RXi Investor Event Oct 21 Final for Thomson USE THIS...
Transcript of RXi Investor Event Oct 21 Final for Thomson USE THIS...
RXi PharmaceuticalsRXi Pharmaceuticals
Investor EventInvestor EventInvestor EventOctober 21, 2008
Investor EventOctober 21, 2008
Next Generation in RNAiNext Generation in RNAi
AgendaAgenda
Breakfast and Registration 8:00-8:30
Welcome and Introduction Tod Woolf, Ph.D.President & CEO 8:30-8:45
RNAi Technology Overview Craig Mello, Ph.D.Founder & SAB Chairman 8:45-9:15
Update on RXi’s R&D Programs Pamela Pavco, Ph.D. 9:15 9:35Update on RXi s R&D Programs ,VP of Pharmaceutical Development 9:15-9:35
Overview of Intellectual Property Tod Woolf, Ph.D. 9:35-10:05
Business & Financial Overview Stephen DiPalma 10:05 10:15Business & Financial Overview pChief Financial Officer 10:05-10:15
Closing Remarks / Q&A Tod Woolf, Ph.D. 10:15-10:30
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Forward Looking StatementsForward Looking Statements
Thi t ti t i f d l ki t t t ithi th i fThis presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements include, but are not limited to, statements about the future development of RXi Pharmaceutical Corporation’s products These forward-lookingRXi Pharmaceutical Corporation s products. These forward-looking statements about future expectations, plans and prospects of the development of RXi Pharmaceutical Corporation’s products involve significant risks, uncertainties and assumptions. Actual results may differ g , p ymaterially from those RXi Pharmaceuticals Corporation contemplated by these forward-looking statements as a result of the risk factors discussed in RXi reports on file with the U.S. securities and exchange commission including, but not limited to, the Annual Report on Form 10-K filed with the SEC. RXi Pharmaceuticals Corporation does not undertake to update any of these forward-looking statements to reflect a change in its views or events or i t th t ft th d t f thi di l
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circumstances that occur after the date of this disclosure.
Company OverviewCompany Overview
New Class of Drugs: RNAi TherapeuticsNew Class of Drugs: RNAi Therapeutics
Began operations Q1 07 in Massachusetts
Co-founded by world-leading RNAi researchers
Began trading March 12th, 2008 (Nasdaq: RXII)
RXi is one of few public pure-plays in RNAi Therapeutics
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RNAi: From Basic Science to TherapeuticsRNAi: From Basic Science to Therapeutics
D R hiD M llDrs. Woolf,
Wi d h lt & M ll D C h & O t ffDr. Ambros
di Dr. Rana achieves systemic delivery
in in vivo model
Dr. Mello co-invents RNAi Therapeutics
Wiederholt & Mello Develop STEALTHRNAi at Sequitur
Drs. Czech & Ostroff achieve oral delivery of RNAi
co-discovers natural RNAi (microRNAs)
1997 2005 20071993 2001 2002 20082000 2006
Dr. Hannon publishes shRNAi
Dr. Pavco files first IND with chemically modified RNAi at Sirna
RXi DevelopsNext Generation rxRNA™
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Growth in Value of RNA FieldGrowth in Value of RNA Field
$1.6 billion in cash spent on RNAi deals
RNA Alliance Total DollarsAcquisitions RNAi PublicationsAcquisitions
$1B$250M
Eyetech
$1B$5B*
$1B$250M $1B$4B
$3B
$2B
$1B
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Agilent (*$ include all potential pre-clinical milestones)
RXi: Next Generation RNAi TherapeuticsRXi: Next Generation RNAi Therapeutics
Accomplished RNAi Product Focused TeamAccomplished RNAi Product Focused Team
RNAi: Potential Paradigm Changing Approach
Advanced Therapeutic PlatformNext Generation rxRNA
Local, Systemic and Oral Delivery
Discovery Pipeline
Early and Broadly Filed Intellectual Property
Business and Financial Overview
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Business and Financial Overview
RXi Senior Corporate ManagementRXi Senior Corporate Management
Tod Woolf Ph D CEO
St h DiP l MBA CFO
Tod Woolf, Ph.D., CEOFounded-CEO of Sequitur, an RNAi company acquired by Invitrogen (IVGN) Co-invented and commercialized Stealth™ RNAiCo-invented two of RPI's (now Sirna-Merck) main RNA technologies
Stephen DiPalma, MBA, CFOFounded and served as President and CEO of Catalyst OncologyFormerly CFO at Milkhaus Laboratory, Phytera and Athena DiagnosticsSuccessfully turned around publicly traded Aquila Biopharmaceuticals
