Results from a 52 Week Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of a Novel, Intra-Articular, Wnt Pathway Inhibitor (SM04690) for the Treatment of Knee Osteoarthritis

Yusuf Yazici¹, Timothy E. McAlindon², Allan Gibofsky³, Nancy E. Lane⁴, Daniel J. Clauw⁵, Eddie Armas⁶, Nebojsa Skrepnik⁷, Christopher J. Swearingen¹, Anita DiFrancesco¹, Jeymi Tambiah¹ and Marc Hochberg⁸, ¹Samumed, LLC, San Diego, CA, ²Division of Rheumatology, Tufts Medical Center, Boston, MA, ³Rheumatology, Weill Cornell Medicine, and Hospital for Special Surgery, New York, NY, ⁴Center for Musculoskeletal Health, University of California at Davis, Hillsborough, CA, ⁵Chronic Pain & Fatigue Research Center, University of Michigan, Ann Arbor, MI, ⁶Well Pharma Medical Research, Miami, FL, ⁷Tuscon Orthopedics Institute, Tuscon, AZ, ⁸Head, Division of Rheumatology & Clinical Immunology; Vice Chair, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: clinical trials, Osteoarthritis, radiography and small molecules, WNT Signaling

Session Information

Date: Sunday, November 5, 2017

Title: Osteoarthritis – Clinical Aspects I: Pain and Functional Outcomes

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Knee osteoarthritis (OA) is characterized by pain, disability and joint deformity due to articular cartilage degradation and bone remodeling. Wnt signaling is involved in these cellular processes and inflammation. SM04690, a small molecule Wnt pathway inhibitor, is in development as a potential disease modifying drug for knee OA. A phase 2, multicenter, 52-week, randomized, double-blind, placebo-controlled (PBO) trial was conducted to determine the safety and efficacy of SM04690.

Methods: Knee OA subjects with Kellgren-Lawrence (KL) grades 2-3, received a single 2 mL injection of 0.03 mg, 0.07 mg, 0.23 mg SM04690 or PBO in target (most painful) knees. Western Ontario and McMaster Universities Arthritis Index Outcome (WOMAC) Pain [0-50] and Function [0-170] were assessed at Weeks 0, 4, 13, 26, 39 and 52, and radiographs were taken at Weeks 0, 26 and 52 for medial joint space width (mJSW). Analysis of covariance adjusted for baseline in the intention-to-treat (ITT) population was conducted with multiple imputation. Two subgroups were explored: 1) unilateral symptomatic knee OA subjects as determined by investigator through history and examination (pre-specified), and 2) unilateral symptomatic knee OA subjects without widespread pain (Widespread Pain Index ≤4 and Symptom Severity ≤2 [WP], post-hoc).

Results: 455 subjects (mean age 60.3 [±8.7], BMI 29.9 [±4.6] kg/m², female 58.9%, KL 3 [64.4%], unilateral symptomatic OA [36.0%]) were enrolled. Serious adverse events, all deemed unrelated to SM04690, were reported in 17 (3.7%) subjects (4.5% [0.03 mg], 3.5% [0.07 mg], 3.8% [0.23 mg], 2.8% [PBO]).

In the ITT population, clinically meaningful outcomes improvements (>10% full range) compared to baseline were seen in all groups at all timepoints. Unilateral symptomatic subjects treated with 0.07 mg SM04690 had significant improvements in WOMAC Pain with clinically meaningful and significant improvements in WOMAC Function compared to PBO at Week 52. Unilateral symptomatic subjects without WP treated with 0.07 mg SM04690 had clinically meaningful and significant improvements in WOMAC Pain and Function compared to PBO at Weeks 26, 39, and 52 (Figure). At Week 52 in the ITT population, mean changes in mJSW were -0.14 mm in PBO, 0.10 mm in 0.03 mg (NS), 0.06 mm in 0.07 mg (NS), and -0.02 mm 0.23 mg (NS).

Conclusion: In this phase 2 study, improvements compared to PBO in WOMAC Pain and Function were seen in study subgroups of unilateral symptomatic and unilateral symptomatic without WP subjects. SM04690 maintained or improved mJSW over 52 weeks. Radiographic and clinical outcomes suggested SM04690 has potential as a DMOAD for knee OA treatment.

Disclosure: Y. Yazici, Samumed, LLC, 3,Samumed, LLC, 1; T. E. McAlindon, None; A. Gibofsky, Pfizer Inc, 1,AbbVie, 1,Amgen, 1,Bristol-Myers Squibb, 1,Johnson & Johnson, 1,Regeneron, 1,AbbVie, 5,AbbVie, 8,Pfizer Inc, 5,Pfizer Inc, 8,Celgene, 8,Novartis Pharmaceutical Corporation, 8,Takeda, 5,Horizon, 5,Relburn, 5,Samumed, 5; N. E. Lane, Pfizer Inc, 5,Eli Lilly and Company, 5,Regeneron, 5,Amgen, 5,Samumed, LLC, 5; D. J. Clauw, Abbott Pharmaceutical, 5,Aptinyx, 5,Astellas Phamaceutical, 5,Cerephex, 5,Daiichi Sankyo, 5,Pfizer Inc, 5,Pierre Fabre, 8,Samumed, 5,Theravance, 5,Tonix, 5; E. Armas, Samumed, LLC, 2; N. Skrepnik, Orthofix, 5,Regeneron, 5,Sanofi-Aventis Pharmaceutical, 5; C. J. Swearingen, Samumed, LLC, 3,Samumed, LLC, 1; A. DiFrancesco, Samumed, LLC, 3,Samumed, LLC, 1; J. Tambiah, Samumed, LLC, 3,Samumed, LLC, 1; M. Hochberg, Bioiberica SA, 5,Bristol-Myers Squibb, 5,EMD Serono, 5,Galapagos, 5,IBSA SA, 5,Novartis Pharmaceutical Corporation, 5,Pfizer Inc, 5,Plexxicon, 5,Samumed LLC, 5,Theralogix LLC, 5,TissueGene, 5,NIH, 2,Theralogix LLC, 1.

To cite this abstract in AMA style:

Yazici Y, McAlindon TE, Gibofsky A, Lane NE, Clauw DJ, Armas E, Skrepnik N, Swearingen CJ, DiFrancesco A, Tambiah J, Hochberg M. Results from a 52 Week Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of a Novel, Intra-Articular, Wnt Pathway Inhibitor (SM04690) for the Treatment of Knee Osteoarthritis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/results-from-a-52-week-randomized-double-blind-placebo-controlled-phase-2-study-of-a-novel-intra-articular-wnt-pathway-inhibitor-sm04690-for-the-treatment-of-knee-osteoarthritis/. Accessed .

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