0 4 11 13 20 21 21 21 27 27 30 49 54 55 56 103 105 130 145 197 504 514 746 0 100 200 300 400 500 600 700 800 Desmoid tumor Neuroendocrine - 300mg 7X/wk Ovarian Cancer - 300 mg Neuroendocrine - 300mg 7X/wk Gastric Cancer - 300mg 3X/wk Neuroendocrine - 200mg 5X/wk Colorectal Cancer- 775 mg Neuroendocrine - 250mg 3X/wk NSCLC Neuroendocrine- 300mg 5X/wk Mucoepidermoid- 575 mg Testicular - 425 mg Triple Negative Breast Cancer - 300 5X/wk Leiomyosarcoma - 50 mg Ovarian Cancer- 100 mg Adenoid cystic carcinoma - 225 mg Squamous Cell Carcinoma-775 mg Cervical Cancer- 150mg 5X/wk Colorectal Cancer - 300 5X/wk Breast - 25 mg Neuroendocrine - 300mg 7X/wk Paraganglioma - 300 mg Neuroendocrine - 300 mg GI Mesenteric Neuroendocrine - 150 mg Results of a Phase 1 Study of RX-5902, an Orally Bioavailable Inhibitor of Phosphorylated p68, Targeting Solid Tumors S. Gail Eckhardt 1 , W. Larry Gluck 2 , Martin Gutierrez 3 , Christine Peterson 4 , Reza Mazhari 4 and Ely Benaim 4 1 University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO, 2 Translational Oncology Research, Greenville, SC, 3 John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, 4 Rexahn Pharmaceuticals, Inc., Rockville, MD For further information about RX-5902 and Rexahn Pharmaceuticals please contact Dr. Ely Benaim: benaime@rexahn.com , (240) 268-5300 x304 Abstract # 2554 1. Christine Peterson, PhD,, Reza Mazhari, PhD, and Ely Benaim, MD – Rexahn Pharmaceuticals Investigator Disclosures Background: RX-5902 is a novel compound that targets phosphorylated p68 RNA helicase (also known as DDX5), a member of the DEAD box family of RNA helicases. Phosphorylated p68 may play a vital role in cell proliferation and tumor/cancer progression. As a single agent, RX-5902 inhibits tumor growth, alters cell migration and enhances survival in a variety of in vivo animal xenograft tumor models (e.g., breast, ovarian, renal, pancreatic). We report the data from the first clinical study of RX-5902 as a single agent to treat solid tumors. Methods: This is a Phase 1 study (NCT02003092) designed to evaluate safety, tolerability and pharmacokinetics following increasing doses of RX-5902 at varying schedules. Primary objectives include safety, tolerability and dose limiting toxicities to identify the maximum tolerated dose and a recommended phase 2 dose and schedule (RP2D). Secondary objectives were pharmacokinetics (PK) and antitumor activity (RECIST v1.1). Eligible subjects (aged ≥ 18 years) with relapsed/refractory solid tumors received oral RX-5902 at 1, 3, 5 or 7 times per week for 3 weeks followed by 1 week of rest or for 4 weeks without a rest. Plasma concentrations were measured using a validated LC-MS/MS assay, and non-compartmental pharmacokinetic parameters were calculated using WinNonlin, Version 6.4. Results: As of January 2016, 18 subjects have been enrolled (8 Females, 10 males). No dose limiting toxicities or treatment related SAEs have been reported. Six subjects have experienced stable disease; three subjects are currently receiving treatment for > 1 year. The most common side effects were grade 1 related adverse events: nausea, vomiting and fatigue; no grade 2 related events have been reported. RX-5902 was orally bioavailable with median Tmax of 2 hours and median elimination half-life of 12 hours. Conclusions: Data from this study support that RX-5902 is safe and well tolerated at the doses and schedules tested. Early Antitumor activity has been observed. A recommended phase 2 dose for RX- 5902 for the treatment of triple negative breast cancer and advanced ovarian cancer will be presented. This is a Phase 1/2a study (NCT02003092) designed to evaluate safety, tolerability and pharmacokinetics (PK) following increasing doses of RX-5902 at varying schedules. Primary objectives include safety, tolerability and dose limiting toxicities to identify the maximum tolerated dose