Clinical Development of RXI-109 to Reduce Dermal Scarring

Transcription

1 Clinical Development of RXI-109 to Reduce Dermal Scarring Next Generation in RNAi Pamela A. Pavco Chief Development Officer RXi Pharmaceuticals Corp. TIDES / Boston May 15, 2013 OTC: RXII

2 2 Forward Looking Statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of Such statements include, but are not limited to, statements about the future development of RXi Pharmaceuticals Corporation s (the Company ) products. These forward-looking statements about future expectations, plans and prospects of the development of the Company's products are subject to a number of risks and uncertainties, including those identified under Risk Factors in the Company s most recently filed Annual Report on Form 10- K, 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 History Founded as RXI Pharmaceuticals in 2007 Named changed to Galena Biopharma, Inc. and then spun out as an independent company in April 2012 (OTC:RXII) Approximately $50 million invested to date to develop a broad-based RNAi technology platform and our lead compound, RXI-109 RXi received FDA clearance to begin clinical trials with RXI-109 in mid-2012 Conducted 2 Phase 1 clinical trials with RXI-109 between June 2012 February 2013 Progress in ophthalmology, neurology and liver fibrosis supported by research grants and collaborative projects Located in the greater Boston area Westborough/Worcester, MA

4 sd-rxrna Combines Features of RNAi and Antisense Technologies 4 Conventional RNAi Potent, long-lasting activity sd-rxrna Medicinal Chemistry Improved cell uptake and PK/PD O Conventional Antisense Clinically relevant, validated PK/PD sd-rxrna therapeutic compounds with drug-like properties Single compound, i.e., no delivery vehicle required Proven robust uptake & silencing in multiple preclinical models Structural diversity = novel intellectual property Combining positives of RNAi & antisense, while avoiding negatives Provides for broad pipeline of RNAi drugs for unmet medical needs

5 5 sd-rxrna: Structural Highlights Single chemically-modified RNA compound No delivery formulation required Efficient cellular uptake and gene silencing Potent, stable, specific Robust, long lasting in vivo efficacy in multiple tissues Manufactured under GMP <15 bp duplex 6 nt & longer tail = standard and modified bases = various hydrophobic moieties = phosphodiester linkages = phosphorothioate linkages = other hydrophobic linkages

6 6 RXi s Lead Clinical Product Candidate: RXI-109 FDA Clearance in June 2012 to Begin Clinical Trials with RXI-109

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 Unproven cosmeceutical products sell well >$100 million annually in USA Large underserved market (>$1 B) in scar prevention or revision Clear development precedent with early efficacy endpoints (Excaliard/Pfizer antisense) Partnership potential / larger market for additional therapeutic uses of CTGF silencing in diseases with a fibrotic component Proliferative vitreoretinopathy, liver fibrosis, surgical adhesions, wet AMD, acute spinal injury, restenosis, etc.

8 Connective Tissue Growth Factor A Central Factor in the Pathway to Fibrosis 8 Tissue Regeneration Connective Tissue Growth Factor Central player in the balance between healthy healing and excessive fibrosis Excessive Fibrosis RXI-109 Cellular Effects Collagen Deposition Adhesion Migration Proliferation Differentiation Pathologic Effects Pulmonary Fibrosis Acute Spinal Injury Dermal Anti-Scarring Restenosis Ocular Scarring Liver Fibrosis

9 RXI-109 Overview: Target Selection and Rationale 9 Numerous studies implicate Connective Tissue Growth Factor (CTGF) overexpression in scarring and fibrotic disease RXI-109, an anti-ctgf sd-rxrna compound, is uniquely suited for local delivery, avoiding delivery challenges of systemic RNA-based drugs Preclinical data demonstrate potent, selective, dosedependent and long-lasting silencing of CTGF with RXI-109 Clinical validation with an anti-ctgf antisense

10 CTGF Expression, % NTC RXI-109 Efficiently Silences CTGF in vitro and in vivo CTGF Expression, % PBS CTGF Silencing in vitro CTGF Silencing in vivo in Rat Skin RXI-109 NTC 1 um RXI-109 ( ) 300ug NTC ( ) 300ug PBS % 67% ** *** NTC 1 um RXI-109 Concentration (mm) NTC (1 mm) RXI-109 mg RXI mg 300 NTC mg 600 NTC mg 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 Property of RXi Pharmaceuticals 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

