City of Hope LR-90 Team Masters Project Keck Graduate Institute - - PowerPoint PPT Presentation

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City of Hope LR-90 Team Masters Project Keck Graduate Institute - - PowerPoint PPT Presentation

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City of Hope LR-90 Team Masters Project Keck Graduate Institute for Applied Life Sciences Matthew Avila James Hasegawa Janice Lee Kyle Mak 5/2/2012 Agenda Team Masters Project Deliverables LR-90 Background Diabetes Market

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SLIDE 1

City of Hope LR-90 Team Masters Project

Keck Graduate Institute for Applied Life Sciences

Matthew Avila James Hasegawa Janice Lee Kyle Mak 5/2/2012

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SLIDE 2
  • Team Master’s Project Deliverables
  • LR-90 Background
  • Diabetes Market

▫ Diabetic Therapies ▫ Development of AGE Inhibitors

  • LR-90 Work to Date
  • Drug Development
  • Scenarios for LR-90 Program
  • Conclusions
  • Acknowledgements

Agenda

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SLIDE 3
  • Team Master’s Project Deliverables
  • LR-90 Background
  • Diabetes Market

▫ Diabetic Therapies ▫ Development of AGE Inhibitors

  • LR-90 Work to Date
  • Drug Development
  • Scenarios for LR-90 Program
  • Conclusions
  • Acknowledgements

Agenda

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SLIDE 4

Team Master’s Project Deliverables

Objective: Identify route for LR-90 commercialization

Semester 1

  • US Diabetes Market analysis
  • Evaluation of AGE inhibitors (Nephropathy)
  • Recommendations for minimal pre-clinical

work to be done

Semester 2

  • Understand implications of patent life*
  • Elucidate testing history of LR-90
  • Identify, evaluate options and potential
  • utcomes for LR-90 program

*Note: KGI Team is not qualified to make formal claims about patent life and is not protected by attorney-client privilege.

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SLIDE 5
  • Team Master’s Project Deliverables
  • LR-90 Background
  • Diabetes Market

▫ Diabetic Therapies ▫ Development of AGE Inhibitors

  • LR-90 Work to Date
  • Drug Development
  • Scenarios for LR-90 Program
  • Conclusions
  • Acknowledgements

Agenda

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SLIDE 6

R-N + Glucose R-Glucose (AGE)

  • Protein cross-linking
  • Inflammation
  • Oxidative stress

Complications

  • Nephropathy
  • Neuropathy/

Retinopathy

  • Atherosclerosis

Advanced Glycation End Product (AGE) Overview

Inhibitors Reduction of AGE products can ameliorate diabetic complications

Source: LR-90 TMP Midyear Report

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SLIDE 7
  • Mechanism unclear: likely chelation

▫ (Nagai 2012) Primarily inhibits AGE formation through metal chelating activity ▫ Potent inhibitors of metal-catalyzed ascorbate oxidation ▫ Reduce AGE protein cross linking

  • Results:

▫ Lowers UA/Cr, AGE in serum

 50% reduction in UA/Cr levels  Up to 40% reduction in serum AGE

▫ Inhibits inflammatory pathways

 NOX2 mRNA reduction

▫ Attenuates RAGE mRNA expression ▫ Reduces plasma lipids

  • Potential benefits:

▫ Nephropathy ▫ Neuropathy ▫ Atherosclerosis

LR-90 Background

Methylene bis [4, 4’-(2 chlorophenylureido phenoxyisobutyric acid)]

Anti-inflammatory effects of the advanced glycation end product inhibitor LR-90 in human monocytes. J. L. Figarola, S. Loera, Y. Weng, N. Shanmugam, R. Natarajan, S. Rahbar, Diabetologia. 2008 May; 51(5): 882–891. Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. Nagai R, Murray DB, Metz TO, Baynes JW. Diabetes. 2012 Mar;61(3):549-59. LR-90 a new advanced glycation endproduct inhibitor prevents progression of diabetic nephropathy in streptozotocin-diabetic rats. J. L. Figarola, S. Scott, S. Loera, C. Tessler, P. Chu, L. Weiss, J. Hardy, S. Rahbar, Diabetologia. 2003 August; 46(8): 1140–1152. LR-90 prevents dyslipidaemia and diabetic nephropathy in the Zucker diabetic fatty rat. James L. Figarola, Narkunaraja Shanmugam, Rama Natarajan, Samuel Rahbar, Diabetes. 2007 March; 56(3): 647–655.