and a recommended phase 2 dose and schedule (RP2D). Secondary objectives were PK and antitumor activity. Eligible subjects (aged ≥ 18 years) with relapsed/refractory solid tumors received oral RX-5902 at 1, 3, 5 or 7 times per week for 3 weeks followed by 1 week of rest or for 4 weeks. Based on the RP2D of the Phase 1, a Phase 2a is ongoing in patients with advanced TNBC and OC in a 2-stage design. Study Design Patient Demographics and Prior Treatments Adverse Event Number of Subjects per severity grade, n Grade 1 Grade 2 Grade 3 Overall Constipation 1 1 Diarrhea 1 1 2 Fatigue 3 2 1 6 Generalized weakness 1 1 Headache 1 1 Hypotension 1 1 Myalgias 1 1 Nausea 2 3 5 Neutropenia 1 1 Somnolence 1 1 Weight Loss 3 2 5 Vomiting 3 1 4 Parameter Overall Gender, n (%) 24 Female 11 (46%) Male 13 (54%) Median age (range) 58 (25-86) Race, n (%) White 23 (96%) Other 1 (4%) ECOG performance status, n (%) 0 6 (25%) 1 18 (75%) Number of prior anticancer treatments, n (%) 1 3 (13%) 2 5 (22%) 3 2 (9%) 4+ 13 (56%) • RX-5902 is safe and well tolerated at the doses and schedules tested. • Early anti-tumor activity was observed in patients with breast, neuroendocrine, paraganglioma, head and neck and colorectal cancers. • Continuous dosing is currently being tested • The study was recently amended to target triple negative breast cancer or ovarian cancer in a 2-stage Phase 2 • p68 phosphorylation at Tyr593 by c-Abl (Yang et al. Cell 2006) • Phospho-p68 promotes EMT via promoting β-catenin nuclear translocation (Yang et al Cell 2006) • Phospho-p68 mediates PDGF stimulated cell proliferation via promoting transcription of cyclin D1 and c-Myc genes (Yang et al J Biol Chem 2007) • Phospho-p68 correlates with cancer progression • β-catenin translocates into the nucleus, where it binds to diverse DNA-binding partners to regulate gene transcription • The β-catenin nuclear translocation and subsequent interaction with various targets (including T-cell factor/lymphoid enhancer factor [TCF/LEF] transcription factors) is required for the EMT process • Studies underway to further characterize β-catenin interaction Wang et al, Mol Cell Proteomics 2012; Yang et al, Cell 2006; He Cell, 2006, Yang J Biol Chem 2007 Baseline Characteristics of Patients. 28 potential patients were screened of which 24 were enrolled and 21 were treated with RX-5902. All 24 patients enrolled entered with Stage IV disease. Pharmacokinetic profiles of RX-5902. Dose proportional increase in plasma exposure up to dose of 575 mg daily, with slight accumulation from Days 1 to 15. Rapid oral absorption, with elimination half life suitable for once daily dosing. Dose N Dose Scheme Dose Number Cmax Tmax T1/2 AUClast AUClast/Dose (mg) (µg/L) (hr) (hr) (hr*µg/L) (hr/L*1000) 100 1 1 / Week 1 252 2 2341 23 150 1 1 / Week 1 226 6 11.4 3280 22 225 1 1 / Week 1 364 4 12.0 4312 19 300 2 1 / Week 1 385 3.8 16.6 5847 19 425 1 1 / Week 1 660 2 14673 35 575 1 1 / Week 1 707 4 10098 18 775 2 1 / Week 1 571 2.8 6570 8 250 1 3 / Week 1 394 2 14.0 5211 21 250 1 3 / Week 7 403 2 7774 31 300 1 3 / Week 1 288 6 10.3 4555 15 300 1 3 / Week 7 301 2 4143 14 150 1 5 / Week 1 227 2 2152 14 150 1 5 / Week 11 347 1 3721 25 200 1 5 / Week 1 337 4 8.5 2752 14 200 1 5 / Week 11 440 2 4034 20 300 2 5 / Week 1 433 1.8 4200 14 300 2 5 / Week 11 498 1.3 4359 15 Patient Demographics and Prior Treatments RX-5902 Proposed Mechanism Safety Profile Pharmacokinetics Pharmacokinetic (PK) samples were collected on Day 1 (for single weekly dosing) and Day 15 (multiple weekly doses) for 48 hours. Plasma concentrations were measured using a validated LC-MS/MS assay, and non-compartmental pharmacokinetic parameters were calculated using WinNonlin, Version 6.4. Population PK model was built and used for pharmacokinetic/pharmacodynamics assessments. Treatment (Days) and Best Response Conclusions Best overall response of stable disease