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Individual Participant Symptom Responses to Intra-Articular Lorecivivint in Knee Osteoarthritis: Post Hoc Analysis of a Phase 2B Trial

Tambiah, Jeyanesh R S; Kennedy, Sarah; Swearingen, Christopher J; Simsek, Ismail; Yazici, Yusuf; Farr, Jack; Conaghan, Philip G
INTRODUCTION/BACKGROUND:Established thresholds for patient-reported outcomes (PROs) provide clinically relevant responder data from trials. Lorecivivint (LOR) is an intra-articular (IA) therapy in development for knee osteoarthritis (OA). A post hoc analysis from a phase 2b trial (NCT03122860) determined proportions of LOR responders. METHODS:A 24-week, randomized trial of 0.07 mg LOR demonstrated PRO improvements compared with PBO in moderate-to-severe knee OA participants. Participants treated with LOR and PBO achieving 30%/50%/70% improvements at weeks 12 and 24 in Pain Numeric Rating Scale (NRS), WOMAC Pain/Function subscales, Patient Global Assessment (PtGA), and OMERACT-OARSI responder criteria were determined. Odds ratios (ORs) and 95% confidence intervals [CIs] were compared with PBO. RESULTS:There were 115 and 116 participants in the LOR and PBO groups, respectively. For Pain NRS, LOR increased ORs of achieving 30% [week 12, OR = 2.47 (1.45, 4.19), P < 0.001; week 24, OR = 2.37 (1.40, 4.02), P < 0.01] and 50% [week 24, OR = 1.89 (1.11, 3.23), P < 0.05] improvements over baseline. For WOMAC Pain, LOR increased ORs of achieving 30% [week 24, OR = 1.79 (1.06, 3.01), P < 0.05] and 50% [week 12, OR = 1.79 (1.06, 3.03), P < 0.05; week 24, OR = 1.73 (1.02, 2.93), P < 0.05] improvements. For WOMAC Function, LOR increased ORs of achieving 30% [week 12, OR = 1.85 (1.10, 3.12), P < 0.05; week 24, OR = 1.93 (1.14, 3.26), P < 0.05] improvements. For PtGA, LOR increased ORs of achieving 50% [week 12, OR = 2.28 (1.25, 4.16), P < 0.01] improvements. LOR produced numerical increases at the 70% threshold. LOR increased ORs of achieving OMERACT-OARSI responses [week 12, OR = 2.21 (1.29, 3.78); P < 0.01; week 24, OR = 2.57 (1.49, 4.43), P < 0.001] and strict responses [week 12, OR = 2.13 (1.26, 3.61), P < 0.01; week 24, OR = 2.05 (1.21, 3.47), P < 0.01]. CONCLUSIONS:LOR (0.07 mg) demonstrated improved PRO threshold responses across single and composite measures of pain, function, and patient global assessment compared with PBO, with benefits sustained to 24 weeks.
PMID: 34101138
ISSN: 2198-6576
CID: 4899782

Faulty analysis of a Takayasu arteritis cohort: Comment on the Article by Goel et al [Letter]

Yazici, Hasan; Oztas, Mert; Yazici, Yusuf
There are important problems with the data analyses, interpretation, and the cited references in the recently reported retrospective cohort study of Takayasu arteritis (TAK) (1).
PMID: 33982898
ISSN: 2326-5205
CID: 4867632

A Phase 2b Randomized Trial of Lorecivivint, a Novel Intra-articular CLK2/DYRK1A Inhibitor and Wnt Pathway Modulator for Knee Osteoarthritis

Yazici, Yusuf; McAlindon, Timothy E; Gibofsky, Allan; Lane, Nancy E; Lattermann, Christian; Skrepnik, Nebojsa; Swearingen, Christopher J; Simsek, Ismail; Ghandehari, Heli; DiFrancesco, Anita; Gibbs, Jamielle; Tambiah, Jeyanesh; Hochberg, Marc C
OBJECTIVE:Lorecivivint (LOR; SM04690), an investigational Wnt pathway modulator, previously demonstrated patient-reported and radiographic outcome improvements versus placebo in clinically relevant subjects with moderate to severe knee osteoarthritis (OA). This study's objective was to identify effective LOR doses. DESIGN/METHODS:Subjects in this 24-week, Phase 2b, multicenter, randomized, double-blind, placebo (PBO)-controlled trial received an intra-articular injection of 2 mL LOR (0.03, 0.07, 0.15, or 0.23 mg), PBO, or dry-needle sham. The primary efficacy endpoints were changes in Pain NRS [0-10], WOMAC Pain [0-100], WOMAC Function [0-100], and radiographic mJSW outcomes, which were measured using baseline-adjusted analysis of covariance at Week 24. Multiple Comparison Procedure-Modeling (MCP-Mod) was performed for dose modeling. RESULTS:In total, 695/700 subjects were treated. Pain NRS showed significant improvements versus PBO after treatment with 0.07 mg and 0.23 mg LOR at Weeks 12 (-0.96, 95% CI [-1.54, -0.37], P=0.001; -0.78, [-1.39, -0.17], P=0.012) and 24 (-0.70, [-1.34, -0.06], P=0.031; -0.82, [-1.51, -0.12], P=0.022). Additionally, 0.07 mg LOR significantly improved WOMAC Pain and Function subscores versus PBO at Week 12 (P=0.04, P=0.021), and 0.23 mg LOR significantly improved both WOMAC subscores at Week 24 (P=0.031, P=0.017). No significant differences from PBO were observed for other doses. No radiographic progression was observed in any group at Week 24. MCP-Mod identified 0.07 mg LOR as the lowest effective dose. CONCLUSION/CONCLUSIONS:This 24-week Phase 2b trial demonstrated the efficacy of LOR on PROs in knee OA subjects. The optimal dose for future studies was identified as 0.07 mg LOR.
PMID: 33588087
ISSN: 1522-9653
CID: 4786552

