RXi Pharmaceuticals Corporation

Transcription

1 RXi Pharmaceuticals Corporation Next Generation in RNAi Piper Jaffray Conference December 4, 2013 OTCQX: RXII

2 2 Forward Looking Statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of Words such as believes, anticipates, plans, expects, indicates, will, intends, potential, suggests and similar expressions are intended to identify forward-looking statements. These statements are based on RXi Pharmaceuticals Corporation s (the Company ) current beliefs and expectations. Such statements include, but are not limited to, statements about the future development of the Company s products (including timing of clinical trials and related matters associated therewith), the expected timing of certain developmental milestones, the reporting of unblinded data, potential partnership opportunities, the Company s competition and market opportunity and pro forma estimates. The inclusion of forward-looking statements should not be regarded as a representation by the Company that any of its plans will be achieved. Actual results may differ from those set forth in this presentation due to risks and uncertainties in the Company s business, including those identified under Risk Factors in the Company s most recently filed Quarterly Report on Form 10-Q and in other filings the Company periodically makes with the U.S Securities and Exchange Commission. The Company does not undertake to update any of these forward-looking statements to reflect a change in its views or events or circumstances that occur after the date of this presentation.

3 3 Corporate Highlights (1) RXi is a leader in development of advanced RNAi-based therapeutics with strong IP position Self-delivering technology has advantages in safety, potency & selectivity Experienced scientific and development team (2) RXI-109, RXi s lead product, silences a clinically validated target and circumvents many challenges facing other RNAi-based drugs Reduction of CTGF with an antisense oligonucleotide correlated with improved scars in well-controlled clinical trials Delivered locally; avoiding many challenges of other RNA-based drugs > $1 billion market opportunity in scar prevention/revision (3) Multiple development opportunities based on its RNAi platform Dermatology, ophthalmology, organ fibrosis, spinal cord injury Platform potential enhanced by OPKO Health, Inc. asset purchase

4 4 Broad Intellectual Property Position in RNAi Compounds and Delivery RXi s Unique RNAi Platform RNA Duplex Length sd-rxrna dsrna Conventional sirna rxrnaori Kreutzer-Limmer sd-rxrna self-delivering compounds can enter cells and tissues to silence, without the need for an additional delivery vehicle Has several properties key to the clinical development of RNAi-based drugs (potency, selectivity/specificity, half-life) rxrnaori Similarities to classic sirna, but slightly longer duplex length The compound is highly active at picomolar levels in vitro Modified to increase resistance to nucleases and to prevent off target effects, including induction of an immune response

5 sd-rxrna Combines Features of RNAi and Antisense Technologies 5 Medicinal Chemistry Improved cell uptake and PK/PD Single compound designed to not require delivery vehicle Conventional RNAi Potent, long-lasting activity O Conventional Antisense Clinically relevant, validated PK/PD Robust uptake & silencing in multiple preclinical models Structural diversity = novel intellectual property Combining many positives of RNAi & antisense, while avoiding many negatives sd-rxrna Provides for broad pipeline of RNAi drugs for unmet medical needs sd-rxrna therapeutic compounds with drug-like properties

6 sd-rxrna: Robust Cellular Uptake in vitro and in vivo 6 Keratinocytes human primary ARPE-19 retinal pigment epithelium SH-SY5Y neuroblastoma Macrophages primary mouse Hepatocytes primary mouse Delivery and silencing demonstrated in many different cell types Human, Primate, Rat, Mouse, Adherent, Non-adherent, Primary, Transformed Efficient delivery of sd-rxrna to multiple tissues in vivo upon local and systemic administration Alveolar Skin Eye Spinal cord macrophages Liver

7 7 Selection of Area of Focus: Dermal Scarring Attractive Therapeutic Opportunity Unmet need with limited competition for truly effective therapies No prescription drugs approved Clear development precedent (Excaliard antisense) Large market in scar prevention/revision 42.3 million surgical procedures per year in the U.S.* Courtesy of Dirk M Elston MD Courtesy skincareguide.ca *US anti-scarring market The Nemetz Group December 2009

