Faculty Bibliography

INTRODUCTION/BACKGROUND:Lorecivivint (LOR), a CDC-like kinase/dual-specificity tyrosine kinase (CLK/DYRK) inhibitor thought to modulate inflammatory and Wnt pathways, is being developed as a potential intra-articular knee osteoarthritis (OA) treatment. The objective of this trial was to evaluate long-term safety of LOR within an observational extension of two phase 2 trials. METHODS:This 60-month, observational extension study (NCT02951026) of a 12-month phase 2a trial (NCT02536833) and 6-month phase 2b trial (NCT03122860) was administratively closed after 36 months as data inferences became limited. Participants received a single intra-articular LOR or placebo (PBO) injection at their parent-trial baseline. The primary outcome was the comparative incidence of serious adverse events (SAEs), with AEs and similar safety measures comprising secondary outcomes. A post hoc baseline-adjusted analysis of covariance (ANCOVA) compared changes from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Function subscores and medial joint space width (JSW) between LOR 0.07 mg and PBO groups in a subpopulation of participants with unilateral knee pain and widespread pain low enough to allow participants to differentiate their target knee pain. RESULTS:The safety analysis set for the extension study included 495 LOR-treated and 208 control participants, with 409 (82.6%) and 175 (84.1%) remaining at study close, respectively. There were 68 SAEs reported in 38 (5.4%) patients; none were considered treatment-related by investigators. The incidence of AEs was similar between groups. In the post hoc subgroup efficacy analyses, LOR 0.07 mg demonstrated greater mean improvements from baseline compared with PBO in WOMAC pain and function scores out to 12 months post-injection. No between-group differences in medial JSW were observed out to 18 months. CONCLUSIONS:LOR appeared generally safe and well tolerated. Efficacy analyses on the subset of completer patients demonstrated durable symptom improvements in WOMAC pain and function for at least 12 months compared to PBO after a single injection of LOR. CLINICAL TRIAL REGISTRATION NUMBER/BACKGROUND:NCT02951026.

OBJECTIVES/OBJECTIVE:To determine the efficacy, safety, and tolerability of intraarticular (IA) lorecivivint (LOR) in the treatment of knee osteoarthritis (OA). METHODS:Patients with American College of Rheumatology criteria-defined knee OA, Kellgren-Lawrence (KL) grades 2-3, and medial Joint Space Width (JSW) by radiograph between 1.5 and 4 mm in the target knee were enrolled in this phase 3, 56-week, multicentre, double-blind, placebo-controlled study. Patients were randomised (1:1) to receive a single IA injection of 0.07 mg LOR or vehicle placebo (PBO) on Day 1. The primary endpoint was the change from baseline in pain Numeric Rating Scale (NRS) at Week 12. Additional outcomes included the change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Function, WOMAC Pain, Patient Global Assessment, medial JSW, and safety. RESULTS:513 patients were randomised. Baseline mean medial JSW was 2.61 (±0.7) mm. The mean change from baseline in weekly average of daily Pain NRS at Week 12 was LOR -2.24 (± 0.13) compared with PBO -2.49 (± 0.13); p=0.185, 95% confidence interval (CI) (-0.12, 0.62). No discernable treatment effects of LOR compared with PBO were revealed by the analysis of other endpoints. Neither treatment group showed meaningful medial JSW loss over 52 weeks. Incidences, severity, and relationship to study treatment of AEs were similar between LOR and PBO treatment groups. CONCLUSIOINS/UNASSIGNED:In this study, LOR was well tolerated although it did not meet the primary endpoint of change from baseline in target knee Pain NRS at Week 12.

OBJECTIVES/OBJECTIVE:To assess the efficacy and safety of an intra-articular (IA) CLK/DYRK inhibitor, lorecivivint (LOR), for the treatment of moderate to severe symptomatic knee osteoarthritis (OA). METHODS:This was a Phase 3, 28-week, multicentre, double-blind, placebo-controlled study evaluating the efficacy and safety of a single IA injection of LOR. Patients with ACR-defined knee OA, Kellgren-Lawrence (KL) grades 2-3, and pain Numeric Rating Scale (NRS) ≥4 and ≤8 in the target knee were randomised (1:1) to receive LOR 0.07 mg or vehicle placebo (PBO) on Day 1. The primary endpoint was the change from baseline in Pain NRS at Week 12 between LOR and PBO. Additional outcomes included the change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Function, WOMAC Pain, Patient Global Assessment and safety. RESULTS:498 patients were randomised, and 51.9% had KL Grade 3 severity. In the full analysis set (FAS), LOR failed to meet the primary endpoint when compared to PBO. No significant treatment differences were noted in other efficacy endpoints. A post-hoc analysis demonstrated a positive treatment effect of LOR relative to PBO in the KL Grade 2 subgroup; the difference in weekly Pain NRS between LOR and PBO groups showed nominal statistical significance at Week 4 (p<0.05). Incidences, seriousness, and severity of adverse events were similar across the treatment groups. CONCLUSIONS:LOR was well tolerated despite not meeting the primary endpoint. Efficacy signals were identified in patients with less severe structural knee OA disease, suggesting earlier intervention may be more effective.

OBJECTIVE:Developing knee osteoarthritis (OA) treatments is challenging due to assessing pain and joint structure outcomes within a highly heterogeneous disease. Lorecivivint (LOR), an intra-articular (IA) CLK/DYRK inhibitor, modulates Wnt and inflammatory pathways. This review analysis of LOR 0.07 mg trial data aims to describe the potential impact of baseline joint structure on OA pain response. METHODS:Two Phase 2 and two Phase 3 trials enrolled knee OA patients with Kellgren-Lawrence (KL) Grades 2-3 and Pain Numeric Rating Scale (NRS [0-10]) ≥4 to ≤ 8 in target knee. Cumulative frequency distribution plots by KL grade summarized the percentages of patients with medial joint space width (medial JSW) < 3 mm. Osteoarthritis Research Society International Joint Space Narrowing grades and treatment responses in trials capturing Pain NRS were similarly summarized. Pain outcome changes were estimated using baseline adjusted ANCOVA. RESULTS:Compared with phase 2 trials, the phase 3 trials had an increased proportion of patients with baseline medial JSW < 3 mm. LOR demonstrated beneficial treatment effects vs placebo in KL 2 subgroups, which were found to have higher proportions of baseline medial JSW > 3 mm, apart from one Phase 3 trial with advanced structural knee OA. CONCLUSION/CONCLUSIONS:Baseline medial JSWs were heterogeneous across trials despite KL inclusion criteria. LOR demonstrated greater symptomatic improvements in patients with less structurally advanced disease, indicative of an association between OA structural damage and pain. Early treatment interventions may improve outcomes and provide insight for future OA trial inclusion criteria development. CLINICAL TRIAL REGISTRATION NUMBERS/BACKGROUND:OA-02, NCT02536833; OA-04, NCT03122860; OA-10, NCT04385303; OA-11, NCT03928184.

PURPOSE OF REVIEW/OBJECTIVE:This review will attempt to summarize the most potentially impactful new data on the way ANCA-associated vasculitis (AAV) is diagnosed, treated, and monitored. RECENT FINDINGS/RESULTS:The newly developed classification criteria for AAV have serious methodological issues that need to be addressed before they are widely adopted. The newly approved drugs and studies into both achieving remission and maintaining it have added to our overall knowledge of managing AAV and should hopefully contribute to improving outcomes in AAV. SUMMARY/CONCLUSIONS:The diagnosis, treatment and monitoring of AAV have seen major improvements in the last two years. The remaining issues outlined in this review still need to be addressed to best serve AAV patients.