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Background: Behcet's syndrome, a chronic, multi-system variable vessel vasculitis, is often characterized by painful oral ulcers (OU) affecting quality of life (QoL). Apremilast (APR), an oral PDE4 inhibitor, demonstrated efficacy in OU treatment in the phase 3 multinational RELIEF study.
Objective(s): To evaluate APR efficacy in OU treatment in patients with active Behcet's syndrome in a prespecified subgroup of patients enrolled in 13 European RELIEF sites (France, Germany, Greece, and Italy).
Method(s): patients were adults with active Behcet's syndrome and >=3 OU at randomization or >=2 OU at screening and randomization, without active major organ involvement. Patients were randomized (1:1) to APR 30 mg BID or PBO during a 12-week double-blind phase. The primary endpoint was area under the curve for the number of OU through Week 12 (AUCWk0-12). Other outcomes were OU pain visual analog scale (VAS); achievement of OU complete response (ie, OU-free) and maintenance of OU complete response (ie, complete response at Week 6 and remaining OU-free for >=6 additional weeks); OU partial response (ie, OU reduction >=50%); disease activity (Behcet's Syndrome Activity Score [BSAS]; Behcet's Disease Current Activity Form [BDCAF], including Behcet's Disease Current Activity Index [BDCAI], and Patient's and Clinician's Perception of Disease Activity); and QoL (BDQoL; Short Form Health Survey version 2 [SF-36v2], including Physical Functioning [PF] scale and Physical and Mental Component Summary [PCS, MCS]).
Result(s): Of 207 patients randomized and treated in RELIEF, 52 were in the European subgroup. Mean (+/-SD) age in the subgroup was 39 (+/-12) years; 54% were women. Baseline disease characteristics were similar between treatment groups (Table 1). Patients receiving APR achieved lower AUCWk0-12 for OU vs PBO (Figure 1) and greater reduction in pain. A greater proportion of patients receiving APR achieved complete, maintained, or partial OU responses at Week 12 vs those receiving PBO (Table 1). Consistent treatment effects favoring APR vs PBO were observed in disease activity, as shown by BSAS and BDCAF component scores at Week 12 (Table 1). Greater improvement in SF-36v2 MCS was observed favoring APR vs PBO at Week 12, and moderate treatment differences were seen for other QoL measures (BDQoL, SF-36v2 PF, and SF-36v2 PCS).
Conclusion(s): In the European subgroup of patients with Behcet's syndrome and OU in RELIEF, APR resulted in greater reduction in OU count, OU pain, and disease activity as well as favorable treatment effect on QoL measures than PBO. These results are consistent with the efficacy of APR treatment in the overall RELIEF population

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.

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).

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.

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.

Introduction: Apremilast demonstrated efficacy in the treatment of the oral ulcers (OU) of Behcet's syndrome in a phase III, multicenter, randomized, double-blind, placebo-controlled study (RELIEF).
Objective(s): To assess apremilast efficacy in patients with Behcet's syndrome for OU, OU pain, disease activity, and QoL, as well as their relationship.
Material(s) and Method(s): 207 patients were randomized (1:1) to apremilast 30 mg BID or placebo for 12 weeks, followed by a 52-week active treatment extension. Patients had active Behcet's syndrome, with >=3 OU at randomization or >=2 OU at screening and randomization, without active major organ involvement. The primary endpoint was area under the curve for number of OU through 12 weeks (AUCWk0-12). Clinical improvement of OU was evaluated by OU pain assessments (100-mm VAS) and measures of disease activity using the Behcet's Syndrome Activity Score (BSAS), Behcet's Disease Current Activity Form (BDCAF), and Behcet's Disease QoL (BDQoL). Pearson's correlation coefficients and associated P values assessed the relationship in change from baseline scores at 12 weeks among BSAS, BDCAI, and BDQoL with OU number and change in OU pain.
Result(s): AUCWk0-12 was significantly lower in apremilast vs. placebo (P<0.0001). This treatment effect is supported by significant improvements in OU number and pain (both P<0.0001), disease activity using BSAS (P<0.0001), BDCAI (P=0.0335), and BDQoL (P=0.0003) at Week 12. With apremilast, significant correlations were observed between numbers of OU vs. change in BSAS (P<0.0001) and BDCAI (P=0.0081); change in OU pain vs. BSAS (P<0.0001), BDQoL (P=0.0036), and BDCAI (P=0.0146); and change in BSAS vs. BDQoL (P=0.0237) and BDCAI (P=0.0007).
Conclusion(s): Apremilast demonstrated significant improvements in number and pain of OU, measures of disease activity and QoL. Significant correlations between improvements in OU number and pain, disease activity, and QoL in apremilast-treated patients suggest that beneficial effects of apremilast are internally consistent