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 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 • 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
Team Master’s Project Deliverables Objective: Identify route for LR-90 commercialization Semester 1 Semester 2 • US Diabetes Market analysis • Understand implications of patent life* • Evaluation of AGE inhibitors (Nephropathy) • Elucidate testing history of LR-90 • Recommendations for minimal pre-clinical • Identify, evaluate options and potential work to be done outcomes 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.
Agenda • 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
Advanced Glycation End Product (AGE) Overview Inhibitors R-Glucose (AGE) Complications • Protein cross-linking • Nephropathy R-N + Glucose • Inflammation • Neuropathy/ Retinopathy • Oxidative stress • Atherosclerosis Reduction of AGE products can ameliorate diabetic complications Source: LR-90 TMP Midyear Report
LR-90 Background • 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 Methylene bis [4, 4’ -(2 chlorophenylureido phenoxyisobutyric acid)] • Potential benefits: ▫ Nephropathy ▫ Neuropathy ▫ Atherosclerosis 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.
Agenda • 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
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
Diabetes Market Prevalence among Diabetics (%) 80 70 60 50 40 30 20 10 0 Diabetes Fact Sheet, CDC
Diabetes Market Category Cost of Complication Direct costs of treatment $22.9B (in 2006) Annual cost of complications $10,000 (of which $1,600 per T2D patient paid out-of-pocket) As incidence of diabetes and its complications rise, there is an increased need for effective treatments for complications. http://harrisschool.uchicago.edu/News/press-releases/media/Diabetes%20Complications%20Report_FINAL.PDF
Diabetic Therapies Glucose Management Small Molecule: Injectables: • Sulfonylureas • Insulin Biguanides • • Symlin • Thiazolidinediones • Byetta • 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 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
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
Development of AGE Inhibitors • Major focus of AGE inhibitor research • No FDA approvals – most failed at Phase II Nephropathy • Biomarker limitations • Benefits assumed, but no human studies performed Neuropathy/Retinopathy • Aldose-reductase inhibitor, AS-3201, undergoing Phase II clinical trials • Benefits assumed, but no human studies performed Atherosclerosis • Statins dominate market – high barrier to entry 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.
Agenda • 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
LR-90 Work to Date Preclinical CMC Testing IND Testing Submission • Completed requirements • Completed Tests • Estimated 2 years • None for regulatory • PD Parameters filings • Outstanding • Outstanding tests requirements: • PK Parameters • Stability • Starting Dose • Characterization • Distribution • Manufacturing • Toxicity controls City of Hope TMP Semester 1 Report. 9 December, 2011. Matsumoto, Catherine. Interview: IND requirements. 8 February, 2012.
Agenda • 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
Drug Development Overview • ~15 years from discovery to FDA approval • Diminishing returns on investment ▫ Patent life ▫ Costs of development • $800M $1B+ • Average Development Time (2000-2009): Innovation gap ails the pharmaceutical industry with decreasing returns on R&D spending (Source: Burrill & Company, PhRMA) ▫ Endocrine drugs: 7.5 years ▫ GI drugs: 8.2 years Sources: Burrill & Company, 2011; DiMasi et al, 2003; Kaitin & DiMasi, 2011
Drug Development Licensing Characteristics Probability of Strength of Factors success/ Market IP failure Payment Up front Milestones Royalties Experimental Determinants Potential Time Success http://www.planetding.org/aboutme/files/license.pdf http://www.wipo.int/sme/en/documents/pharma_licensing.html#P510_29610
Drug Development LR-90 Patent Portfolio • Diverse patent portfolio ▫ 30 Patents Filed • Patent types ▫ Composition of matter ▫ Method • Range of filing dates ▫ Earliest: US 5,268,500 Filing: October 18 th , 1991 ▫ Most recent: US 8,124,655 Filing: June 16 th , 2008 LR-90 options contingent upon professional patent life interpretation 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
Agenda • 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
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