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SLIDE 8
  • Team Master’s Project Deliverables
  • LR-90 Background
  • Diabetes Market

▫ Diabetic Therapies ▫ Development of AGE Inhibitors

  • LR-90 Work to Date
  • Drug Development
  • Scenarios for LR-90 Program
  • Conclusions
  • Acknowledgements

Agenda

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SLIDE 9

Diabetes Market

Diabetes Mellitus Statistics (2010) Affected Population 25.8M (8.3% of population) Diagnosed 18.8M Undiagnosed 7.0M Pre-diabetics 79M Type II Diabetics 90-95% of all diabetics

Diabetes Fact Sheet, CDC http://www.cdc.gov/diabetes/statistics

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SLIDE 10

Diabetes Market

Diabetes Fact Sheet, CDC

10 20 30 40 50 60 70 80

Prevalence among Diabetics (%)

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Diabetes Market

Category Cost of Complication Direct costs of treatment $22.9B (in 2006) Annual cost of complications per T2D patient $10,000 (of which $1,600 paid out-of-pocket)

http://harrisschool.uchicago.edu/News/press-releases/media/Diabetes%20Complications%20Report_FINAL.PDF

As incidence of diabetes and its complications rise, there is an increased need for effective treatments for complications.

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SLIDE 12

Injectables:

  • Insulin
  • Symlin
  • Byetta

Small Molecule:

  • Sulfonylureas
  • Biguanides
  • Thiazolidinediones
  • Alpha-glucosidase

Inhibitors

  • Meglitinides
  • Dipeptidyl peptidase 4

inhibitors

Kalorama Information 2010. World Market for Diabetes Treatment http://www.consumerreports.org/health/resources/pdf/best-buy- drugs/diabetes12-10FINAL.pdf

Diabetic Therapies

Glucose Management

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SLIDE 13

Diabetic Therapies

Secondary Complications

Nephropathy:

  • Beta-blocker medications
  • Angiotensin-converting enzyme (ACE)

inhibitors

  • Dialysis

Retinopathy:

  • Focal laser treatment
  • Scatter laser treatment
  • Vitrectomy

Atherosclerosis:

  • Statins
  • Beta-blocker medications
  • Angiotensin-converting enzyme (ACE)

inhibitor

http://www.mayoclinic.com/health/diabetic-retinopathy/DS00447/DSECTION=treatments-and-drugsism http://www.nei.nih.gov/health/diabetic/retinopathy.asp#4a http://www.mayoclinic.com/health/arteriosclerosis-atherosclerosis/DS00525/DSECTION=treatments-and-drugs

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SLIDE 14

Implications of Current Treatments

1) Provide glucose management OR/AND 2) Treat downstream diabetic complications Neither treatment inhibits AGE adequately AGE continues to form, causing downstream diabetic complications

Opportunities exist to add therapeutic value in this market space

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SLIDE 15

Development of AGE Inhibitors

  • Major focus of AGE inhibitor research
  • No FDA approvals – most failed at Phase II
  • Biomarker limitations

Nephropathy

  • Benefits assumed, but no human studies

performed

  • Aldose-reductase inhibitor, AS-3201,

undergoing Phase II clinical trials

Neuropathy/Retinopathy

  • Benefits assumed, but no human studies

performed

  • Statins dominate market – high barrier to

entry

Atherosclerosis

City of Hope TMP Semester 1 Report. 9 December, 2011. CDC Division of Diabetes Translation. (2011). National Diabetes Fact Sheet, 2011. Retrieved 12 04, 2011, from Centers for Disease Control and Prevention: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf Tesfaye, S., & Selvarajah, D. (2012). Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metabolism Research and Reviews , 28 (Suppl 1), 8-24. Tesfaye, S., Vileikyte, L., Rayman, G., Sindrup, S., Perkins, B., Baconja, M., et al. (2011). Painful diabetic peripheral neuropathy: consensus recommendations on diagnosis, assessment and management. Diabetes Metabolism Research and Reviews , 27, 629-638.

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SLIDE 16
  • Team Master’s Project Deliverables
  • LR-90 Background
  • Diabetes Market

▫ Diabetic Therapies ▫ Development of AGE Inhibitors

  • LR-90 Work to Date
  • Drug Development
  • Scenarios for LR-90 Program
  • Conclusions
  • Acknowledgements

Agenda

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SLIDE 17

LR-90 Work to Date

Preclinical Testing

  • Completed Tests
  • PD Parameters
  • Outstanding tests
  • PK Parameters
  • Starting Dose
  • Distribution
  • Toxicity

CMC Testing

  • Completed

requirements

  • None
  • Outstanding

requirements:

  • Stability
  • Characterization
  • Manufacturing

controls

IND Submission

  • Estimated 2 years

for regulatory filings

City of Hope TMP Semester 1 Report. 9 December, 2011. Matsumoto, Catherine. Interview: IND requirements. 8 February, 2012.