Dmitry Samarsky, Ph.D., VP of Technology DevelopmentRecently served as Director of Technology Development at DharmaconFormer Business Development Manager at Invitrogen (IVGN)Opinion leader in the field of RNAi
Donna Falcetti, Director of Investor RelationsServed as Product Manager of RNAi Technologies at InvitrogenBroad experience with RNAi in numerous assays and model systemsOver 15 years of management experience
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RXi Senior Scientific ManagementRXi Senior Scientific Management
P l P Ph D VP f Ph ti l D l tPamela Pavco, Ph.D., VP of Pharmaceutical DevelopmentBrought Sirna's lead RNAi candidate to Phase I in under 12 monthsThree additional RNA drug candidates through IND at Sirna (RPI)Managed Sirna's Allergan and Huntington Disease collaborations
Anastasia Khvorova, Ph.D., Chief Scientific OfficerServed as CSO at Dharmacon, a ThermoFisher Scientific CompanyDesigned and commercialized RNAi compounds targeting virtually all the known human genesDeveloped self delivering RNAi
Joanne Kamens, Ph.D., Director of DiscoveryMore than 15 years of experience in immunology and inflammationFormerly group leader at Abbott Laboratories
Developed self delivering RNAi
Extensive experience with RNAi in complex model systems
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RXi Founders & Scientific AdvisorsRXi Founders & Scientific Advisors
Craig Mello, Ph.D. (SAB Chairman)• 2006 Nobel Prize in Medicine for RNAi
Blais University Chair in Molecular Medicine UMMC• Blais University Chair in Molecular Medicine, UMMC• Co-discovered RNAi and invented RNAi therapeutics • Howard Hughes Medical Institute Investigator • Member of the National Academy of Sciences
Mi h l C h Ph DMichael Czech, Ph.D.• Professor and Chair, Program in Molecular Medicine, UMMC• American Diabetes Association's Eli Lilly Award for Diabetes • Banting Award for scientific achievement
Tariq Rana, Ph.D.• Professor and Director, Program for RNAi Biology, Burnham Institute• Discovered key parameters to stabilize RNAi• Developed RXi's Nanotransporter technology
Greg Hannon, Ph.D. • HHMI Investigator at Cold Spring Harbor Laboratory• Discovered mechanism of RNAi in human cells
D l d th id l d hRNAi
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• Developed the widely used shRNAi• Identified the p21, p15 and p16 as tumor suppressor genes
Scientific Advisors: Drug DevelopmentScientific Advisors: Drug Development
Victor R. Ambros, Ph.D.P f f M l l M di i UMMS
N i U Ph D
• Professor of Molecular Medicine, UMMS • Discovered the first microRNA, lin-4• In 2008 received the Gairdner International Award,
the Benjamin Franklin Medal and the Lasker Prize
Nassim Usman, Ph.D.• CEO of Catalyst Biosciences• Held positions of CSO and COO at Sirna• Negotiated Lilly, Allergan and GSK alliances• 130 patents and patent applications: Main RNAi synthesis chemistry
Robert H. Brown, Jr., M.D., Ph.D.• Chair of the Department of Neurology at UMMC• Former Professor of Neurology at Harvard Medical School• Founder of the Day Neuromuscular Lab at MGH
Id tifi d SOD1’ l i f ili l ALS
Nicholas Dean, Ph.D.• Founder and CSO of Excaliard Pharmaceuticals, Inc.• Held VP positions in oncology and pharmacology at ISIS
• Identified SOD1’s roles in familial ALS
• Over 100 patents and publications in RNA therapeutics• Managed $100M budget for Isis - Eli Lilly collaboration
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Building the Pipeline: Initial FocusBuilding the Pipeline: Initial Focus
Metabolic DiseaseMetabolic DiseaseHigh cholesterol targetRIP140 for obesity and type 2 diabetes
InflammationInflammationOral delivery to inflammatory cells (macrophages)
NeurologyALS (Lou Gehrig’s Disease)ALS (Lou Gehrig s Disease)Alzheimer’s (undisclosed target)
Other therapeutic areas may be pursued through partnershipspartnerships
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RXi: Next Generation RNAi TherapeuticsRXi: Next Generation RNAi Therapeutics
Accomplished RNAi Product Focused TeamAccomplished RNAi Product Focused Team
RNAi: Potential Paradigm Changing Approach
Advanced Therapeutic PlatformNext Generation rxRNA
Local, Systemic and Oral Delivery
Discovery Pipeline
Early and Broadly Filed Intellectual Property
Business and Financial OverviewBusiness and Financial Overview
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RNAi: From Mechanism to Medicine
RNAi: From Mechanism to Medicineto Medicineto Medicine
Craig C Mello Ph DCraig C Mello Ph DCraig C. Mello, Ph.D.
