Efficacy and safety of lorecivivint for the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials

Abstract

Osteoarthritis is a prevalent joint disorder with limited disease-modifying treatments, particularly of the knee. Lorecivivint is an intra-articular Wnt pathway inhibitor investigated as a potential disease-modifying agent for knee osteoarthritis. To investigate its therapeutic potential, a systematic review and meta-analyses of six randomized controlled trials including 2,179 patients comparing lorecivivint with placebo up to January 2026 was conducted. Lorecivivint exhibited modest improvements in WOMAC pain scores at weeks 12 and 24. However, it did not significantly improve functional outcomes, Pain Numeric Rating Scale scores, patient global assessment, or structural changes at the assessed time points. In the subgroup analyses, no constant dose-response relationship was observed, and no meaningful improvements were seen with 0.07 mg dose. Safety outcomes were also comparable to placebo. Although pain reduction was seen, further long-term studies are required to validate its clinical importance.

Graphical Abstract

Keywords

lorecivivint osteoarthritis Wnt pathway inhibitor knee OA pain outcomes randomized controlled trials

1. Introduction

Osteoarthritis (OA) is the most common multifactorial joint disorder involving structural and functional changes of the entire joint, resulting in pain, stiffness, and impaired joint movement.¹ Its prevalence increases with age, and the burden is expected to rise with population ageing.² Globally, 7.6% of the population was living with OA in 2020, representing a substantial increase since 1990. Knee OA, the most common type, is a major cause of disability.³

Over the past twenty years, research on OA has advanced significantly, revealing that both mechanical and inflammatory factors contribute to the disease. Despite numerous proposed therapies, no definitive treatment currently exists.⁴ Current OA treatments mainly relieve symptoms, with many patients eventually needing joint replacement. Disease-modifying drugs, including sprifermin, bisphosphonates, and MMP inhibitors, have so far failed due to factors such as side effects, structural–symptom discordance, incorrect endpoints, and high placebo effects. Current symptomatic treatments provide only modest relief.⁵

Lorecivivint is a small-molecule inhibitor of the intranuclear kinases CLK2 (CDC-like kinase 2) and DYRK1A (dual-specificity tyrosine-phosphorylation-regulated kinase 1A), which regulate Wnt pathway splicing and inflammatory signalling.⁶ Through CLK2/DYRK1A inhibition, lorecivivint aims to support chondrocytes and slow OA progression, representing a mechanism-based approach that aims to go beyond symptom relief, with potential for disease modification pending further clinical validation.^6,7

Multiple clinical trials have investigated lorecivivint for OA. Early phase studies established an acceptable safety profile but produced mixed efficacy signals. A Phase IIa study did not meet its primary pain endpoint at 13 weeks, although subgroup analyses suggested modest longer-term benefits in unilateral knee OA.⁷ A larger Phase IIb trial enrolled approximately 700 patients and reported reductions in weekly average pain and improvements in WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) domains for select doses without meaningful radiographic progression.⁶ Two pivotal Phase III trials did not demonstrate overall superiority versus placebo for the prespecified primary endpoint of week-12 pain change, though post-hoc or subgroup analyses hinted at possible effects in earlier-stage disease and in enriched populations.^8,9 An extension study assessing repeated dosing and longer follow-up observed symptomatic improvements after re-injection and suggested preservation of medial joint space width over three years, with no new safety signals.¹⁰ Collectively, the clinical program indicates that lorecivivint is generally well tolerated but its efficacy is seen only in selected subgroups and with longer exposure, warranting further targeted investigation. Most of the available data come from trials funded by the manufacturers.^7–9 While open-label extension studies suggest possible benefits for both structure and symptoms, their design has inherent biases.¹⁰ The only previously published meta-analysis was later retracted, emphasizing the need for a comprehensive synthesis of the available evidence to draw a reliable conclusion regarding its efficacy and safety.^11,12 Additionally, there is not much biomarker data, and the clinical importance of minor changes in joint space is still uncertain, highlighting key areas that need to be addressed in future, well-designed trials.^7,9,10

Consequently, this meta-analysis aims to systematically evaluate the efficacy and safety profile of lorecivivint in the context of OA treatment by synthesizing evidence from available clinical trials, in order to provide a clearer understanding of the overall therapeutic profile of lorecivivint and its prospective application in the management of OA.