Comment on: 'It can't be zero!' Difficulties in completing patient global assessment in rheumatoid arthritis: a mixed methods study

Pincus, Theodore; Gibson, Kathryn A; Yazici, Yusuf; Bergman, Martin; Schmukler, Juan; Block, Joel A
PMID: 33020808
ISSN: 1462-0332
CID: 4626772

The OMERACT Core Set of Domains for Outcome Measures in Behçet Syndrome

Hatemi, Gülen; Meara, Alexa; Ozguler, Yesim; Direskeneli, Haner; Mahr, Alfred; Shea, Beverly; Cam, Esen; Gul, Ahmet; Yazici, Yusuf; Tugwell, Peter; Yazici, Hasan; Merkel, Peter A
OBJECTIVE:There is an unmet need for reliable, validated, and widely-accepted outcome measures for randomized clinical trials in Behçet syndrome (BS). The Outcome Measures in Rheumatology Clinical Trials (OMERACT) BS Working Group, a large, multi-disciplinary group of experts in BS and patients with BS, worked to develop a Core Set of data-driven outcome measures for use in all clinical trials of BS. METHODS:The Core Domain Set was developed through a comprehensive, iterative, multi-stage project which included a systematic review, a focus group meeting and qualitative patient interviews, a survey among experts in BS, a Delphi exercise involving both patients and physician-experts in BS, and utilization of the data, insight, and feedback generated by these processes to develop a final Core Domain Set. RESULTS:All steps were completed and domains were delineated across the organ systems involved in this disease. Since trials in BS often focus on specific manifestations and not the disease in its entirety, the final proposed Core Set includes 5 domains mandatory for study in all trials in BS (disease activity, new organ involvement, quality of life, adverse events, and death) with additional sub-domains mandatory for study of specific organ-systems. The final Core Set was endorsed at the 2018 OMERACT meeting. CONCLUSION/CONCLUSIONS:The Core Set of Domains in BS provides the foundation through which the international research community, including clinical investigators, patients, biopharmaceutical industry, and government regulatory bodies can harmonize the study of this complex disease, compare findings across studies, and advance development of effective therapies.
PMID: 33202101
ISSN: 2151-4658
CID: 4672612

SM04755, a Small-Molecule Inhibitor of the Wnt Pathway, as a Potential Topical Treatment for Tendinopathy

Deshmukh, Vishal; Seo, Tim; Lauren O'Green, Alyssa; Ibanez, Maureen; Hofilena, Brian; Sunil, K C; Stewart, Joshua; Dellamary, Luis; Chiu, Kevin; Ghias, Abdullah; Barroga, Charlene; Kennedy, Sarah; Tambiah, Jeymi; Hood, John; Yazici, Yusuf
The Wnt pathway is upregulated in tendinopathy, affecting inflammation and tenocyte differentiation. Given its potential role in tendinopathy, this signaling pathway may be a relevant target for treatment. The current study examined the therapeutic potential of SM04755, a topical, small-molecule Wnt pathway inhibitor, for the treatment of tendinopathy using in vitro assays and animal models. In vitro, SM04755 decreased Wnt pathway activity, induced tenocyte differentiation, and inhibited catabolic enzymes and pro-inflammatory cytokines in human mesenchymal stem cells, rat tendon-derived stem cells, and human peripheral blood mononuclear cells. Evaluation of the mechanism of action of SM04755 by biochemical profiling and computational modeling identified CDC-like kinase 2 (CLK2) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as molecular targets. CLK and DYRK1A inhibition by siRNA knockdown or pharmacological inhibition induced tenocyte differentiation and reduced tenocyte catabolism. In vivo, topically applied SM04755 showed therapeutically relevant exposure in tendons with low systemic exposure and no detectable toxicity in rats. Moreover, SM04755 reduced tendon inflammation and showed evidence of tendon regeneration, decreased pain, and improved weight-bearing function in rat collagenase-induced tendinopathy models compared with vehicle control. Together, these data demonstrate that CLK2 and DYRK1A inhibition by SM04755 resulted in Wnt pathway inhibition, enhanced tenocyte differentiation and protection, and reduced inflammation. SM04755 has potential to benefit symptoms and modify disease processes in tendinopathy. This article is protected by copyright. All rights reserved.
PMID: 33104243
ISSN: 1554-527x
CID: 4646332

