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Impact of structural severity on outcomes in knee osteoarthritis: an analysis of data from phase 2 and phase 3
Jeyanesh Tambiah1, Sarah Kennedy1, Christopher Swearingen1
1Biosplice Therapeutics, San Diego, CA, United States.
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 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 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.
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:
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.
Trial Registration:
OA-02, NCT02536833; OA-04, NCT03122860; OA-10, NCT04385303; OA-11, NCT03928184.
Insights
Lorecivivint (LOR) showed greater pain relief in knee osteoarthritis patients with less joint damage. Early treatment may improve outcomes for osteoarthritis, guiding future clinical trial criteria.
Area of Science:
- Rheumatology and Orthopedics
- Pharmacology and Drug Development
Background:
- Developing effective knee osteoarthritis (OA) treatments is hindered by disease heterogeneity and challenges in assessing pain and joint structure outcomes.
- Lorecivivint (LOR), an intra-articular CLK/DYRK inhibitor, targets Wnt and inflammatory pathways implicated in OA pathogenesis.
- Clinical trials for OA treatments require careful consideration of patient heterogeneity and outcome measures.
Purpose of the Study:
- To analyze data from Lorecivivint (LOR) 0.07 mg trials to understand how baseline joint structure influences OA pain response.
- To investigate the relationship between structural joint damage and symptomatic improvement in knee osteoarthritis patients treated with LOR.
- To provide insights for optimizing future osteoarthritis clinical trial design and inclusion criteria.
Main Methods:
- Analysis of data from two Phase 2 and two Phase 3 clinical trials involving knee OA patients (Kellgren-Lawrence Grades 2-3, Pain NRS ≥ 4).
- Assessment of baseline medial joint space width (mJSW) and Osteoarthritis Research Society International (OARSI) Joint Space Narrowing (JSN) grades.
- Estimation of pain outcome changes using baseline-adjusted Analysis of Covariance (ANCOVA).
Main Results:
- Phase 3 trials included a higher proportion of patients with baseline medial joint space width (mJSW) < 3 mm compared to Phase 2 trials.
- Lorecivivint (LOR) demonstrated beneficial effects versus placebo in Kellgren-Lawrence (KL) Grade 2 subgroups with higher baseline mJSW (>3 mm), except in one Phase 3 trial with advanced structural disease.
- A trend suggests LOR provided greater symptomatic improvement in patients with less structurally advanced knee osteoarthritis.
Conclusions:
- Baseline joint space width was heterogeneous across trials, despite standardized Kellgren-Lawrence (KL) inclusion criteria.
- Lorecivivint (LOR) showed greater efficacy in patients with less severe structural joint damage, indicating a link between structural integrity and pain response.
- Early intervention with LOR may enhance outcomes, and findings support refining future OA trial inclusion criteria based on structural parameters.
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