2. Method

2.1. Protocol registration

The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines were followed to perform and report this systematic review and meta-analysis¹³. Registration of the protocol with the International Prospective Register of Systematic Reviews (PROSPERO) was performed with the reference number CRD420261338621¹⁴.

2.2. Data sources and search strategy

Electronic databases including PubMed/MEDLINE, ClinicalTrials.gov, Cochrane CENTRAL, Embase, and Scopus were systematically searched for the identification of all eligible studies. The search was performed from inception to January 2026. The reference lists of included articles and related reviews were manually screened for detection of any further articles. No limitations were applied on language or publication year during the search.

A mix of MeSH terms and associated keywords such as (“Osteoarthritis” OR “OA” OR “Degenerative joint disease”) AND (“Lorecivivint” OR “SM04690” OR “Wnt inhibitor”) AND (“Placebo” OR “Control”) were utilized for the development of a broad search strategy. The detailed search strategy for each database is provided in Supplementary Table 1.

2.3. Study selection and eligibility criteria

Articles were imported into Rayyan.ai after identification, followed by the removal of duplicate articles.¹⁵ Afterwards, two authors independently screened the titles and abstracts of imported records for potential eligibility. Hereafter, the full texts of included articles were retrieved and were assessed with respect to the predefined inclusion criteria. Any disagreements between the two authors were resolved either via consensus or by consultation with a third author.

In the included randomized controlled trials (RCTs), the Population (P) consisted of adults aged 40-80 years with symptomatic knee OA. The American College of Rheumatology (ACR) criteria were utilized to define knee OA, typically with Kellgren-Lawrence (KL) grades 2-3. Participants primarily reported moderate-to-severe pain.

The Intervention (I) was a single intra-articular (IA) injection of lorecivivint into the target knee. Studied doses included 0.03 mg, 0.07 mg, 0.15 mg, and 0.23 mg, with 0.07 mg being studied the most. However, 0.15 mg was not included in the analysis as it was only reported in one study.

The Comparator (C) was a vehicle placebo (PBO) injection. To maintain blinding and allow clear assessment of the treatment’s specific effects, it was provided in an identical injection form.

The Outcomes (O) were assessed for both efficacy and safety:

Primary outcomes: Pain reduction was measured at pre-defined follow-up timepoints using Pain Numerical Rating Scale (NRS) scores and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain scale scores.

Secondary outcomes: Physical function was measured using WOMAC Function scores, while structural modification was assessed by mean joint space width (mJSW) via radiography, along with cartilage thickness and joint integrity in exploratory imaging.

Safety outcomes: A multitude of safety outcomes were assessed such as treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse event-related treatment discontinuations, and injection site reactions.

The Study design (S) was restricted exclusively to RCTs. Non-randomized studies, observational studies, case reports, reviews, and studies lacking a relevant comparator or outcome data were excluded.

2.4. Data extraction

A standard Microsoft Excel sheet was utilized by two authors independently to extract data from the included studies. The extracted information comprised of (i) study identifiers (authors, year), (ii) baseline characteristics of the study populations (such as age, sex, BMI, KL Grade 3), and all relevant efficacy and safety outcomes.

2.5. Quality assessment

For the assessment of the methodological quality of the included RCTs, the Cochrane Risk of Bias 2 (RoB-2) tool was utilized.¹⁶ The risk of bias was measured across five domains: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. Based on the domain-level assessment, the studies were classified as having a “low risk,” “some concerns,” or “high risk” of bias.

2.6. Statistical analysis

Statistical analysis was performed using the R programming language (version 4.3.1), primarily with the ‘meta’ and ‘metafor’ packages. For dichotomous outcomes, risk ratios (RRs) with 95% confidence intervals (CIs) were calculated, while for continuous outcomes, standardized mean differences (SMDs) with 95% CIs were calculated. For the results to be considered statistically significant, 95% CIs, and a P-value of ≤ 0.05 were reported for all analyses.

2.7. Assessment of heterogeneity

The I² statistic was evaluated to assess statistical heterogeneity, with values of <25%, 25-50%, and >50% representing low, moderate, and high heterogeneity, respectively. To determine which study was driving significant heterogeneity, a sensitivity analysis was conducted using a leave-one-out approach, in which each study was sequentially excluded one at a time.