11 Relative Wound Width (% Day 0) Property of RXi Pharmaceuticals % Re-epithelialization CTGF mrna - Relative to PBS 11 CTGF Silencing Does Not Delay Early Wound Healing in a Rodent Model Dose ID 48 hr before Dose ID wound at wounding Dose ID 7 days post wound Silencing of CTGF mrna (Day 5 post wound) Days ** Excisional Wound Harvest Group 1 5 days post wound Harvest Group 2 9 days post wound Harvest Group 3 15 days post wound RXI-109 PBS Wound Width Wound Re-epithelialization * * * RXI-109 PBS * Day 5 Day 15 RXI-109 PBS Days Post Wounding

12 12 RXI-109 Phase 1: Clinical Development Plan Study 1201 (First in Man): Phase 1 single center, randomized, single dose, double-blind, ascending dose, within-subject controlled study of RXI-109 for the treatment of incision scars 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 - Pharmacokinetic parameters after local intradermal injection - Photographic comparison versus vehicle - Histological comparison of the scar sites versus vehicle

13 13 RXI : Overview RXI-109 vs. PBS administered on separate sides of the abdomen Single intradermal dose Dose levels: 5 cohorts of 3 subjects each 1, 2.5, 5, 7.5 and 10 mg per 2 cm incision site Endpoints PK Parameters Safety assessed throughout the 3-month study period Photographs Biomarker / histology assessment at end of study, Day 84 Abdominoplasty on Day 84

14 RXI : Abdominal Incision Layout 14 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.

15 RXI : Preliminary Safety Summary Comparison of Treatment-Related Adverse Events by Study Day Local Skin Study Day Assessment 1 Day 1 Day 2 Day 3 Day 5 Day 8 Day 12 Day 28 Day 56 Day 84 Erythema 14 (23%) 23 (38%) 52 (87%) 30 (50%) 46 (77%) 47 (78%) 60 (100%) 60 (100%) 60 (100%) Tenderness 2 (3%) 16 (27%) 33 (55%) 14 (23%) 14 (23%) 16 (27%) Induration 16 (27%) 11 (18%) 14 (23%) Pain (17%) Urticaria/Pruritis 4 (7%) 1 (2%) 11 (18%) 16 (27%) 29 (48%) 21 (35%) 4 (7%) 6 (10%) 0 Systemic Adverse Study Day Events 2 Day 1 Day 2 Day 3 Day 5 Day 8 Day 12 Day 28 Day 56 Day 84 3 Rash 1 (7%) Xerostomia 1 (7%) 1 (7%) 1 (7%) 1 (7%) 1 (7%) Fever 1 (7%) Nausea 1 (7%) Joint Pain 1 (7%) AEs are graded based on Common Terminology Criteria for Adverse Events (CTCAE) 1 Local skin assessments based on a total of 60 treatment sites (i.e., 15 subjects, 4 sites each) 2 Systemic AEs based on a total of 15 subjects. All systemic AEs are Grade 1, except for Fever (Grade 2). 3 Post Day 84: 1 wound infection 4 days post abdominoplasty (SAE, Grade 3) requiring hospitalization and parenteral antibiotic treatment and 2 instances of seroma (Grade 1) Property of RXi Pharmaceuticals 15

16 # of Incidences ( Grade 2) # of Incidences Property of RXi Pharmaceuticals 16 RXI : Preliminary Safety Summary by Cohort and Grade A. Summary of skin assessments, all grades 30 ERYTHEMA TENDERNESS INDURATION PAIN Day D 1 D 2 D 3 D 5 D 8 12 D 28 D 56 D 84 D D 1 D 2 D 3 D 5 D 8 12 D 28 D 56 D 84 D D 1 D 2 D 3 D 5 D 8 12 D 28 D 56 D 84 D D 1 D 2 D 3 D 5 D 8 12 D D 28 D 56 D 84 D 1 D 2 D 3 D 5 D 8 12 D D 28 D 56 D Cohort Cohort Cohort Cohort Cohort Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 B. Summary of skin assessments, Grade Day Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5

17 ng/ml Protocol RXI : Pharmacokinetic Parameters Following 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

18 Post-dose (Bb mg/ml) Protocol RXI : No Complement Activation After Intradermal Dosing Individual Bb Levels hr hr Pre-dose (Bb mg/ml) No evidence of an RXI-109-related increase in Bb in any subject at any dose level.