Lorecivivint, a Novel Intra-articular CLK/DYRK1A Inhibitor and Wnt Pathway Modulator for Treatment of Knee Osteoarthritis: A Phase 2 Randomized Trial

Yazici, Yusuf; McAlindon, Timothy E; Gibofsky, Allan; Lane, Nancy E; Clauw, Daniel; Jones, Morgan; Bergfeld, John; Swearingen, Christopher J; DiFrancesco, Anita; Simsek, Ismail; Tambiah, Jeyanesh; Hochberg, Marc C
OBJECTIVE:To assess the safety and efficacy of the novel Wnt pathway modulator lorecivivint (SM04690) for treating pain and inhibiting structural progression in moderate-to-severe symptomatic knee osteoarthritis (OA). METHODS:Subjects in this 52-week, Phase 2a, multicenter, randomized, double-blind, placebo (PBO)-controlled, dose-ranging trial received a single, 2 mL, intra-articular injection of 0.03 mg, 0.07 mg, or 0.23 mg lorecivivint, or PBO. Efficacy was assessed by change in WOMAC Pain [0-100] and WOMAC Function [0-100] subscales and radiographic medial joint space width (mJSW). Baseline-adjusted analysis of covariance with multiple imputation was performed separately to evaluate efficacy. This proof-of-concept study evaluated the intention-to-treat population as well as a prespecified group of subjects with unilateral symptoms (UNI) and an additional post hoc subgroup of unilateral symptomatic subjects without widespread pain (UNI WP-). RESULTS:Four hundred fifty-five subjects were randomized. The primary endpoint, improvement in WOMAC Pain compared with PBO at Week 13, was not met by any dose group (change from baseline, 0.03 mg, -23.3±2.2; 0.07 mg, -23.5±2.1; 0.23 mg, -21.3±2.2; PBO, -22.1±2.1; all P>0.05). All groups (including PBO) demonstrated clinically meaningful (≥20-point) improvements from baseline. The durability of response was evaluated through Week 52. In the prespecified UNI and post hoc UNI WP-groups at Week 52, 0.07 mg lorecivivint significantly improved WOMAC Pain (between-group differences [95% CIs]: UNI, -8.73 [-17.44, -0.03], P=0.049; UNI WP-, -11.21 [-20.99, -1.43], P=0.025) and WOMAC Function (UNI, -10.26 [-19.82, -0.69], P=0.036; UNI WP-, -13.38 [-24.33, -2.43], P=0.017) compared with PBO. Compared with baseline, the mean change in mJSW at Week 52 was -0.04 mm in the 0.03 mg cohort, -0.09 mm in the 0.07 mg cohort, -0.16 mm in the 0.23 mg cohort, and -0.14 mm in the PBO cohort; no treatment group achieved a statistically significant change in mJSW compared with PBO at Week 52. In both unilateral subgroups, the 0.07 mg dose significantly increased mJSW compared with PBO at 52 weeks, (UNI, 0.39 mm [0.06, 0.72], P=0.021; UNI WP-, 0.42 mm [0.04, 0.80], P=0.032). Changes in the 0.03 mg and 0.23 mg dose groups were not statistically different from PBO in any of these measures. Lorecivivint appeared safe and well tolerated. CONCLUSION/CONCLUSIONS:This Phase 2a, proof-of-concept trial did not meet its primary endpoint; however, it identified a target population in which to evaluate the potential efficacy of lorecivivint.
PMID: 32432388
ISSN: 2326-5205
CID: 4444302

Correspondence on 'classification criteria: time for a rethink 'by D Porter et al' [Letter]

Yazici, Hasan; Yazici, Yusuf
PMID: 32938636
ISSN: 1468-2060
CID: 4593182

A Small-Molecule Inhibitor of the Wnt Pathway, Lorecivivint (SM04690), as a Potential Disease-Modifying Agent for the Treatment of Degenerative Disc Disease