8 8 RXI-109 Selection Rationale & Overview RXi s Lead Clinical Product Candidate: RXI-109 Numerous studies implicate Connective Tissue Growth Factor (CTGF) overexpression in scarring and fibrotic diseases CTGF-targeting antisense oligo demonstrated improved scarring (vs. placebo) in 3, Phase 2 trials by another company RXI-109, an anti-ctgf sd-rxrna compound, is delivered locally, avoiding delivery challenges of systemic RNA-based drugs Preclinical data demonstrate potent, selective, dose-dependent and long-lasting silencing of CTGF with RXI-109 RXI-109 addresses a large market opportunity in scar prevention/revision, that today is underserved (>40 million surgical procedures) Phase 1 human data supports the biological MOA of RXI-109

9 CTGF Expression, % NTC CTGF Expression, % PBS 9 RXI-109 Efficiently Silences CTGF in in vitro and in vivo Preclinical Experiments CTGF Silencing in vitro RXI NTC 1 um CTGF Silencing in vivo in Rat Skin RXI-109 ( ) 300ug NTC ( ) 300ug PBS 51% 67% ** *** NTC 1 um RXI-109 Concentration (mm) NTC (1 mm) RXI-109 mg RXI mg 300 NTCmg 600 NTCmg PBS ( ) ( ) ( ) ( ) RXI-109 NTC 300ug 600ug 300ug 600ug RXI-109 injections Day A549 cells were treated with RXI-109 and NTC Passive uptake 48 hours EC50 = /- 6.3 nm Excisional Wound mrna levels were quantified by QPCR on Day 8, normalized to the housekeeping gene and set relative to PBS. **p=0.0015, *** (relative to the dose-matched NTC) PBS = Phosphate Buffered Saline (Vehicle Control) NTC = Non-Targeting Control sd-rxrna Harvest

10 10 RXI-109 Phase 1 Clinical Trials (1) Study 1201: Phase 1 single center, randomized, single-dose, double-blind, ascending dose, within-subject controlled study of RXI-109 for the treatment of incision scars (2) Study 1202: Phase 1 single center, randomized, multi-dose double-blind, ascending dose, within-subject controlled study of RXI-109 for the treatment of incision scars Parameters evaluated: - Safety & side effect assessment versus vehicle - Photographic comparison versus vehicle - Histological comparison of the scar sites versus vehicle - Pharmacokinetic parameters after local intradermal injection

11 RXI : Abdominal Incision Layout Study Data Locked and Unblinded 11 A o B 1 2 Wound Addresses Column A (Right) Column B (Left) Row 1 1A 1B Row 2 2A 2B Four injections and incisions (2 cm in length) were made on the abdomen. The A and B columns were at least 4 cm lateral to the midline of the abdomen. Rows were spaced at least 4 cm apart. Treatment at each incision site was made by intradermal injection according to a predetermined randomization pattern for each subject. Half of the sites were treated with RXI-109, half with placebo.

12 RXI : Safety Data Monitoring for side effects, safety and toxicity in the 7 days post injection, and regularly afterwards for up to 3 months. Parameters monitored included: ECG Blood Biochemistry Blood Count Urinalysis and LFTs Complement and Coagulation Clinical Assessments of Incisions by Physician & Subjects RXI-109 in Systemic Circulation after Intradermal Injection Conclusions: No significant side effects nor toxicity were observed. Incisions did not show slower healing on the active or the placebo side, i.e. no negative effect on wound healing/closure. Maximum blood level of RXI-109 is only 5% of intradermally administered dose 12

13 RXI-109 in whole blood (ng/ml) Protocol RXI : Pharmacokinetic Parameters After Intradermal Dosing mg 5 mg 10 mg 15 mg 20 mg Hours Cohort Total Dose (mg) Tmax (hr) Cmax (ng/ml) AUClast (hr*ng/ml) ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 3394

14 14 150% RXI-109 Reduction of CTGF Protein Levels in RXI Day 84 Level of CTGF protein in RXI-109 dosed sites are shown as a percent of placebo dosed sites 125% ** 100% 100% 97% 102% * 87% 83% 85% 75% 50% Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 4 &5 Paired t-test p-values