Founder and Scientific Advisory Board Chairman, RXi Pharmaceuticals
Bl i U i it Ch i i M l l M di i
Craig C. Mello, Ph.D.
Founder and Scientific Advisory Board Chairman, RXi Pharmaceuticals
Bl i U i it Ch i i M l l M di i
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Blais University Chair in Molecular Medicine, UMMC
Blais University Chair in Molecular Medicine, UMMC
RNAi Targets Protein Production in CellsRNAi Targets Protein Production in Cells
www.nature.com/focus/rnai/animations/index.html 15
RNA Interference:A “Search Engine” For Disease Causing GenesRNA Interference:A “Search Engine” For Disease Causing Genes
dsRNA target mRNA
AAAAAAAAAA
cell driven scanning of target
AAAAAAAAAA
target RNA is cut and destroyed,ta get s cut a d dest oyed,blocking deleterious protein expression
AAAAAAAAAA
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Potent catalytic destruction of target RNA sequenceMello & Fire (1998); Hannon et al (2002)
RNAi is an ACTIVE Process!(1994-1997)
RNAi is an ACTIVE Process!(1994-1997)
Cat alyt ic model of RNAi
Inject ed dsRNA
Degradat ion
Foreign dsRNA Recognition
Transport into the cellsTarget t issueTransport
RNA-dependentRNA degradat ion
pre - mRNA
RNA-degradat ion
Silencing
Accumulat ion of RNAi act ive molecules in the target t issue
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Hiroaki’s Screen for RNAi Deficient Mutants (1998-1999)Hiroaki’s Screen for RNAi Deficient Mutants (1998-1999)
P0
Mutagenize
P0
F2Feed dsRNA F2
Hiroaki T b
Feed dsRNA(Lisa Timmons)
Tabarawt RNAi induced
dead eggsRNAi-deficientviable progeny dead eggsab e p oge y
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Alla Grishok Discovery of RNAi Machinery in Mammals and Other SpeciesAlla Grishok Discovery of RNAi Machinery in Mammals and Other Species
Alla Grishok
RDE-1cePRG-1cePRG-2
ceCSR-1
Niraj H. Tolia and Leemor Joshua-Tor
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The Discovery of Natural RNAi (microRNAs)The Discovery of Natural RNAi (microRNAs)
Victor AmbrosL t l 1993
WT dcr-1 alglin-4Lee et al., 1993
Gary RuvkunReinhart et al 2000 pre miRNApre miRNA
lin-4let-7
Reinhart et al., 2000Pasquinelli et al., 2000
pre-miRNApre-miRNA
ALG-1/ALG-2
Alla Grishokd A P i lliand Amy Pasquinelli
Grishok et al, 2001 miRNAmiRNA21 ntmature miRNA
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Micro RNAs Play Major Roles in BiologyMicro RNAs Play Major Roles in Biology
iRNAiRNA
micro RNAsdrive
gene silencing pre-miRNApre-miRNA
Dicer
gene silencing during
normal developmentnormal developmentAND Cancer
miRNAmiRNA
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microRNA Inhibitors Block Brain Tumor Growth in Mice! microRNA Inhibitors Block Brain Tumor Growth in Mice!
Control miRNAInhibitor
Day 2
Day 4
Anna M Krichevsky
Day 6
Anna M. Krichevsky Brigham and Womens
&Khalid Shah
GDay 6 MGH.
