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A5927 - A Phase 2 Trial of KD025 to Assess Efficacy, Safety and Tolerability in Patients with Idiopathic Pulmonary Fibrosis
Author Block: F. Averill1, T. E. Albertson2, D. M. Baratz3, S. Chaudhary4, S. Mobin5, T. O'Brien6, M. B. Scholand7, T. P. M. Whelan8, M. Poyurovsky9, O. Schueller9, J. Ryan9, K. F. Gibson10; 1St. Francis Medical Center, Clearwater, FL, United States, 2University of California, Davis, Sacramento, CA, United States, 3Pulmonary Associates, PA, Phoenix, AZ, United States, 4University of Arizona CATS Research Center, Tucson, AZ, United States, 5Central Florida Pulmonary Group, Orlando, FL, United States, 6Pulmonary Disease Specialists, Kissimmee, FL, United States, 7University of Utah Pulmonary Clinical Research, Salt Lake City, UT, United States, 8Medical University of South Carolina, Charleston, SC, United States, 9Kadmon Corporation, LLC, New York, NY, United States, 10Univ of Pittsburgh Med Ctr, Pittsburgh, PA, United States.
RATIONALE Rho-Associated Coiled-Coil Kinases (ROCK1 and ROCK2) are regulators of the actomyosin cytoskeleton and function as central downstream mediators of multiple pro-fibrotic signaling pathways. KD025 (ROCK2 selective inhibitor in biochemical assays) demonstrated attenuation of fibrosis, immune cell infiltration and collagen deposition in mouse models of bleomycin‑induced pulmonary fibrosis and cGvHD. METHODS In this open-label Phase 2 study, IPF patients who had previously received pirfenidone and/or nintedanib (P/N) or had been offered both were randomly assigned (2:1) to receive KD025 400 mg QD or standard of care excluding P/N (SOC). The primary endpoint was change in forced vital capacity (FVC) from baseline to week 24 (w24). Patients could elect to continue KD025 to 96 weeks. Secondary endpoints include change in severity of fibrosis by HRCT and change in 6-minute walk distance. SOC patients who experienced progression could cross-over to KD025 at any time. RESULTS 39 patients were assigned to KD025 (n=25) or SOC (n=14). 74% were male, average age 72.5. %Predicted FVC (%FVC) at baseline was 67.8% for KD025 and 70.2% for SOC. Average time since IPF diagnosis was ~2.5 years. As of 15 October 2017, 11 evaluable patients treated with KD025 have reached w24, and 4 evaluable patients in the SOC arm have reached w24 without crossing-over to KD025. The change in FVC was -68(±170) mL with KD025 and -173(±130) mL with SOC, or -1.5%(±4.2) vs -5.0%(±5.0) %FVC, respectively. With KD025, only 1/11 evaluable patients experienced a decline in FVC >5%, compared to 3/4 with SOC. All 11 patients on KD025 elected to continue KD025 treatment. 6 SOC patients crossed-over before w24. Two have completed 24 weeks with KD025 and both had stable FVC (changes: -50mL and +10mL). In preliminary safety analyses (n=31 KD025 (including cross-overs), n=14 SOC), median durations of exposure were 167 and 110 days. Commonly reported AEs (KD025, SOC) were: cough (10%,21%), fatigue (16%,7%), dyspnea (13%,14%), dizziness (13%,7%). Elevated LFTs were reported for 6(19%) and 2(14%) patients, including 1 on KD025 with reversible Gr3. SAEs were reported for 9 on KD025 and 0 SOC. The only SAEs in >1 patient were acute respiratory failure and MI (n=2). No SAEs were considered possibly/probably related to KD025. CONCLUSIONS KD025 was safe and well-tolerated in IPF patients. Early data show a numerically lower decline in FVC with KD025 than with SOC without antifibrotic therapy, with only 1/11 KD025 vs 3/4 SOC evaluable patients experiencing an FVC decline >5% at w24.