15 15 RXI : Clinical & Histological Data 12 Weeks Post-Treatment Normal Skin 1A - RXI-109 1B - Placebo Unblinded data Trichrome staining of incision sites from one of three subjects in Cohort 4 Single injection of 7.5 mg Images taken at 20X magnification 2A - RXI-109 2B - Placebo

16 16 Conclusions: RXI No negative effect on healing with single injection of RXI-109 Statistically significant lowering of CTGF protein concentration in RXI-109 treated incisions compared to placebo control 3 months after a single dose (i.e., potent and long lasting) Trend for dose dependent silencing with more pronounced effect at the 2 highest doses

17 17 RXI : Abdominal Incision Layout Study Data Locked and Unblinded for 1202a A o B 1 2 Wound Addresses Side A (Right) Side B (Left) 1A 3A 3B 1B 2A 4A 4B 2B 8 injections and incisions (2 cm in length) were made on the abdomen each incision received 3 injections over a given time period. The A and B columns were at least 4 cm lateral to the midline of the abdomen. Rows were spaced at least 4 cm apart. Treatment at each incision site was made by intradermal injection according to a predetermined randomization pattern for each subject. Half of the sites were treated with RXI-109, half with placebo.

18 RXI : Safety Data Monitoring for side effects, safety and toxicity after each injection; 7 days post 1 st and 2 nd injections, 3 days post 3 rd injection, and regularly afterwards for up to 3 months. Parameters monitored included: ECG Blood Biochemistry Blood Count Urinalysis and LFTs Complement and coagulation Clinical Assessments of Incisions by Physician & Subjects RXI-109 in Systemic Circulation after Intradermal Injection Conclusions: No significant side effects nor toxicity were observed. Incisions did not show slower healing on the active or the placebo side, i.e. no negative effect on wound healing/closure. Maximum blood level of RXI-109 is only 5% of intradermally administered dose 18

19 RXI-109 in whole blood (ng/ml Protocol RXI : Pharmacokinetic Parameters After Intradermal Dosing Cohort Averages by Day Dose 1-10 mg Dose 3-10 mg Dose 1-20 mg Dose 3-20 mg Dose 1-30 mg Dose 3-30 mg Dose 1-40 mg Dose 3-40 mg Cohort Hours Dose Per Treatment Day (mg) Day Tmax (hr) Cmax (ng/ml) AUClast (hr*ng/ml) ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

20 Pharmacokinetic Conclusions from the Phase 1 Program 20 C max and AUC increase proportionally with increased administered dose up to 30 mg Based on human and animal data, intradermal injection of RXI-109 results in little distribution from the site of administration and low maximum systemic exposure (~5% of administered dose) There is no evidence of significant accumulation of RXI-109 in the blood after repeat administration with this dosing regimen

21 CTGF % Unwounded Expression RXI CTGF mrna Silencing by Cohort 1200 CTGF mrna Three Days Post Third Dose 1000 Placebo RXI % * 43% 50% 45% ** 200 mg RXI-109 per incision on each treatment day 0 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 2,3,4 p = 0.80 p = p = 0.12 p = 0.14 p = Note: No additional benefit was seen on CTGF mrna reduction in Cohort 5 (delayed dosing regimen, 10 mg per incision) 21

22 % CTGF relative to normal % CTGF relative to normal RXI : CTGF mrna Data from Cohort 3 (Subject Unblinded) 600 Top Sites RXI Placebo RXI-109 Bottom Sites Placebo RXI-109 1R Placebo 1L 22

23 23 Biomarker Analysis Summary Preclinical data demonstrates potent, dose dependent silencing of CTGF with RXI-109 in vitro and in vivo No delay in early wound healing RXI : Statistically significant lowering of CTGF protein concentration in RXI-109 treated incisions compared to placebo control 3 months after a single dose Trend toward dose dependent reduction in CTGF protein with more pronounced effect at higher doses RXI : Statistically significant reduction in CTGF mrna three days after the third dose in RXI-109 treated sites compared to placebo control Dose dependent CTGF mrna silencing with more pronounced effect (45% silencing, p<0.002) with higher doses tested (Cohorts 2-4) Data consistent with expected mechanism of action of RXI-109

