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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

Drug Development Outside the Academic Environment

Vernon Rowe, M.D.

CEO, Rowe Neurology Institute

Adjunct Professor of Neurology, KUMC

conflicts of interest
Conflicts of Interest

CEO Verrow Pharmaceuticals, Inc.

Board Member, Capiod

steps in drug development
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
Site of Discovery

Pharma—In House Discovery or Acquisition

Academia

Other

Role of Angel Investors

Role of Venture Capital

push technology
Push Technology

Scientists Make a Discovery

Funding Entity Patents the Discovery

Funding Entity Defines Commercialization Pathway In Consultation with FDA

pull technology
Pull Technology

Clinicians identify a need

Scientists Find a Solution

Clinicians Test the Solution

Physician Scientists—a Dying Breed

rowe neurology institute
Rowe Neurology Institute

8550 Marshall Drive Suite 100

back to the future
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

consultants in neurology pa
Consultants in Neurology, PA

Headache Center

Sleep Center

MS Center

Memory Loss Center

headache center
Headache Center

Physical

Therapy

Find the underlying cause of headache

Infusion center keeps acute migraine

patients out of costly ER

accredited sleep disorders center
Accredited Sleep Disorders Center

John Hunter Cord Huston

multiple sclerosis center
Multiple Sclerosis Center

Accurate Diagnosis

Follow each patient carefully

Treat the whole patient

Don’t blame everything on MS

OCT

methotrexate a new old treatment for multiple sclerosis
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.

scd reformulations shepherd toxic drugs through the kidney
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

slide21

Iohexol-Captisol:Preventing Contrast-Induced Acute Kidney Injury

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

contrast induced acute kidney injury
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

incidence of contrast induced acute kidney injury
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
cost impact of contrast induced acute kidney injury
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.

slide26

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)
components of iohexol sbecd product
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
iohexol sbecd
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
contrast induced acute kidney injury model
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.

veropaque blocks kidney damage in mouse model
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

iohexol sbecd development strategy
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
iohexol sbecd regulatory strategy
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
iohexol sbecd project timeline
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

high dose iodinated x ray imaging agents 2012 us market data
High-dose Iodinated X-ray Imaging Agents:2012 US Market Data

High dose agents defined as those >300mg iodine/ml

Source: IMS Health 2012

patent protection to at least 2028
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
summary evaluation for iohexol sbecd for preventing contrast induced acute kidney injury
Summary Evaluation for Iohexol-SBECD for Preventing Contrast-Induced Acute Kidney Injury
midamerica neuroscience research foundation

MidAmerica Neuroscience Research Foundation

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

problem
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
Remyelination Problem
  • What’s the fix?
    • Introduce mature oligodendrocytes to demyelinated sites
    • Stimulate oligodendrocytes already present into creating myelin
remyelination problem1
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
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 myelin1
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
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
Klotho

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

klotho1
Klotho

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

klotho and myelination
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
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 d1
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
Implication in MS

Klotho

Mature Oligodendrocytes

Myelination

Vitamin D

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