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SLIDE 18
  • Team Master’s Project Deliverables
  • LR-90 Background
  • Diabetes Market

▫ Diabetic Therapies ▫ Development of AGE Inhibitors

  • LR-90 Work to Date
  • Drug Development
  • Scenarios for LR-90 Program
  • Conclusions
  • Acknowledgements

Agenda

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SLIDE 19
  • ~15 years from discovery

to FDA approval

  • Diminishing returns on

investment ▫ Patent life ▫ Costs of development

  • $800M  $1B+
  • Average Development

Time (2000-2009): ▫ Endocrine drugs: 7.5 years ▫ GI drugs: 8.2 years

Innovation gap ails the pharmaceutical industry with decreasing returns on R&D spending (Source: Burrill & Company, PhRMA)

Sources: Burrill & Company, 2011; DiMasi et al, 2003; Kaitin & DiMasi, 2011

Drug Development

Overview

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SLIDE 20

Factors

Strength of IP Probability of success/ failure Market

Payment

Up front Milestones Royalties

Determinants

Experimental Success Potential Time

http://www.planetding.org/aboutme/files/license.pdf http://www.wipo.int/sme/en/documents/pharma_licensing.html#P510_29610

Drug Development

Licensing Characteristics

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SLIDE 21
  • Diverse patent portfolio

▫ 30 Patents Filed

  • Patent types

▫ Composition of matter ▫ Method

  • Range of filing dates

▫ Earliest: US 5,268,500

 Filing: October 18th, 1991

▫ Most recent: US 8,124,655

 Filing: June 16th, 2008 LR-90 options contingent upon professional patent life interpretation

Drug Development

LR-90 Patent Portfolio

http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=LR-90&OS=LR-90&RS=LR-90

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SLIDE 22
  • Team Master’s Project Deliverables
  • LR-90 Background
  • Diabetes Market

▫ Diabetic Therapies ▫ Development of AGE Inhibitors

  • LR-90 Work to Date
  • Drug Development
  • Scenarios for LR-90 Program
  • Conclusions
  • Acknowledgements

Agenda

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SLIDE 23

Scenarios for LR-90 Program

Best Case:

  • Develop and

License

Middle Case:

  • Compound

Modification

  • Orphan Drug

Designation

Worst Case:

  • Public-Private

Partnership

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SLIDE 24

Scenarios for LR-90 Program

Best Case:

  • Develop and

License

Middle Case:

  • Compound

Modification

  • Orphan Drug

Designation

Worst Case:

  • Public-Private

Partnership

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SLIDE 25

Best Case

Develop & License

Sources: World Market for Diabetes Treatments, Kalorama Information, Oct. 2010; Email communication, Charles River, 2012; Product, Financial, and Pipeline information on pharma companies’ websites

  • Goal #1: Finish preclinical and CMC, File IND

Selection Criteria Company Benefit for LR-90 Market Share Novo Nordisk Future distribution Pipeline Strength Eli Lilly Commitment to diabetic drug innovation Co-Therapy Approach AstraZeneca Grow with strength of cardiovascular line

Selection Criteria In-House (COH) Outsourcing (CRO) Control +++ + Cost $, $$ (Need Estimate) $$$ ($550k-$700k) Quality ++ Varies (+, +++) Experience + Specialized (+++) Time/Effort Direct coordination Indirect coordination IP Protection +++ Risk varies (+, +++)

  • Goal #2: Seek out licensing partners
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Best Case

Potential Partners with Diabetic Complication Focus

Diabetic Complication Company Pipeline Product Phase Diabetic Nephropathy Sanofi Aventis Rho Kinase Inhibitor I Pfizer PF-03882845 I Eli Lilly Mineralocortocoid receptor antagonist II Transforming Growth Factor  monoclonal antibody II Diabetic Neuropathy Takeda TAK-428 (neurotrophic factor production accelerator) II Diabetic Retinopathy Eli Lilly Arxxant (Ruboxistaurin) NDA Submitted (Terminated)

Sources: Sanofi Aventis, Pfizer, Eli Lilly, Takeda websites

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SLIDE 27

Scenarios for LR-90 Program

Best Case:

  • Develop and

License

Middle Case:

  • Compound

Modification

  • Orphan Drug

Designation

Worst Case:

  • Public-Private

Partnership

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SLIDE 28

Middle Case

  • Goal: Mitigate the risk of impeding patent expiration

Seek Patent Attorney

  • Analyze current

patent portfolio

Identify Options

  • Compound

Modification

Extend Patent Life

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SLIDE 29

Compound Modification

Required Actions

Outcomes

New or derivative compound, with extended patent life, pursue clinical trials No improvements for LR-90

Perform LR-90 Enhancements

Animal model testing comparison vs LR-90

Feasibility Report

Costs Resources Time Benefit/ Risk

Assemble Expertise

COH: Dr. Chris Lincoln/ Dr. David Horne, consultant?