24 24 Planned Phase 2 Program for RXI randomized, within-subject controlled studies Potential indications include: Lower abdominal scar revision Bilateral keloid scar revision Scar revision following cosmetic breast surgery Study objectives include: Determination of optimal dose and schedule Demonstration of efficacy and safety Phase 2 initiated in November 2013

25 25 Estimated Timeline for P2 Trials Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q P1 (1201) 5 cohorts P1 (1202) 3 cohorts 2 cohorts P2 Scar revision (lower abdomen) (1301) P2 Keloid removal (1302) P2 Scar revision (breast surgery) (14XX) Estimated start Estimated start Estimated start

26 Advancing the Product Pipeline Multiple Development Opportunities Program Discovery Preclinical Clinical Anti-Scarring (RXI-109) Ophthalmology (PVR) Ophthalmology (Macular Degeneration) Ophthalmology (Retinoblastoma) Ophthalmology (Bevasiranib sequence based) Liver disease / Liver fibrosis (RXI-209) CNS (ALS) Phase 1 Phase 2 Phase 3 Core focus Strategic interest Ophthalmology franchise Projected next steps 26

27 Property 27 of RXi Pharmaceuticals Retinal Scarring as a Second Local Application of RXI Local delivery possible by intravitreal injection As used by current treatments for AMD CTGF is implicated in retinal scarring IND-supporting toxicology studies overlap IV toxicology studies and P2-supporting genotoxicity studies are complete Requires additional ocular toxicity studies only Retinal scarring can result in irreversible damage to the retina and vision loss

28 sd-rxrna: In Ophthalmology: Improved Delivery vs. Stabilized RNAi Byrne et al., JOPT. November 2013, published online ahead of print 28 sd-rxrna Stabilized Placebo sirna Mouse immediately post-dose Mouse at 24 hours post-dose Mouse at 24 hours post-dose Rabbit at 24 hours post-dose sd-rxrna chemistry is required for robust uptake to the cells of the eye No overt toxicity observed after sd-rxrna treatment to the eye Dosing by intravitreal injection to mouse or rabbit eye Dy547-labeled sd-rxrna, stabilized sirna or placebo

29 PPIB Expression, % of NTC sd-rxrna: Extended Silencing in vivo in the Rodent Eye Byrne et al., JOPT. November 2013, published online ahead of print 29 Duration of Silencing Induced by PPIB Targeting sd-rxrna % ** 45% ** 32% ** Time after injection, days 22% ** PBS NTC PPIB 3 mg PPIB or NTC administered by intravitreal injection (in 1 ml) to mouse eyes mrna levels were quantified by Quantitative PCR (QPCR) and normalized to b-actin Data assembled from 5 different studies to enable sufficient n for each data point (n=5-8); graphed +/- SD relative to PBS in each study; * p 0.05, ** p 0.01 PBS = Phosphate Buffered Saline (Placebo) NTC = Non-Targeting Control sd-rxrna PPIB = Anti-cyclophilin B sd-rxrna

30 RXI-109 in Proliferative Vitreoretinopathy (PVR) 30 PVR is caused by scar tissue formation within the eye Most common complication of a retinal detachment (RD) Occurs in approximately 8-10% of patients who develop an RD Preclinical data strongly support CTGF involvement A potential orphan indication with unmet need Collaboration with Steven Fisher, Ph.D. and Geoff Lewis, Ph.D. (UCSB) to demonstrate efficacy in the rat retina scar model Potential to file an IND cross referencing the RXI-109 anti-scarring IND with minimal ocular toxicity studies

31 In Vivo Silencing of CTGF and Uptake in Model of Retinal Detachment In vivo silencing In vivo retinal uptake in rat retinal detachment model In vivo cellular uptake by reactive cells involved in retinal scarring RXI-209 silences CTGF in a normal rat retina 48 hours post intravitreal administration fl-rxi-109 (red) is detectable in all retinal layers 24 hours post injection both in the presence and absence of a detachment and at 14 days in a detached retina. Specifically, RXI-109 is taken up by Müller cells and photoreceptors. 31

