1. Vernon Rowe, M.D. CEO, Rowe Neurology Institute Adjunct Professor of Neurology, KUMC

2. CEO Verrow Pharmaceuticals, Inc. Board Member, Capiod

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

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

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

7. 8550 Marshall Drive Suite 100

9. CLINICLAB  Successes of the early years of the NIH inspired MANI as an experiment to more closely tie the bench to the bedside

10. Headache Center Sleep Center MS Center Memory Loss Center

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

12. John Hunter Cord Huston

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

14. Basic Research Clinical Research

17. 1. Cohen JA, et.al. Neurology. Sep 10 2002;59(5):679-87. High Dose IV Methotrexate By Itself Helps MS But Kidney Toxicity Is a major Problem

18. SCD and Drug in Vial

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 21

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 Coll Cardiol 2008; 51:1419-28 22

23. Incidence of Contrast-Induced Acute 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 23

24. Cost Impact of Contrast-Induced Acute 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 Med Econ 2007;10:119 –34. 24

25. The Product Iohexol-SBECD

26. Cyclodextrins 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) Naturally occurring oligosaccharides containing 6, 7, or 8 glucopyranose units in a donut shape with hydrophobic pocket 26

27. Components of Iohexol-SBECD Product 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 Iohexol (OMNIPAQUE) SBECD (CAPTISOL) 27

28. Iohexol-SBECDIohexol-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 28

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 AnimalsC57BL6 female mice (8-10 weeks old) or Sprague Dawley male rats (9 to 11 weeks old) Renal Compromise Model Intraperitoneal injections of 10 mg/kg N-nitro-L-arginine methyl ester (L-NAME) followed in 10 minutes by 10 mg/kg indomethacin IV injection of contrast formulation 20 minutes later through the tail vein Contrast Treatment Dose=1.5 g Iodine/kg contrast with or without sulfobutylether β-cyclodextrin (SBECD) or hydroxypropyl β-cyclodextrin Varying Iohexol : SCD mole ratios (The dose of iohexol used in these studies is the human equivalent of 300 mL of Omnipaque 350) AnalysisAnimals are sacrificed at 12-72 h, kidneys processed & examined for pathology Blood & urine collected and analyzed for creatinine and/or other markers 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. 30

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

32. SBECD decreases renal pathology in the mouse and rat 32

33. SBECD decreases plasma creatinine in the mouse and rat 33

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 35

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 36

37. Iohexol-SBECD Project Timeline 37 Development Nonclinical Human proof-of-concept ClinicalSafety and Bioequivalence Pivotal Efficacy Regulatory interactions Launch 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 201420132015 2016 20172018 Exit Readiness Partner Identification Assessment Partnering outreach End Phase III exit EOP2 Meeting Period of initial focus toward earliest exit NDA Approval Pre NDA IND CTA Proof-of- concept exit Pre-launch exit

38. High-dose Iodinated X-ray Imaging Agents: 2012 US Market Data Generic nameBrand nameManufacturer2012 US salesMarket Share IohexolOMNIPAQUEGE Healthcare$262M31% IopamidolISOVUEBracco Intl$262M31% IodixanolVISIPAQUEGE Healthcare$181M18% IoversolOPTIRAYMallinckrodt$123M15% Others$22M3% High dose agents defined as those >300mg iodine/ml Source: IMS Health 2012 38

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 39

40. Summary Evaluation for Iohexol-SBECD for Preventing Contrast-Induced Acute Kidney Injury Key CriteriaCommentsY/N Does the innovation address a clinical need? CI-AKI, defined by a temporal rise in serum creatinine, is a frequent complication of all iodinated contrast media. Risk factors are well understood and are common in the population undergoing vascular imaging. Y Will the market value the innovation be willing to pay for it? Current $900M+ US market with no product differentiation. Likely premium pricing to current contrast media with good efficacy and HECON data; CMS interest as a hospital-acquired condition heightens payer interest Y Can the product be developed?  Clinical  Regulatory  Manufacturing 505(b)(2) agreed with FDA; bioequivalence to iohexol, followed by pivotal program to create labeling differentiation on incidence of rise in serum creatinine. Leverages Captisol DMF. API sources identified. Y Can the innovation be protected in the marketplace? Iohexol-SBECD US formulation patent issued to 2028. Protected global market opportunity Y 40

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. 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

51. Klotho and Vitamin D Vitamin D (1,25 dihydroxyvitamin D3) up-regulates klotho Klotho is involved in a feed back mechanism that inhibits vitamin D metabolism Lau, Wie Ling et. Al. Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mince with chronic kidney disease fed a high phosphate diet. Kidney International. 2012. (82) 1262-1270.

52. Klotho and Vitamin D Nabeshima, Yo-ichi. Klotho deficient mouse: an in vivo model for human aging. Drug Discovery Today: Disease Models. (2004) 1(3), 223-227.

53. Implication in MS KlothoMature Oligodendrocytes Myelination Vitamin D