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#8225 RXI-109 Reduces a Key Component of Dermal Scarring, Connective Tissue Growth Factor (CTGF) mRNA, in a MultiDose Phase 1 Clinical Trial 1Lyn Libertine MD, 1Pamela Pavco PhD, 1Karen Bulock PhD, Katherine Holton, 2Nelly Paz MD, 1Geert Cauwenbergh Dr. Dr. Med. Sc. 1RXi Pharmaceuticals, Corp., Westborough MA 2Hospital y Clinica Bendana, Honduras This work was supported entirely by RXi Pharmaceuticals. Property of RXi Pharmaceuticals 72nd Annual Meeting of the American Academy of Dermatology March 21-25, 2014, in Denver, CO RXI-109 Background There are currently no drugs approved to prevent hypertrophic scar or keloid formation RXI-109 targets and reduces CTGF, a key regulator of the dermal scarring pathway RXI-109 is an sd-rxRNA® that works through an RNA interference (RNAi) mechanism sd-rxRNAs are small interfering RNAs (siRNA) designed with RXi’s proprietary technology sd-rxRNAs are efficiently taken up by cells RXI-109 is delivered locally to the incision/scar site Early treatment with RXI-109 may reduce hypertrophic scarring and keloid formation Two Phase 1 safety trials have been completed RXI-109-1201, an ascending dose, single dose study is presented in Poster #8214 RXI-109-1202, an ascending dose, multi-dose study is presented here Phase 2 trials have initiated Additional related work presented at AAD 2104: 2 Preclinical data: Poster #8326 Property of RXi Pharmaceuticals Study RXI-109-1202: Overview A 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 placebo - Histological comparison of the scar sites versus placebo - Pharmacokinetic parameters after local intradermal injection - CTGF protein & mRNA levels - Photographic comparison versus placebo 3 Property of RXi Pharmaceuticals RXI-109-1202: Study Design and Abdominal Incision Layout RXI-109-1202 Multi-dose 5 dose cohorts (1 cohort w/ delayed dosing); 3 subjects each Dose range 2.5 – 10 mg per incision site Biopsies on Days 18 and 84 A o B 1 2 • Eight (8) injections and incisions (2 cm in length) were made on the abdomen of healthy volunteers. • Treatment at each incision site was made by intradermal injection according to a predetermined randomization pattern for each subject. • Randomized treatment to one side with RXI-109, one side with placebo. • Each incision received 3 injections over a given time period. • Incisions were spaced at least 4 cm apart. • Safety assessments were made throughout the 3-month study. 4 Property of RXi Pharmaceuticals Study RXI-109-1202: Safety Results Conclusions: • No significant side effects nor toxicity were observed. • Treatments did not reduce 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 • No immunological reactions • No changes noted in liver function tests, kidney or cardiovascular function, complement, coagulation, urinalysis, hematology or blood chemistry Monitored for side effects, safety and toxicity in the 7 days post injections, 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 5 Property of RXi Pharmaceuticals Protocol RXI-109-1202: Pharmacokinetic Parameters After Intradermal Dosing Cohort Averages by Day 400 Dose 1 - 10 mg Dose 3 - 10 mg RXI-109 in whole blood (ng/mL 350 Dose 1 - 20 mg 300 Dose 3 - 20 mg 250 Dose 1 - 30 mg 200 Dose 3 - 30 mg 150 Dose 1 - 40 mg 100 Dose 3 - 40 mg 50 0 0 10 20 Cohort Total Dose Per Treatment Day (mg) 1 10 2 20 3 30 4 40 6 30 40 Hours 50 60 70 80 Day Tmax (hr) Cmax (ng/mL) AUClast (hr*ng/mL) 1 14.7 ± 5.9 80.4 ± 14.7 3706 ± 624 15 13.4 ± 9.3 97.0 ± 19.6 4073 ± 815 1 15 1 15 1 15 20.0 ± 6.9 13.5 ± 9.4 20.0 ± 6.9 13.3 ± 9.3 20 ± 6.93 13.4 ± 10.1 161 ± 35 185 ± 23 239 ± 53 275 ± 55 172 ± 54 258 ± 110 7553 ± 1385 7293 ±1037 10695 ± 1835 11704 ± 119 8341 ± 2087 11044 ± 3493 Property of RXi Pharmaceuticals RXI-109-1202 Skin Assessments Number of Incidences RXI-109 Treatment Placebo Treatment 7 Property of RXi Pharmaceuticals RXI-109-1202 Safety Conclusions Local side effect profile more closely related to the mechanics of incisions and injections than drug Local effects were bilateral in nature Most erythema was noted to be mild (Grade 1) In 1201 local side effects presented unilaterally 8 All sites with early side effects were dosed with RXI-109 Property of RXi Pharmaceuticals RXI-109-1202: CTGF mRNA Silencing by Cohort CTGF mRNA Three Days Post Third Dose CTGF % Unwounded Expression 1200 Placebo 1000 RXI-109 800 600 43% * 400 43% 50% 45% ** 200 0 (RXI-109 mg/incision each treatment day) Cohort 1 Cohort 2 Cohort 3 Cohort 4 (2.5 mg) (5 mg) (7.5 mg) (10 mg) Cohort 2,3,4 (5-10 mg) p = 0.80 p = 0.046 p = 0.12 p = 0.14 p = 0.002 CTGF mRNA levels were upregulated in biopsies collected 3 days after the third dose compared to samples of unwounded skin Skin samples treated with the higher doses of RXI-109 (Cohorts 2-4 combined) had a statistically significant reduction of CTGF mRNA compared to samples treated with placebo No additional benefit was seen on CTGF mRNA reduction using a delayed dosing regimen, 10 mg per incision Reduction of CTGF mRNA in RXI-109 treated sites is consistent with mechanism of action of the drug Study RXI-109-1202: Conclusions Safety and Pharmacokinetics Safe and well tolerated at all dose levels tested (single and multi-dose) No negative effect on healing in healthy volunteers with no predisposition for bad scarring Cmax and AUC increase proportionally with increased administered dose Maximum blood level of RXI-109 is only 5% of intradermally administered dose There is no evidence of significant accumulation of RXI-109 in the blood after repeat administration with this dosing regimen Biomarkers Preclinical data demonstrate potent, dose dependent silencing of CTGF with RXI109 in vitro and in vivo with no delay in early wound healing RXI-109-1202: Statistically significant reduction in CTGF mRNA three days after the third dose in RXI-109 treated sites compared to placebo control. Dose dependent silencing with more pronounced effect (average 45% silencing, p<0.002) with higher doses tested. Data consistent with the expected mechanism of action of RXI-109 10 Property of RXi Pharmaceuticals