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Drug Development Outside the Academic Environment

Drug Development Outside the Academic Environment. Vernon Rowe, M.D. CEO, Rowe Neurology Institute Adjunct Professor of Neurology, KUMC. Conflicts of Interest . CEO Verrow Pharmaceuticals, Inc. Board Member, Capiod. Steps in Drug Development. Discovery

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Drug Development Outside the Academic Environment

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  1. Drug Development Outside the Academic Environment Vernon Rowe, M.D. CEO, Rowe Neurology Institute Adjunct Professor of Neurology, KUMC

  2. Conflicts of Interest CEO Verrow Pharmaceuticals, Inc. Board Member, Capiod

  3. Steps in Drug Development Discovery Protection of Intellectual Property—Patents, an Art Form Role of the FDA Preclinical development Clinical Development—Phase 1 safety, Phase 2 dose-finding, Phase 3 efficacy, NDA, Launch

  4. Site of Discovery Pharma—In House Discovery or Acquisition Academia Other Role of Angel Investors Role of Venture Capital

  5. Push Technology Scientists Make a Discovery Funding Entity Patents the Discovery Funding Entity Defines Commercialization Pathway In Consultation with FDA

  6. Pull Technology Clinicians identify a need Scientists Find a Solution Clinicians Test the Solution Physician Scientists—a Dying Breed

  7. Rowe Neurology Institute 8550 Marshall Drive Suite 100

  8. RNI TRIAD

  9. Back To The Future • Successes of the early years of the NIH inspired MANI as an experiment to more closely tie the bench to the bedside CLINIC LAB

  10. Consultants in Neurology, PA Headache Center Sleep Center MS Center Memory Loss Center

  11. Headache Center Physical Therapy Find the underlying cause of headache Infusion center keeps acute migraine patients out of costly ER

  12. Accredited Sleep Disorders Center John Hunter Cord Huston

  13. Multiple Sclerosis Center Accurate Diagnosis Follow each patient carefully Treat the whole patient Don’t blame everything on MS OCT

  14. MidAmerica Neuroscience Research Foundation- 501 (c)3 Basic Research Clinical Research

  15. Basic Research

  16. Clinical Research

  17. Methotrexate: A New Old Treatment For Multiple Sclerosis High Dose IV Methotrexate By Itself Helps MS ButKidney Toxicity Is a major Problem 1. Cohen JA, et.al. Neurology. Sep 10 2002;59(5):679-87.

  18. SCD reformulations shepherd toxic drugs through the kidney SCD and Drug in Bloodstream SCD and Drug safely exit through kidney SCD and Drug in Vial Dilution Concentration

  19. We Make Drugs Safer Confidential

  20. The Product Iohexol-SBECD

  21. Iohexol-Captisol:Preventing Contrast-Induced Acute Kidney Injury A safer contrast agent has been a "holy grail" for decades

  22. Contrast-Induced Acute Kidney Injury • The most commonly used definition (of AKI) … is a rise in serum creatinine of 0.5mg/dl or a 25% increase from the baseline value, assessed at 48h after the procedure • A series of ten consensus statements provide the important principles describing the occurrence of contrast-induced acute kidney injury (attached) • Contrast-induced acute kidney injury is synonymous with contrast-induced nephropathy (CIN) Contrast-Induced Nephropathy (CIN) Consensus Working Panel as referenced by McCullough PA. Contrast-Induced Acute Kidney Injury. J Am CollCardiol 2008; 51:1419-28

  23. Incidence of Contrast-InducedAcute Kidney Injury • Published incidence of contrast-induced AKI ranges from 5-50% depending on definition of AKI used, time course of assessing renal function and risk profile of patient • Most comprehensive study using Mehran scoring assessment shows baseline incidence of 7% in lowest risk patients (Mehran et al, 2004 – see next slide for data) • In population undergoing vascular imaging, incidence of AKI may be significantly higher because of underlying patient risk factors • Vascular imaging represents up to 90% of current use of injectable iodinated contrast agents as evidenced by usage of high dose (>300mg/ml) iodine products

  24. Cost Impact of Contrast-InducedAcute Kidney Injury • Average additional cost* estimated to be: • $10,345 for hospital stay • $11,812 for costs through 1 year • Incremental cost impact of (AKI) estimated to be $1000 per PCI procedure • Due to the frequency of imaging procedures and the complication rate of contrast-induced acute kidney injury, Centers for Medicare and Medicaid Services are evaluating this as a hospital-acquired condition for which it will adjust reimbursement to improve outcomes * Subramanian S, Tumlin J, Bapat B, et al. Economic burden of contrast-induced nephropathy: implications for prevention strategies. J MedEcon 2007;10:119 –34.

  25. The Product Iohexol-SBECD

  26. Cyclodextrins Naturally occurring oligosaccharides containing 6, 7, or 8 glucopyranose units in a donut shape with hydrophobic pocket • Function as solubilizers by including insoluble drug molecule in the pocket • Unsubstituted (natural) cyclodextrins show some toxicity when given IV • Only two specific substituted cyclodextrins have been found safe enough for parenteral administration and are used in FDA approved drug products (hydroxy propyl and sulfobutyl derivatives)

  27. Components of Iohexol-SBECD Product SBECD (CAPTISOL) Iohexol (OMNIPAQUE) • Market leading iodinated contrast agent • Globally available • Marketed by GE Healthcare, Bayer-Schering (EU) and Daiichi- Sankyo (Japan) • Available as generic outside US where primary manufacturer is Hovione • Used as a solubilizing agent in multiple approved products • Safety well established with DMF referencable by FDA • Observed to protect kidney from renal tubular adverse effects of multiple compounds (e.g. methotrexate, gentamicin, doxorubicin, cisplatin, iohexol) • Primary manufacturer Hovione

