Faculty Bibliography

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

Background: Painful, recurring oral ulcers (OU) associated with Behcet's syndrome negatively affect quality of life (QoL). Differences across sexes were reported in the frequency of disease manifestations, disease course, and response to colchicine. The phase 3, randomized, double-blind, placebo (PBO)-controlled RELIEF study showed overall efficacy of apremilast (APR) for OU associated with Behcet's syndrome, including improvements in OU pain, disease activity, and QoL.
Objective(s): To evaluate the consistency of efficacy with APR in men and women with Behcet's syndrome.
Method(s): Adults with active Behcet's syndrome and >=3 OU at randomization or >=2 OU at screening and randomization, without active major organ involvement, were randomized to APR 30 mg BID or PBO during the 12-wk PBO-controlled phase. Randomization was stratified by sex. The primary endpoint was area under the curve for the number of OU through Wk 12 (AUCWk0-12) to assess continued efficacy over the time period in a symptom that waxed and waned. Key secondary endpoints included OU pain, complete response (OU-free), maintenance of complete response, and QoL at Wk 12. Disease activity was also assessed using Behcet's Syndrome Activity Score (BSAS) and Behcet's Disease Current Activity Index Form (BDCAF). QoL was assessed using Behcet's Disease QoL (BDQoL). Prespecified subgroup analyses in men and women were performed to assess treatment effect in primary and secondary endpoints.
Result(s): Eighty men and 127 women were randomized and received >=1 dose of study medication. Mean age was 38.7 yrs (men) and 40.8 yrs (women). Mean (SD) OU count at baseline was 3.4 (1.4) (PBO) and 3.7 (1.5) (APR) for men and 4.3 (3.2) (PBO) and 4.5 (4.5) (APR) for women. Greater improvements in favor of APR vs PBO were observed in AUCWk0-12 in men and women (Figure 1). Consistency in efficacy with APR was observed between men and women, with greater reduction in pain and achievement of OU complete response (OU-free) and maintenance of response at Wk 12 vs PBO (Table 1). In men and women, consistent treatment effects in favor of APR vs PBO were observed for disease activity and QoL measures, although moderate treatment differences were observed in BDCAI (men/women) and BDQoL (men) (Table 1).
Conclusion(s): Consistent treatment effects in favor of APR vs PBO in clinically relevant outcomes, including OU number and pain, OU complete response, and disease activity measures, were observed in men and women with OU associated with Behcet's syndrome. (Figure Presented)

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.

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.

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.

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.

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/BACKGROUND:ClinicalTrials.gov, http://clinicaltrials.gov: NCT00929864 (AMPLE); NCT01142726 (AVERT).

The two articles presenting ACR committee recommendations for functional status measures and disease activity indices for rheumatoid arthritis (RA) in the December 2019 issue of Arthritis Care and Research are of great interest. The recommendations are based on traditional psychometric and statistical methodology, without information from clinical experience. Possible limitations of traditional psychometric and statistical methodology in the absence of data from clinical experience may be seen in the observation that high scores for both functional status measures and "disease activity" indices, including DAS28, CDAI, and RAPID3 that may be strongly affected by fibromyalgia and/or joint damage, even with minimal inflammatory activity.