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Potential Applications of RNAiPotential Applications of RNAi
Research tool to determine gene function in disease
Natural RNAi’s are involved in many disease states
RNAi TherapeuticsBlock the expression of disease causing genesBlock the expression of disease causing genes
Increase the expression of beneficial genes (antigomers)(antigomers)
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Discovery of a Diabetes and Obesity Target with RNAi: RIP140
Discovery of a Diabetes and Obesity Target with RNAi: RIP140
Czech et al (2006) J Clin Invest; exclusive therapeutic license to RXi
Synthetic siRNA Screening
A high-throughput screen using siRNA-mediated gene silencing toidentify genes that regulate insulin signaling in 3T3-L1 adipocytes
S ll l l t ti i i t i d 5 f ld f t d d t h i•Small scale electroporation - miniaturized 5 fold from standard techniques•Select 3000 candidate genes from Affymetrix gene profiling•Dharmacon SMART pool siRNA--mixture of 4 sequences per gene•Assays conducted in 96 well plates
Fat CellsTargetsiRNA: F….A B C D E
96-well plate
•Glucose Transport Assay•Oxygen Consumption Assay
p
Powelka et al JCI 200626
Discovery of a Diabetes and Obesity Target with RNAi: RIP140Discovery of a Diabetes and Obesity Target with RNAi: RIP140
Czech et al (2006) J Clin Invest; exclusive therapeutic license to RXi
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Diabetes and Obesity Target: RIP140Diabetes and Obesity Target: RIP140Czech et al (2006) J Clin Invest; Leonardson et al (2004) Proc Natl Acad Asi USA
Metabolism(RNAi knockdown in cell culture) Body fat
RIP140
400
500
600
700
ry U
nits
inguinal MRI
(RNAi knockdown in cell culture) Body fat
control
0
100
200
300
Arb
itrar
total body fat
Time (sec)KO = RIP140genetic knockout
E l i Th ti Li t RXiExclusive Therapeutic License to RXi
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Potential Applications of RNAiPotential Applications of RNAi
RNAi Therapeutics
Block the expression of disease causing genes
Increase the expression of beneficial genes
(antigomers)(a t go e s)
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RNAi Potential AdvantagesRNAi Potential Advantages
High potency (low doses)Low toxicity, natural mechanism of action High specificity for target genesAbility to interfere with the expression of any geneAccelerated lead generation
rapid
RNAi
rapid lead ID &
optimization
Prone to Failure
clinicaltrials
animalstudies
leadoptimization
target discovery
validation
HTSassay
lead ID
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Time ConsumingExpensive
Prone to Failure
Traditional Drug Development
Pharmacokinetics: A Development Hurdle for Duplex RNAPharmacokinetics: A Development Hurdle for Duplex RNA
Oligonucleotides have poor in vivo PKOligonucleotides have poor in vivo PK parameters following systemic administration
Short half life in circulationShort half life in circulationRapid elimination by the kidneysLimited tissue exposurep
Local delivery is one solutionLonger tissue exposureMultiple applications
Nanoparticles for systemic deliveryStructure can dictate organ exposure
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Systemic in vivo Delivery with RXi NanoparticlesSystemic in vivo Delivery with RXi Nanoparticlespp
Rana et al (2007) ACS Chemical Biol
<80 nm complex size
Readily formulated
Does NOT induce interferon
Charge and ligands can be varied
Demonstrated in vivo activity in animal modelsDemonstrated in vivo activity in animal models
Delivery to multiple organs in animal models
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RNAi SummaryRNAi Summary
Fast pace of scientific and commercialFast pace of scientific and commercial applications
Natural Mechanism: Promoted by cellularNatural Mechanism: Promoted by cellular machinery
Understanding mechanism allows for design ofUnderstanding mechanism allows for design of advanced RNAi compounds
Delivery vehicles are expanding the potential ofDelivery vehicles are expanding the potential of RNAi therapeutics