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SLIDE 30

Compound Modification

Case Study Example

Compound modifications are commonly used to extend patent life in the pharmaceutical industry

http://www.amcp.org/data/jmcp/formular_746-754.pdf

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SLIDE 31

Middle Case

Orphan Drug Designation (ODD)

  • LR-90 has an indication for retinopathy/ neuropathy
  • Competitor: Ranirestat currently undergoing Phase II

clinical trials for diabetic retinopathy

Background

  • Segment patient population
  • COH applies for ODD
  • Seek out potential partners

Actions

  • 7 year market exclusivity
  • Office of Orphan Products Development (OOPD)

administers : Two grant programs; funding for clinical research that tests the safety and efficacy

  • Tax incentives; FDA fee waivers

Outcomes

http://clinicaltrials.gov/ct2/show/NCT00927914 http://www.fda.gov/forindustry/developingproductsforrarediseasesconditions/default.htm http://www.ncbi.nlm.nih.gov/pubmed/19087348

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SLIDE 32

Scenarios for LR-90 Program

Best Case:

  • Develop and

License

Middle Case:

  • Compound

Modification

  • Orphan Drug

Designation

Worst Case:

  • Public-Private

Partnership

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SLIDE 33

Worst Case

Public-Private Partnership

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SLIDE 34

Worst Case

Public-Private Partnership: Risks

No first world drug has ever been developed by PPP

Coordination Financing Interests

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SLIDE 35
  • Team Master’s Project Deliverables
  • LR-90 Background
  • Diabetes Market

▫ Diabetic Therapies ▫ Development of AGE Inhibitors

  • LR-90 Work to Date
  • Drug Development
  • Scenarios for LR-90 Program
  • Conclusions
  • Acknowledgements

Agenda

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SLIDE 36

Conclusions

  • LR- 90 is a novel and promising treatment for

diabetic complications

  • Lower dosage (50 mg/kg)
  • Impressive preliminary efficacy studies
  • More potent chelator than competition
  • Growing unmet need for diabetic complications
  • LR-90’s commercialization path contingent on

qualified patent evaluation

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SLIDE 37
  • Team Master’s Project Deliverables
  • LR-90 Background
  • Diabetes Market

▫ Diabetic Therapies ▫ Development of AGE Inhibitors

  • LR-90 Work to Date
  • Drug Development
  • Scenarios for LR-90 Program
  • Conclusions
  • Acknowledgements

Agenda

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SLIDE 38

Acknowledgements

  • We would like to thank the following organizations and single out special

people for their input and expertise as well as support of our project:

  • The Beckman Research Institute of The City of Hope National Medical Center
  • Dr. Samuel Rahbar
  • Dr. James L. Figarola
  • Dr. Art Riggs
  • Matthew Grunseth, MBS 2008
  • Keck Graduate Institute of Applied Life Sciences (KGI)
  • Craig Adams – TMP Faculty Advisor & TMP Program Director
  • Ian Phillips – Secondary Faculty Evaluator, Semester 1
  • Tim Cote, Molly Schmid, & Tina Etcheverry – FDA translational services
  • Mark Ghamsary – Biostatistician
  • Luann Bangsund, Yvonne Klaue, Joel West – KGI Faculty Panel Evaluators, Semester 2
  • Thomas K. Bane – TMP Team Member, Semester 1
  • Key Opinion Leaders
  • Dr. John Baynes, Distinguished Professor Emeritus, University of South Carolina
  • Dr. Alan Miller – Chief of Oncology, Baylor University Medical Center at Dallas (Clinical

Trials)

  • Dr. Rama Natarajan, Professor, Diabetes and Metabolic Diseases Research, City of Hope
  • Dr. Jeffrey Wang, Associate Professor of Pharmaceutical Sciences, Western University of

Health Sciences College of Pharmacy

  • Dr. Jun Wu, Assistant Research Professor, Division of Comparative Medicine, City of Hope
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SLIDE 39

Acknowledgements