DRUG DEVELOPMENT OUTSIDE THE ACADEMIC

ENVIRONMENTVernon Rowe, M.D.

CEO, Rowe Neurology InstituteAdjunct Professor of Neurology,

KUMC

Conflicts of Interest

CEO Verrow Pharmaceuticals, Inc.Board Member, Capiod

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

Site of Discovery• Pharma—In House Discovery or

Acquisition• Academia• Other• Role of Angel Investors• Role of Venture Capital

Push Technology• Scientists Make a Discovery• Funding Entity Patents the Discovery• Funding Entity Defines

Commercialization Pathway In Consultation with FDA

Pull Technology

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

Rowe Neurology Institute

8550 Marshall Drive Suite 100

RNI TRIAD

Back To The Future

CLINIC LAB

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

Consultants in Neurology, PA

Headache CenterSleep CenterMS CenterMemory Loss Center

Headache Center

Find the underlying cause of headache

Infusion center keeps acute migraine patients out of costly ER

PhysicalTherapy

Accredited Sleep Disorders Center

John Hunter Cord Huston

Multiple Sclerosis Center

Accurate Diagnosis

Follow each patient carefully

Don’t blame everything on MS

Treat the whole patient

OCT

MidAmerica Neuroscience Research Foundation- 501 (c)3

Basic ResearchClinical Research

Basic Research

Clinical Research

Methotrexate: A New Old Treatment For Multiple Sclerosis

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

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IV MethotrexateStudy

Avonex Study

Placebo inAvonex Study

SCD reformulations shepherd toxic drugs through the

kidney

SCD and Drug in Vial

SCD and Drug in Bloodstream

Dilution Concentration

SCD and Drug safely exitthrough kidney

We Make Drugs Safer

Confidential

The Product Iohexol-SBECD

Iohexol-Captisol:Preventing Contrast-

Induced Acute Kidney Injury

A safer contrast agent has been a "holy grail" for decades

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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; 51:1419-2822

Incidence of Contrast-Induced Acute Kidney

InjuryPublished 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

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Cost Impact of Contrast-Induced Acute Kidney

InjuryAverage 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.

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The Product Iohexol-SBECD

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

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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)

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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

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Nonclinical Data

Contrast-Induced Acute Kidney Injury Model

A multiple-insult rodent model has been used to evaluate the nephroprotective activity of the Iohexol-SBECD formulation

Animals C57BL6 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)

Analysis Animals are sacrificed at 12-72 h, kidneys processed & examined for pathology

Blood & urine collected and analyzed for creatinine and/or other markers1 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.

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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

Veropaque Blocks Kidney Damage in Mouse Model

A B

SBECD decreases renal pathology in the mouse and

rat

Control Renally Com-promised, RC

RC-Iohexol RC-Iohexol + SBECD (1:0.025 ra-

tio)

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Effect of SCD on Iohexol Induced Outer Renal Cortex Pathology in Mice (24h) and Rats (48h)

(n= 8)(n= 5)(n=3) (n=4) (n= 14)(n= 14)

(n= 20)(n= 12)

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SBECD decreases plasma creatinine in the mouse and rat

Predose RC RC-SBECD RC-Iohexol RC-Iohexol + SBECD (0.025

ratio)

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Plasma Creatinine Levels at 24h (mouse) or 48h (rat) Post Treatment in Renally Compromised (RC) Rodents

MouseRat

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mg

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(n=67) (5) (8) (3) (12) (15)

(13) (16)

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Development Strategy for Iohexol-SBECD

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

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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

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Iohexol-SBECD Project Timeline

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Development

NonclinicalHuman proof-of-conceptClinical Safety and BioequivalencePivotal Efficacy

Regulatory interactions

Launch

ManufacturingFormulation DevelopmentDevelopment and clinical trial materialScale Up and NDA registration materialCommercialization AssessmentUS market, customer and payer researchEx-US market, customer and payer research

20142013 2015 2016 2017 2018

Exit ReadinessPartner Identification AssessmentPartnering outreach

End Phase III exit

EOP2 Meetin

g

Period of initial focus toward earliest exit

NDA

NDAApprova

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PreNDA

INDCTA

Proof-of-concept

exit

Pre-launch exit

High-dose Iodinated X-ray Imaging Agents:

2012 US Market DataGeneric name

Brand name

Manufacturer 2012 US sales

Market Share

Iohexol OMNIPAQUE

GE Healthcare

$262M 31%

Iopamidol ISOVUE Bracco Intl $262M 31%

Iodixanol VISIPAQUE GE Healthcare

$181M 18%

Ioversol OPTIRAY Mallinckrodt $123M 15%

Others $22M 3%

High dose agents defined as those >300mg iodine/mlSource: IMS Health 2012

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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 restoration39

Summary Evaluation for Iohexol-SBECD for Preventing Contrast-Induced Acute

Kidney InjuryKey Criteria Comments Y/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?ClinicalRegulatoryManufacturing

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

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MidAmerica Neuroscience Research Foundation

Mission: focus on pull research to move patient solutions from bedside

to bench to beside

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

Remyelination Problem

• What’s the fix?– Introduce mature oligodendrocytes to

demyelinated sites– Stimulate oligodendrocytes already present into

creating myelin

Remyelination Problem

• What’s the fix?– Introduce mature oligodendrocytes to

demyelinated sites– Stimulate oligodendrocytes already present into

creating myelin

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

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

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

Klotho

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

Klotho

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

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

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.

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.

Implication in MS

Klotho Mature Oligodendrocytes

Myelination

Vitamin D