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RXi: Next Generation RNAi TherapeuticsRXi: Next Generation RNAi Therapeutics
Accomplished RNAi Product Focused TeamAccomplished RNAi Product Focused Team
RNAi: Potential Paradigm Changing Approach
Advanced Therapeutic PlatformNext Generation rxRNA
Local, Systemic and Oral Delivery
Discovery Pipeline
Early and Broadly Filed Intellectual Property
Business and Financial OverviewBusiness and Financial Overview
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rxRNA: Potential Therapeutic AdvantagesrxRNA: Potential Therapeutic Advantages
Classic Classic rxRNArxRNA
♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦
siRNA siRNA 20012001
Properties rxRNA rxRNA 20072007
No High potency (cell culture) √ Yes
No Nuclease resistant √ Yes
No Reduced off-target effects √ Yes
Yes/No Reduced interferon induction √ Yes
Yes Relative ease of manufacturing √ Yes
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rxRNA results demonstrated in RXi preclinical studies
rxRNA: High Potency in CellsrxRNA: High Potency in CellsKamens et al., RXi Pharmaceuticals, 2007
80
100Typical 21mer siRNAOptimized rxRNATM
RN
A
60
on P
PIB
mR
RNA Duplex EC50 (pM)
Optimized
20
40%
Red
uctioOptimized
rxRNA 30
Typical 21mer 1074
01 10 100 103 104
[RNA] pM
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rxRNA: Nuclease ResistantrxRNA: Nuclease Resistant
rxRNA Modifications Reduce Degradation in Serum
Kamens et al., RXi Pharmaceuticals, 2007
rxRNA Modifications Reduce Degradation in Serum
0 2 4 6 24 0 2 4 6 24Time (hours)
No modifications rxRNA modifications
marker
• Duplexes incubated with 10% serum at 37oC
No modifications(21-mer)
rxRNA modifications(25-mer)
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• Samples separated in 20% TBE PAAG and stained with SYBR green• Marker: dsRNA (17, 21, 25 bp)
rxRNA: Reduced Interferon Induction in CellsrxRNA: Reduced Interferon Induction in Cells
Woolf et al. 2003, Sequitur unpublished data
1601 1962 2792 2289 2164
ker
erfe
ron
Mar 12 h
24 h
72 h
Int 96 h
37 37 2121 27272727chemical modification++ +-- ---
duplex length (nt)
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rxRNA chemistry appears more reliable than length at blocking immune side effects
rxRNA: Relative Ease of ManufacturerxRNA: Relative Ease of Manufacture
Cell culture scale (1000’s of rxRNAs per month)Cell culture scale (1000 s of rxRNAs per month)
Precursors manufactured in large scale
Non-clinical & clinical (GMP) development grade supply chain established
RXi believes rxRNA scalable using current methods
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rxRNA: Potential Therapeutic AdvantagesrxRNA: Potential Therapeutic Advantagesgg
Properties rxRNA 2007
High potency (cell culture) √ Yes
Nuclease resistant √ Yes
Reduced off-target effects √ Yes
Reduced interferon induction √ Yes
√Relative ease of manufacturing √ Yes
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rxRNA results demonstrated in RXi preclinical studies
RXi’s Comprehensive Approach to RNAi Delivery RXi’s Comprehensive Approach to RNAi Delivery yy
Local Administration
--CNS--
• Direct administration
• Minimal systemic exposure
• CNS, eye, lung, etc.
Systemic Delivery--Metabolic Disease--
• Nanotransporter
• Metabolic and Liver diseases
CNS, eye, lung, etc.
Metabolic Disease• Proprietary cationic lipids, self-delivering rxRNAs
Oral Delivery• Glucan-encapsulated siRNA Particles (GeRPs)
S ifi d li t h f i fl t diy
--Inflammation--• Specific delivery to macrophages for inflammatory disease
• Minimal systemic exposure
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Local Delivery of SOD1 RNAi Compound Delays ALS Progression in MiceLocal Delivery of SOD1 RNAi Compound Delays ALS Progression in Mice
Rana et al (2008) J Biol Chem; exclusive therapeutic license to RXi
Sta
ge
ControlRNAi
rcen
t at E
nd
Per
• Intrathecal delivery via osmotic pump• 7-day administration (mRNA, protein endpoints)• 28 day administration in survival study (4 µg / day)
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RNAi has potential to target disease genes in the central nervous system
