezor

45 Acknowledgements

46 Investors In Our Program Acknowledgements The University of Kansas The University of Kansas Medical Center The University of Kansas Endowment Association The University of Kansas Cancer Center The Ewing Marion Kauffman Foundation Kansas Bioscience Authority Many Private Donors

47 Acknowledgements The IAMI Team Michael Baltezor, PhD Melinda Broward, MSc Tyce Bruns, MSc Michael Hughes, MBA Kevin Schorno, MBA Ross Stein, PhD Scott Weir, PharmD, PhD Robyn Wood, BGS Laura Yeager, BS

48 External Advisory Board Christopher Austin, MD Steven Averbuch, MD Anand Burman, PhD John Fisher, MD Lesa Mitchell, MBA Michael Powell, PhD Michael Webb, MBA Joy Wheeler, MPA Tom Wiggans, MBA Adjunct Faculty Anthony Barnes, PhD, MBA Michael Beckloff, BSc Kenneth Lynn, JD, MBA Karl Strohmeier, MSc, RPh Acknowledgements