Deshmukh, Vishal; Ibanez, Maureen; Hu, Haide; Cahiwat, Joseph; Wei, Ying; Stewart, Joshua; Hood, John; Yazici, Yusuf
BACKGROUND CONTEXT/BACKGROUND:Abnormal Wnt signaling in intervertebral discs (IVDs) progresses degenerative disc disease (DDD) pathogenesis by impairing nucleus pulposus (NP) cell function, decreasing matrix deposition, and accelerating fibrosis. PURPOSE/OBJECTIVE:This study was conducted to evaluate the effects of lorecivivint (LOR; SM04690), a small-molecule Wnt pathway inhibitor, on IVD cells and in an animal model of DDD. STUDY DESIGN/METHODS:We used in vitro assays and a rat model of DDD to test the effects of LOR on NP cell senescence and viability, annulus fibrosus (AF) cell fibrosis, and cartilage regeneration and protection. METHODS:Wnt pathway gene expression was measured in human NP and AF cell cultures treated with LOR or DMSO (vehicle). Chondrocyte-like differentiation of rat and human NP cells, NP cell senescence and protection, and AF cell fibrosis were assessed using gene expression and immunocytochemistry. Disc and plasma pharmacokinetics were analyzed following intradiscal LOR injection in rats. In vivo effects of LOR and vehicle on AF integrity, AF/NP junction, NP cellularity and matrix, and disc height (DH) were compared using histopathology and radiography in a rat coccygeal IVD needle-puncture model of DDD. RESULTS:In NP and AF cell cultures, LOR inhibited Wnt pathway gene expression compared with vehicle. In NP cells, LOR inhibited senescence, decreased catabolism, and induced differentiation into chondrocyte-like cells; in AF cells, LOR decreased catabolism and inhibited fibrosis. A single intradiscal LOR injection in rats resulted in therapeutic disc concentrations (∼30 nM) for >180 days and minimal systemic exposure. DDD-model rats receiving LOR qualitatively demonstrated increased cartilage matrix and reduced AF lamellar disorganization and fragmentation with significantly (P<0.05) improved histology scores and increased DH compared with vehicle. CONCLUSIONS:LOR showed beneficial effects on IVD cells in vitro and reduced disease progression in a rat model of DDD compared with vehicle, suggesting that LOR may have disease-modifying therapeutic potential. CLINICAL SIGNIFICANCE/CONCLUSIONS:The current therapeutic options for DDD are pain management and surgical intervention; there are no approved therapies that alter the progression of DDD. Our data support advancing LOR into clinical development as an injectable, small-molecule, potential disease-modifying treatment for DDD in humans.
PMID: 32413487
ISSN: 1878-1632
CID: 4431762

Disease activity measures at baseline predict structural damage progression: data from the randomized, controlled AMPLE and AVERT trials

Keystone, Edward C; Ahmad, Harris A; Yazici, Yusuf; Bergman, Martin J
OBJECTIVE:Data from two double-blind, randomized, Phase III studies were analysed to investigate the ability of Routine Assessment of Patient Index Data 3, DAS28 (CRP), modified (M)-DAS28 (CRP) and Simplified or Clinical Disease Activity Indices to predict structural damage progression in RA. METHODS:This post hoc analysis included data from the 2-year Abatacept vs adaliMumab comParison in bioLogic-naïvE RA subjects with background MTX (AMPLE) trial in biologic-naïve patients with active RA (<5 years) and an inadequate response to MTX, and the 12-month treatment period of the Assessing Very Early Rheumatoid arthritis Treatment (AVERT) trial in MTX-naïve patients with early RA (⩽2 years) and poor prognostic indicators. Adjusted logistic regression analysis assessed the relationship between baseline disease activity and structural damage progression (defined as change from baseline greater than the smallest detectable change) at 12 and 24 months in AMPLE and 6 and 12 months in AVERT. Areas under the receiver operating characteristic curves for the impact of baseline disease activity on structural damage progression were calculated. RESULTS:Adjusted logistic regression analyses included all randomized and treated patients in AMPLE (N = 646) and those who received abatacept plus MTX or MTX monotherapy in AVERT (N = 235). Baseline Routine Assessment of Patient Index Data 3, DAS28 (CRP) and M-DAS28 (CRP) scores significantly predicted structural progression at months 12 and 24 in AMPLE (P < 0.05) and months 6 and 12 in AVERT (P < 0.01), and were stronger predictors than Simplified or Clinical Disease Activity Indices. CONCLUSION/CONCLUSIONS:In this post hoc analysis of two patient populations with RA, Routine Assessment of Patient Index Data 3, DAS28 (CRP) and M-DAS28 (CRP) were good at predicting structural damage. TRIAL REGISTRATION/, NCT00929864 (AMPLE); NCT01142726 (AVERT).
PMID: 31819995
ISSN: 1462-0332
CID: 4234302