19 RXI : Examples of Preliminary Blinded Histology Data Weeks Post-Treatment Normal Skin 1A 1B Preliminary blinded 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 Full analysis will provide wound area assessments on all subjects 2A 2B

20 Scar Area (mm2) 20 RXI , Single Dose Cohort 4: Area (mm 2 ) of Scar Tissue (BLINDED) Example of blinded data from the lower 2 sites on each subject (reported as sum of area from three sections per site) Average of 31% Difference between Sides A B A B A B A and B sides are treated with RXI-109 or placebo Blinded data

21 21 RXI : Example of Preliminary Blinded Biomarker Data 2A 2B Subject Cohort 4 CTGF Trichrome Treatment per side is still blinded Smaller wound area appears to track with lower CTGF expression levels Images of CTGF and Trichrome taken at 20X magnification a-sma image collected at 40X magnification and from adjacent sections a-sma

22 22 RXI : Overview RXI-109 vs. PBS administered on separate sides of the abdomen Three intradermal doses over 2 weeks Dose levels: 3 cohorts of 3 subjects each 2.5, 5 and 7.5 mg per 2 cm incision site Endpoints PK parameters after 1 st and 3 rd dose Safety assessed throughout the 3-month study Photographs Biomarker / histology assessment early (after 2 week dosing period) and late (at end of study, Day 84)

23 RXI : Abdominal Incision Layout 23 R o L 1 2 Wound Addresses R (Right) L (Left) Row 1 1R 1L Row 2 2R 2L 8 injections and incisions (2 cm in length) were made on the abdomen each incision received 3 injections over a given time period. The R and L incisions 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.

24 RXI : Preliminary Safety Summary 24 Dose escalation study w/ three doses and twice the number of sites compared to the first study To date: Local skin observations are not increased in number or severity over a single dose Mild bilateral erythema is common No skin assessment observations >Grade 1 1 AE (Grade 1): folliculitis (resolved with medication) No SAEs

25 Preliminary Plan for Phase 2 Program for RXI randomized, double-blind, within-subject controlled studies Potential indications include: Hysterectomy scar revision Cesarean section scar revision Scar revision following cosmetic breast surgery Bilateral keloid scar revision Study objectives include: Determination of optimal dose and schedule Demonstration of safety and efficacy Planned initiation in H2 of 2013

26 RXI-109 Phase 1: Summary of Observations to Date 26 First studies aimed at showing safety and initial indications of clinical efficacy within months of study initiation with limited number of subjects First P1 single dose study started in June 2012; last dose administered in September 2012 Multi-dose volunteer P1 study started December 2012; last dose administered February 2013 Tolerance and safety considered excellent by investigators & volunteers. No negative effect of RXI-109 on wound healing. Side effects minimal with injection site redness as possibly drug related; the redness was NOT dose related Based on human and animal exposure intradermal injection provides <5% maximum systemic exposure as compared to intravenous injection Differences between R & L sites can be seen but studies are still blinded

27 27 RXi Pharmaceuticals Milestones Q2 2013: Unblinded data on RXI-109 single dose Phase 1 (safety, side effects, PK, clinical & histology) mid-2013: Unblinded data on RXI-109 multi-dose Phase 1: H2 2013: Start Phase 2 studies with RXI-109 in scar revision Partnering activities in additional areas

28 28 RXi s Product Pipeline Program Discovery Preclinical Clinical Anti-Scarring (RXI-109) Ophthalmology (PVR) Liver disease / Liver fibrosis (RXI-209) Ophthalmology (Macular Degeneration) Ophthalmology (Retinoblastoma) CNS (ALS) Phase 1 Phase 2 Phase 3 core focus strategic interest projected next steps

29 29 sd-rxrna: Delivery Technology Results in Robust Cellular Uptake in vitro and in vivo 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 column macrophages Liver

30 30 sd-rxrna: Improved Retinal Delivery vs. Stabilized RNAi Compounds sd-rxrna Conventional 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 with Dy547-labeled sdrxrna, conventional sirna or placebo

31 PPIB Expression, % of NTC sd-rxrna: Extended Silencing in vivo in the Rodent Eye 31 Duration of Silencing Induced by PPIB Targeting sd-rxrna % ** 45% ** 32% ** Time after injection, days 22% ** PBS NTC PPIB * p 0.05 ** p 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 PBS = Phosphate Buffered Saline (Placebo) NTC = Non-Targeting Control sd-rxrna PPIB = Anti-cyclophilin B sd-rxrna

32 32 Acknowledgements RXi Pharmaceuticals Geert Cauwenbergh CEO Pamela Pavco CDO Karen Bulock VP Research Lyn Libertine VP Medical Affairs/Safety Assessment Michael Byrne Scientist II Pathi Pandarinathan Scientist II James Cardia Manager, Platform Technology Katherine Holton Associate Scientist Tamara McGrillen Manager, Operations and Administration Caitlin Kontulis Controller, Finance Scientific Advisory Board Craig Mello UMass Medical School Leroy Young General / Plastic Surgery, Director BodyAesthetic Research Center, PI for RXI Jeannette Graf Clinical and Research Dermatologist, Assistant Clinical Professor of Dermatology, Mount Sinai School of Medicine