• 28-day administration in survival study (4 µg / day)
Systemic Delivery with RXi NanotransportersSystemic Delivery with RXi Nanotransporterspp
Rana et al. (2007) ACS Chemical Biol
Novel systemExclusive therapeutic plicense from UMASS
~80 nm complex size
Relatively easily formulatedRelatively easily formulated
Toxicity and immune stimulation not observed
Charge and ligands can be variedCharge and ligands can be varied
Demonstrated in vivo activity in mice
Potential delivery to multiple organs
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Using Nanotransporter Delivery to Target a Cholesterol Gene in vivoUsing Nanotransporter Delivery to Target a Cholesterol Gene in vivo
Rana et al. (2007) ACS Chemical Biol
gg
80
100
120
Apo B-100
Apo B-48
20
40
60Apo BProtein
0
20
Control Apo B MM Apo B siRNA
Intravenous; daily for 3 days; N = 3-4 mice
5 mg/kg siRNA:nanoparticle
Stabilized siRNA (MM=mismatch)
B th i f d i li ( t d) A B 48 i f d i i t tiBoth isoforms expressed in liver (secreted), ApoB-48 isoform expressed in intestine
Plasma sampled at 24 hr post last dose
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Nanotransporters Deliver RNAi to TissuesNanotransporters Deliver RNAi to TissuesRana et al. (2007)
siRNANT1tRNA
NT1
NT2 siRNA
tRNA
NT3siRNA
tRNA
Mice were treated with 1 mg/kg siRNA:nanotransporter containing stabilized siRNA
Tissues were sampled 48 hr post dose
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Northern blot analyses were conducted using a DNA probe to detect the antisense strand of siRNA
10 µg of total RNA were loaded with tRNA shown as a loading control
Oral Delivery of RNAi Compounds to Macrophages Oral Delivery of RNAi Compounds to Macrophages p gp g
Rieux, et al., J of Cont Release, 2006
•Particles•Bacteria
Glucan-encapsulated siRNA Particles
•Yeast •GeRPs Intestinal Lumen
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Intestinal tissue
Gut Macrophages Migrate to Other TissuesGut Macrophages Migrate to Other Tissues
Small intestinal mucosa:
M ll
This is the anticipated mechanism of this technology
M cell β− Glucan
M Cell transcytosis
Intestinal macrophagesDectin-1 mediated
Phagocytosis
Macrophage Migration
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SpleenBone Lung Liver
Oral Delivery of β-Glucan-encapsulated RNAi May Reduce Systemic InflammationOral Delivery of β-Glucan-encapsulated RNAi May Reduce Systemic Inflammation
Package RNAi compound into GeRPs
Orally deliver GeRPs to small intestinal mucosa
Intestinal macrophages engulf GeRPs by phagocytosis
GeRPs transcytose through M cells
GeRPs by phagocytosis(Dectin-1 receptor mediated)
GeRPs release RNAi compound and inflammation target is silenced within the macrophage
Macrophages migrate to various sites in body (bone, spleen liver, lung, joints, etc.)
target is silenced within the macrophage
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Reduced systemic inflammatory response
GeRP Delivery of rxRNA to Macrophages ex vivoGeRP Delivery of rxRNA to Macrophages ex vivop gp g
Macrophages purified from Cynomolgus macaque whole blood
Phase contrast image at 20x magnification Dy547 fluorescent image at 20x magnification Phase contrast and fluorescent images merged
Macrophages purified from Cynomolgus macaque whole blood
Transfected ex vivo with GeRPs:rxRNA
rxRNA is fluorescently labeled with Dy547 (red)
Photographed 48 hrs post transfection
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Therapeutic Potential of Oral Delivery using GeRP TechnologyTherapeutic Potential of Oral Delivery using GeRP Technologyg gyg gy
Represents potential breakthrough in RNAi deliveryRepresents potential breakthrough in RNAi deliveryDelivers RNAi compound directly to macrophage
Target in macrophage is silenced, less inflammation at site
Limited systemic exposure in animal models
Proof of principle demonstrated in animal models
Targeting macrophages may allow treatment of a large number of inflammatory diseases with significant marketsmarkets
Arthritis, Asthma, Crohn’s Disease, Atherosclerosis, Psoriasis, Type II diabetes, etc.