  28. Iohexol-SBECD • Combining iohexol with SBECD would create a new imaging agent rather than a new treatment to be used in conjunction with existing imaging agents • Leverages the knowledge base and Drug Master File of SBECD using a 505(b)(2) regulatory filing strategy • Management team has extensive experience of working with SBECD in nonclinical, clinical, regulatory and CMC settings

  29. Nonclinical Data

  30. Contrast-Induced Acute Kidney Injury Model A multiple-insult rodent model has been used to evaluate the nephroprotective activity of the Iohexol-SBECD formulation 1 Agmon, et al, “Nitric Oxide and Prostanoids Protect the Renal Outer Medulla from Radiocontrast Toxicity in the Rat”, J Clin Invest, (1994) 94:1069-1075. 2 Heyman, et al, (2010) In-Vivo Models of Acute Kidney Injury”, Drug Discovery Today-Disease Models 7(1-2): 51-56.

  31. Veropaque Blocks Kidney Damage in Mouse Model B A Tubular dilatation, degeneration, and cast formation 48 hours after 1.5 gI/kg iohexol administration Absence of renal pathology 48 hours after 1.5 gI/kg Veropaque administration

  32. SBECD decreases renal pathology in the mouse and rat

  33. SBECD decreases plasma creatinine in the mouse and rat

  34. Development Strategy for Iohexol-SBECD

  35. Iohexol-SBECD Development Strategy • Pre-IND guidance received permits start of human clinical studies • Human bioequivalence to iohexol is basis for approval • Use of serum creatinine confirmed in favor of other biomarkers • Other IND requirements confirmed • 505(b)(2) filing approach agreed • Development plan will provide for an NDA submission within 3 years and approval within 4 years

  36. Iohexol-SBECD Regulatory Strategy • Achieve NDA approval using 505(b)(2) pathway • Seek patent term restoration based on time in development and time under NDA review • Apply to list all relevant patents in Orange Book • File Citizens Petition to withdraw iohexol on the basis that iohexol-SBECD is safer

  37. Iohexol-SBECD Project Timeline Proof-of-concept exit End Phase III exit Pre-launch exit Development Nonclinical Human proof-of-concept Clinical Safety and Bioequivalence Pivotal Efficacy Regulatory interactions IND CTA NDA Pre NDA NDA Approval EOP2 Meeting Manufacturing Formulation Development Development and clinical trial material Scale Up and NDA registration material Commercialization Assessment US market, customer and payer research Ex-US market, customer and payer research Launch Exit Readiness Partner Identification Assessment Partnering outreach 2013 2014 2015 2016 2017 2018 Period of initial focus toward earliest exit

  38. High-dose Iodinated X-ray Imaging Agents:2012 US Market Data High dose agents defined as those >300mg iodine/ml Source: IMS Health 2012

  39. Patent Protection To At Least 2028 • Patents filed in US, EU, and other ROW markets • Patents issued in US, Mexico, and New Zealand • US patent 8,277,779 (Iohexol-SBECD) • Compositions and methods • Issued October 2, 2012 • Expiry date January 27, 2028 • Opportunity for patent-term restoration • US patent 7,658,913 (Iohexol-Hydroxypropyl-β-cyclodextrin) • Compositions and methods • Issued February 9, 2010 • Expiry date May 25, 2027 • Opportunity for patent-term restoration

  40. Summary Evaluation for Iohexol-SBECD for Preventing Contrast-Induced Acute Kidney Injury

  41. MidAmerica Neuroscience Research Foundation Mission: focus on pull research to move patient solutions from bedside to bench to beside

  42. Problem • Remyelination • Normal brain • Oligodendrocyte precursor cells Mature oligodendrocytes new myelin sheath • MS brain • Oligodendrocyte precursor cells Mature oligodendrocytes new myelin sheath • Process is inefficient or nonexistent

  43. Remyelination Problem • What’s the fix? • Introduce mature oligodendrocytes to demyelinated sites • Stimulate oligodendrocytes already present into creating myelin

  44. Remyelination Problem • What’s the fix? • Introduce mature oligodendrocytes to demyelinated sites • Stimulate oligodendrocytes already present into creating myelin

  45. Stimulate oligodendrocytes already present into creating myelin • One of the Holy Grails of MS research • Can look at know pathways for myelin production • Use drug screens to seen if anything activates those pathways • Identify a novel drug target

  46. Stimulate oligodendrocytes already present into creating myelin • One of the Holy Grails of MS research • Can look at know pathways for myelin production • Use drug screens to seen if anything activates those pathways • Identify a novel drug target

  47. Identify a novel drug target • What protein, when it’s gene is knocked out, leads to decreased myelination? • What protein is putatively involved in the oligodendrocyte maturation process? • What protein is up-regulated by vitamin D? Klotho

  48. Klotho Huang, Chou-Long. Regulation of ion channels by secreted Klotho: mechanisms and implications. Kidney International (2010) 77, 855-860.

  49. Klotho Huang, Chou-Long. Regulation of ion channels by secreted Klotho: mechanisms and implications. Kidney International (2010) 77, 855-860.

  50. Klotho and Myelination • Lab of Dr. Carmela Abraham at Boston University School of Medicine • Treated OPCs with Klotho • Klotho enhanced their maturation • Activated AKT and Erk1/2 signaling pathways possibly through FGFR • Klotho treatment also increased myelin protein production Chen, Ci-Di et. Al. The antiaging protein klotho enhances oligodendrocyte maturation and myelination of the CNS. The Journal of Neuroscience. 2013. 33(5):1927-1939

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