Transcript Drug Development Outside the Academic Environment

Vernon Rowe, M.D.
CEO, Rowe Neurology Institute
Adjunct Professor of Neurology, KUMC
CEO Verrow Pharmaceuticals, Inc.
Board Member, Capiod
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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
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Pharma—In House Discovery or
Acquisition
Academia
Other
Role of Angel Investors
Role of Venture Capital
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Scientists Make a Discovery
Funding Entity Patents the Discovery
Funding Entity Defines
Commercialization Pathway In
Consultation with FDA
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Clinicians identify a need
Scientists Find a Solution
Clinicians Test the Solution
Physician Scientists—a Dying Breed
8550 Marshall Drive Suite 100

Successes of the early years of the NIH
inspired MANI as an experiment to more
closely tie the bench to the bedside
CLINIC
LAB
Headache Center
Sleep Center
MS Center
Memory Loss Center
Physical
Therapy
Find the underlying cause of headache
Infusion center keeps acute migraine
patients out of costly ER
John Hunter
Cord Huston
Accurate Diagnosis
Follow each patient carefully
Treat the whole
patient
OCT
Don’t blame everything on MS
Basic Research
Clinical Research
High Dose IV Methotrexate By Itself Helps
MS
But Kidney Toxicity Is a major
Problem
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IV Methotrexate
Study
Avonex Study
-0.4
Placebo in
Avonex Study
-0.8
-1.2
r2
Ye
a
r1
Ye
a
el
in
e
-1.6
B
as
Functional Composite Score
(MSFC)
0.4
1. Cohen JA, et.al. Neurology. Sep 10 2002;59(5):679-87.
SCD and Drug in Bloodstream
SCD and Drug in Vial
Dilution
SCD and Drug
safely exit
through kidney
Concentration
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; 51:1419-28
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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
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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.
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The Product
Iohexol-SBECD
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)
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Components of Iohexol-SBECD Product
SBECD (CAPTISOL)
Iohexol (OMNIPAQUE)
Market leading iodinated
contrast agent
Used as a solubilizing agent in
multiple approved products
Globally available
Safety well established with
DMF referencable by FDA
Marketed by GE Healthcare,
Bayer-Schering (EU) and
Daiichi- Sankyo (Japan)
Observed to protect kidney
from renal tubular adverse
effects of multiple compounds
(e.g. methotrexate,
gentamicin, doxorubicin,
cisplatin, iohexol)
Available as generic outside
US where primary
manufacturer is Hovione
Primary manufacturer Hovione
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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
Contrast
Treatment
Dose=1.5 g Iodine/kg contrast with or without sulfobutylether β-cyclodextrin (SBECD)
or hydroxypropyl β-cyclodextrin
IV injection of contrast formulation 20 minutes later through the tail vein
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 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.
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Veropaque Blocks Kidney Damage in Mouse
Model
A
Tubular dilatation, degeneration, and
cast formation 48 hours after 1.5 gI/kg
iohexol administration
B
Absence of renal pathology 48 hours
after 1.5 gI/kg Veropaque
administration
SBECD decreases renal pathology in the
mouse and rat
Effect of SCD on Iohexol Induced Outer Renal Cortex Pathology in
Mice (24h) and Rats (48h)
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(n= 12) (n= 20)
Mouse
Rat
Mean Pathology Score
6
5
4
(n=3)
(n=4)
(n= 5) (n= 8)
(n= 14) (n= 14)
3
2
1
0
Control
Renally
Compromised, RC
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RC-Iohexol
RC-Iohexol + SBECD
(1:0.025 ratio)
SBECD decreases plasma creatinine in the
mouse and rat
1.6
Plasma Creatinine Levels at 24h (mouse) or 48h (rat) Post
Treatment in Renally Compromised (RC) Rodents
(13) (16)
Creatinine [mg/dl]
1.4
Mouse
Rat
1.2
1.0
0.8
(n=67)
(5)
(8)
(12) (15)
(3)
0.6
0.4
0.2
0.0
Predose
RC
RC-SBECD
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RC-Iohexol
RC-Iohexol +
SBECD (0.025
ratio)
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
Proof-ofconcept exit
Development
End Phase III
exit
Pre-launch
exit
Nonclinical
Human proof-of-concept
ClinicalSafety and Bioequivalence
Pivotal Efficacy
Regulatory interactions
IND
CTA
Pre NDA
NDA
EOP2
Meeting
NDA
Approval
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
Period of initial focus
toward earliest exit
2014
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2015
2016
2017
2018
High-dose Iodinated X-ray Imaging Agents:
2012 US Market Data
Generic name
Brand name
Iohexol
Manufacturer
2012 US sales
Market Share
OMNIPAQUE GE Healthcare
$262M
31%
Iopamidol
ISOVUE
Bracco Intl
$262M
31%
Iodixanol
VISIPAQUE
GE Healthcare
$181M
18%
Ioversol
OPTIRAY
Mallinckrodt
$123M
15%
$22M
3%
Others
High dose agents defined as those >300mg iodine/ml
Source: 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 restoration
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Summary Evaluation for Iohexol-SBECD
for Preventing Contrast-Induced Acute Kidney Injury
Key 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?
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
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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