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RXi’s Discovery PipelineRXi’s Discovery Pipeline
Demonstrated in vivo efficacy with RNAi compounds using three y p gdelivery modalities
Local Administration NeurologyDirect intrathecal infusion to CNS with mini-osmotic pumpPublished efficacy in ALS animal model
Systemic Delivery Metabolic Disease Nanoparticles--for liver (and other) delivery Published efficacy for cholesterol lowering in mice
Oral Delivery Inflammatory DiseaseGeRPs Direct targeting of macrophages
Several excellent opportunities for therapeutic developmentInitial development program will be data driven
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Initial development program will be data driven
RXi: Next Generation RNAi TherapeuticsRXi: Next Generation RNAi Therapeutics
Accomplished RNAi Product Focused TeamAccomplished RNAi Product Focused Team
RNAi: Potential Paradigm Changing Approach
Advanced Therapeutic PlatformNext Generation rxRNA
Local, Systemic and Oral Delivery
Discovery Pipeline
Early and Broadly Filed Intellectual Property
Business and Financial OverviewBusiness and Financial Overview
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General RNAi Patent ConsiderationsGeneral RNAi Patent Considerations
“Fire and Mello” licensed non-exclusively to manyFire and Mello licensed non exclusively to many organizations
No single company “owns” the field of RNA interferenceAdditi l i t i ti f th tiAdditional improvement inventions necessary for therapeuticsA limited number of companies and universities own or control specific therapeutic RNAi technology improvements
US Patent and Trademark Office has generally become conservative with RNAi patent applicationsIssued patents in the field tend to be very specific andIssued patents in the field tend to be very specific and narrowly directed to discrete improvements
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IP SummaryIP Summary
RXi’s owned and licensed IP may be used toRXi s owned and licensed IP may be used to impede unlicensed parties from employing rxRNA and our proprietary delivery technologies.
Our proprietary rxRNA compounds provide multiple parallel paths to achieving RNAi which are not covered by our competitors patents.
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Example of rxRNA Configuration Example of rxRNA Configuration
♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦
rxRNA Ver. 1
25-27 units long
“Blunt ends” (no overhangs)
Advanced pattern of chemical modifications
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Fire-MelloFire-Mello
Filed in 1997 Non-Exclusively licensedDouble-stranded RNA to inhibit gene expressionWith or without chemical modificationsSpecifically cites 25-400 unit lengthsHuman therapeutic usesu a t e apeut c uses
Foundational patent “prior art” has lead to the rejection of many claims of more recently filed patent applicationsy p pp
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25-400 units
STEALTH I: 25-27 Blunt ConfigurationSTEALTH I: 25-27 Blunt Configuration
Filed in 2002Filed in 2002
Exclusively
25-30 units
Blunt ended (without overhangs)
25-30 units without overhangs59
STEALTH II: Modified ChemistrySTEALTH II: Modified Chemistry
Filed in 2003Filed in 2003
Exclusive
STEALTH chemical modificationsReduced immune side effects
Enhanced specificity
Nuclease resistantNuclease resistant
25-30 units without overhangs
♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦
25 30 units without overhangs+ STEALTH chemistry in sense strand
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rxRNArxRNA
Owned exclusively by RXiOwned exclusively by RXi2007 Priority Date25-30 unitsBl t d d ( ith t h )Blunt ended (without overhangs)Advanced rxRNA chemical modification pattern
Further reduced immune side effectsEnhanced specificityFurther nuclease resistance
♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦
25-30 units without overhangs
♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦
25 30 units without overhangs+ rxRNA chemistry in sense strand
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Multiple Layers of IP Protection for rxRNAMultiple Layers of IP Protection for rxRNA
1997 non disclosed1997 non-disclosed
2002 Sequitur2002 Subsequences
2001 Hannon1998 Mello
Actual Sequence2007 RXi
2003 Sequitur
Actual Chemistry
rxRNATM
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+ undisclosed FTO on subsequence strategy+ undisclosed optional feature
Broad, Early Intellectual Property Estate with Multiple Layers of ProtectionBroad, Early Intellectual Property Estate with Multiple Layers of Protection
RNAi–Mello
Delivery
Targetsg
rxRNA Chemistry and Configuration
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IP SummaryIP Summary
RXi’s owned and licensed IP protect RXiRXi s owned and licensed IP protect RXi from unlicensed parties from employing rxRNA and our proprietary deliveryrxRNA and our proprietary delivery technologies.
Our proprietary rxRNA compoundsOur proprietary rxRNA compounds provides multiple parallel paths to achieving RNAi which are not covered byachieving RNAi which are not covered by our competitors patents.