32 32 Potential for Combination Treatment of Ocular Neovascularization / Fibrotic Disorders VEGF-targeting sd-rxrna Dose dependent mrna silencing of up to 90% with a duration of action through 14 days in vivo in rat retina Potential treatment either alone or in combination with a CTGF-targeting sd-rxrna for retinopathy disorders Therapeutics relying on suppression of VEGFA address the neovascularization component of these disorders but not the subsequent retinal scarring that often occurs* Potential indications include proliferative diabetic retinopathy (PDR), wet AMD and others *Van Geest, et al Br J Ophthalmol 2012:96:

33 Conversion of Bevasiranib to a Self Delivering RNAi Compound 33 Passenger Strand Guide Strand Bevasiranib Configuration 19 bp duplex Key = standard ribonucleotide bases = 2 deoxyribose bases = phosphodiester linkages Phase III Clinical Trial of Bevasiranib was initiated in 2007 NDA not filed with FDA Conversion of Bevasiranib into a sd-rxrna Reduce length of Passenger strand (<15 bp duplex) Identify optimal self delivering chemical modification pattern Add hydrophobic conjugate to Passenger strand to enhance cellular penetration Example sd-rxrna Bevasiranib Configuration Key = standard and modified bases Passenger Strand = various hydrophobic moieties Guide Strand = phosphodiester linkages <15 bp duplex 5 nt & longer tail = phosphorothioate linkages = other hydrophobic linkages

34 34 Retinoblastoma Retinoblastoma is a cancer that originates in the retina and primarily affects young children. Accounts for about 3% of cancers occurring in children younger than 15 years of age. The heritable form is driven by mutations in the retinoblastoma (RB1) gene. Expression of genes involved in the normal signaling circuitry of retinal cells are also involved. Our goal is to develop compounds against novel retinoblastoma therapeutic targets. Progress to date: Dose-dependent mrna silencing in retinoblastoma cell lines Uptake by human retinoblastoma cells in vivo in a mouse model Funded by NIH/NCI SBIR grant

35 35 Twenty-four Hours Post Injection sd-rxrna Co-localize with Tumor Cells Throughout the Eye Retinoblastoma = tumor cells = sd-rxrna + Subretinal space Vitreous Uptake of sd-rxrna in vivo in mouse retina and tumor cells 24 hr post injection Retina Mouse eyes were seeded subretinally with Y79 retinoblastoma cells 10 µg of DY547-labeled sd-rxrna (red) was administered by intravitreal injection (1µl) 3 weeks after seeding

36 36 Milestones Milestone Goal 30-to-1 reverse split access to large institutional funds July 2013 RXI-109 annual report and updated IND to FDA August 2013 Enrolled 2 more cohorts in multi-dose Phase 1 study August 2013 Start 2 nd production batch RXI-109 to support all Phase 2 trials August 2013 Phase 2 protocol + updated investigator s brochure to FDA September 2013 Phase 2 site initiation visit for hypertrophic scars October month data from the 2 additional Phase 1 cohorts Q Request PIND meeting with FDA for ophthalmology program Q First patient in - Phase 2 study Q Start keloid revision surgery study Q Exchange uplisting pending: subject to a $4 closing price for some days

37 37 Financial Overview Cash a/o 9/30/13 Burn rate ~$15.8 million ~$1.5-2 million/quarter Available cash with current plan Q No Debt Common shares outstanding a/o 9/30/13 ~11.7 million Closing share price 9/30/13 $3.50 Market Cap ~$41 million

38 38 Investment Thesis (1) RXi is a leader in development of advanced RNAi-based therapeutics with strong IP position Self-delivering technology has advantages in safety, potency & selectivity Experienced scientific and development team (2) RXI-109, RXi s lead product, silences a clinically validated target and circumvents many challenges facing other RNAi-based drugs Reduction of CTGF with an antisense oligonucleotide correlated with improved scars in well-controlled clinical trials Delivered locally; avoiding many challenges of other RNA-based drugs > $1 billion market opportunity in scar prevention/revision (3) Multiple development opportunities based on its RNAi platform Dermatology, ophthalmology, organ fibrosis, spinal cord injury Platform potential enhanced by OPKO Health, Inc. asset purchase