Tambiah Jeyanesh, Kennedy Sarah, Swearingen Christopher, McAlindon Timothy, Yazici Yusuf
Biosplice Therapeutics, San Diego, CA, United States.
Tufts Medical Center, Boston, MA, United States.
Rheumatology (Oxford). 2025 May 1;64(5):2583-2590. doi: 10.1093/rheumatology/keae610.
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 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.
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 their 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.
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.
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.
OA-02, NCT02536833; OA-04, NCT03122860; OA-10, NCT04385303; OA-11, NCT03928184.
由于要在高度异质性疾病中评估疼痛和关节结构结果，开发膝骨关节炎（OA）治疗方法具有挑战性。关节内CLK/DYRK抑制剂洛雷西维文（LOR）可调节Wnt和炎症信号通路。本对LOR 0.07mg试验数据的综述分析旨在描述基线关节结构对OA疼痛反应的潜在影响。
两项2期试验和两项3期试验纳入了目标膝关节Kellgren-Lawrence（KL）分级为2-3级且疼痛数字评定量表[NRS（0-10）]≥4至≤8的膝OA患者。按KL分级绘制的累积频率分布图总结了内侧关节间隙宽度（内侧JSW）<3mm患者的百分比。在记录疼痛NRS的试验中，对国际骨关节炎研究学会关节间隙变窄分级和治疗反应进行了类似总结。使用基线调整后的协方差分析估计疼痛结果变化。
与2期试验相比，3期试验中基线内侧JSW<3mm的患者比例增加。除一项患有晚期结构性膝OA的3期试验外，LOR在KL 2亚组中显示出优于安慰剂的治疗效果，这些亚组中基线内侧JSW>3mm的比例更高。
尽管有KL纳入标准，但各试验的基线内侧JSW存在异质性。LOR在结构病变较轻的患者中显示出更大的症状改善，表明OA结构损伤与疼痛之间存在关联。早期治疗干预可能改善结果，并为未来OA试验纳入标准的制定提供见解。
OA-02，NCT02536833；OA-04，NCT03122860；OA-10，NCT04385303；OA-11，NCT03928184。