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rxRNA Provides Multiple Parallel Paths to RNA Interference* rxRNA Provides Multiple Parallel Paths to RNA Interference*
Alnylam IPClassic siRNA rxRNA (Ia) rxRNA (Ib) rxRNA (II)
(structure not disclosed)
Tuschl I 19-24 bp Y N N N
Tuschl II Overhangs Y N N N
Kreutzer-Limmer Y * N N
ISIS Antisense Chemistries(1980-1990)
N N N N
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*Kreutzer Limmer is under opposition by multiple groups in Europe and has not issued in the US
Tuschl ITuschl I
Projected to issue for 19-23 units lengthsProjected to issue for 19 23 units lengths
Does not cover rxRNA
rxRNA♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦
25-27 units without overhangs
♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦
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25 27 units without overhangs+ chemistry in sense strand
Tuschl IITuschl II
All claims require “overhangs”All claims require overhangs
Does not cover rxRNA
rxRNA
25-27 units without overhangs
♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦
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25 27 units without overhangs+ chemistry in sense strand
Early Antisense Chemistries (1980-1990)Early Antisense Chemistries (1980-1990)
Common modified RNA chemistries (i e 2’-O-Common modified RNA chemistries (i.e., 2 -O-methyl RNA and phosphorothioates) have been known since 1980-1990
Expired or will expire prior to the expected sale of RXi’s therapeutics
Key to RNAi chemistry IP lies in the placement (configuration) of chemical modifications and not the chemistry per se
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IP SummaryIP Summary
RXi’s owned and licensed IP may be used toRXi s owned and licensed IP may be used to impede unlicensed parties from employing rxRNA and our proprietary delivery technologies.
Our proprietary rxRNA compounds provide multiple parallel paths to achieving RNAi which are not covered by our competitors patents.
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RXi: Next Generation RNAi TherapeuticsRXi: Next Generation RNAi Therapeutics
Accomplished RNAi Product Focused TeamAccomplished RNAi Product Focused Team
RNAi: Potential Paradigm Changing Approach
Advanced Therapeutic PlatformNext Generation rxRNA
Local, Systemic and Oral Delivery
Discovery Pipeline
Early and Broadly Filed Intellectual Property
Business and Financial OverviewBusiness and Financial Overview
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RXi Commercial Strategy RXi Commercial Strategy
RXi’s broad technology platform supports multiple product gy p pp p popportunities
Potential of rxRNA to silence virtually any geneMultiple/expanding delivery approaches to a variety of tissuesp p g y pp y
Enables a two-pronged strategyInternal product development programsPartnering to fund a larger number of product development programsPartnering to fund a larger number of product development programs
Efforts focused on building partner awareness of RXi as: As a major force in RNAi therapeuticsProviding FTO in RNAi chemistryOffering deep expertise to enable discovery and preclinical development
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RXi Partnering ProgramRXi Partnering Program
The nature, scope and value of deals is expected toThe nature, scope and value of deals is expected to expand over time
Early deals are expected to focus on discovery of rxRNAs against gene targets of interest to the partnerg g g p
ExpandableOption to employ existing delivery technologies (e.g. nanotransporter)
In the future, RXi partnerships may include:Broader scope, encompassing more targets or entire therapeutic indicationsMore delivery options, such as recently announced oral deliverySpecific products with clinical dataPotential retention of certain commercialize rights (e.g. co-Potential retention of certain commercialize rights (e.g. comarketing) by RXi
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RXi Financial OverviewRXi Financial Overview
Company historyp y yFounded in 2006Operations began in January 2007Initial funding of $15 million in April 2007Initial funding of $15 million in April 2007
Public trading initiated March 12, 2008Completed PIPE June 25, 2008; gross proceeds approx. $8.7 millionmillionCapitalization - outstanding
13.7mm common shares2mm options/warrants
Cash of $15.1 million as of June 30, 2008
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RXi’s 2008-2009 Corporate GoalsRXi’s 2008-2009 Corporate Goals
Commence Public Trading
Consummate First Development Partnership in 2008p p
Consummate Second Development Partnership in 2009
File First IND with the FDA in 2009
Identify Lead rxRNA compound for Second Clinical y pProgram in 2009
Continue to Expand RXi’s Technology Lead p gy
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RXi: Next Generation RNAi TherapeuticsRXi: Next Generation RNAi Therapeutics
RNAi
Management TeamSeasoned &
Potential New Class of Drugs High Value
Therapeutic PipelineNeurology
RNAi Focused Metabolic DiseaseInflammation
RXi Pharmaceuticals
Intellectual Property
Alternative path
RXi’s Therapeutic Platform
rxRNA™
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Alternative pathMultiple LayersOral, systemic and local
delivery