2.8. Subgroup analysis

A subgroup analysis stratified by dose (0.03 mg, 0.07 mg, and 0.23 mg) was performed to evaluate potential dose-response relationships in efficacy outcomes. The outcomes which underwent this analysis were WOMAC Pain and Function at weeks 12 and 24 and mJSW at weeks 24 and 52.

2.9. Certainty of evidence (GRADE assessment)

The certainty of the evidence for each primary outcome was conducted using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework.¹⁷ The evaluation was carried out in accordance with five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. The final certainty of evidence was rated as high, moderate, low, or very low. The GRADE assessment is provided in Supplementary Table 2.

3. Results

3.1. Literature search

The search of electronic databases yielded a total of 260 records (PubMed = 20,ClinicalTrials.gov= 11, Cochrane = 70, Scopus = 32, Embase = 127). After removal of 70 duplicate records, 190 unique records remained for screening. Title and abstract screening excluded 132 records, leaving 58 reports for full-text retrieval and detailed eligibility assessment. Of these, 14 reports could not be retrieved, and 44 full-text reports were assessed. Twenty-nine reports were excluded for the following reasons: wrong study design (n=15), no outcomes of interest (n=10), wrong population (n=9), and wrong intervention (n=4). Ultimately, five reports corresponding to six studies met the inclusion criteria and were included in this systematic review and meta-analysis. The PRISMA flowchart as illustrated in (Figure 1) outlines the systematic screening process.

Figure 1.

Flowchart of literature screening.

3.2. Quality assessment of included studies

The risk of bias assessment of the six included studies was conducted using the Cochrane RoB 2 tool (Figure 2) (Figure 3) across five domains. Overall, three studies (Yazici 2021 Phase 2b, OA-10, and OA-11) were judged to have low risk of bias across all domains. The remaining three studies (Yazici Phase 1 2017, Yazici 2020 Phase 2, and OA-6) were rated as having some concerns, primarily driven by issues in missing outcome data, selection of the reported result, and deviations from intended interventions.

Figure 2.

Risk of bias summary plot.

Figure 3.

Risk of bias traffic light plot.

3.3. Study and patient characteristics

A total of 1,329 participants received intra-articular lorecivivint (primarily at doses of 0.03 mg, 0.07 mg, 0.15 mg, or 0.23 mg), while 850 received control treatment. Pooled weighted mean age was 60.0 years in the lorecivivint groups and 60.6 years in controls. Mean body mass index (BMI) was comparable at 30.1 kg/m² (lorecivivint) versus 29.9 kg/m² (controls), with individual trial means ranging from 28.5 to 31.7 kg/m². Females comprised 60.4% of lorecivivint-treated participants and 61.4% of controls. Kellgren-Lawrence (KL) grade 3 disease in the target knee was present in 56.8% of the lorecivivint group and 53.1% of controls. Proportions of participants with unilateral osteoarthritis were also similar between arms in trials reporting this variable. Detailed study and baseline characteristics are provided in Table 1.

Table 1.

Baseline characteristics of studies and patients.

Study	Group	N	Age (mean ± SD)	BMI (mean ± SD)	Female (%)	KL Grade 3 (%)	Unilateral OA (%)
Yazici 2017	Lorecivivint 0.03 mg	17	63.2 ± 6.55	31.42 ± 4.79	58.8	41.2	-
	Lorecivivint 0.07 mg	17	60.5 ± 5.32	30.60 ± 4.86	76.5	47.1	-
	Lorecivivint 0.23 mg	16	63.1 ± 4.90	28.71 ± 5.00	75	68.8	-
	Placebo	11	64.1 ± 5.92	31.16 ± 3.37	54.5	45.5	-
Yazici 2020	Lorecivivint 0.03 mg	112	59.0 ± 9.0	30.81 ± 4.74	60.7	66.1	40.2
	Lorecivivint 0.07 mg	117	60.0 ± 8.2	30.81 ± 4.74	51.3	63.2	29.9
	Lorecivivint 0.23 mg	109	61.3 ± 8.7	29.64 ± 4.45	61.8	63.6	40.9
	Placebo	114	60.7 ± 8.9	29.17 ± 4.40	62.1	63.8	33.6
Yazici 2021	Lorecivivint 0.03 mg	116	57.9 ± 7.9	29.2 ± 3.8	65.5	54.3	50.9
	Lorecivivint 0.07 mg	115	59.9 ± 8.6	29.1 ± 3.6	57.4	64.3	53.9
	Lorecivivint 0.15 mg	115	58.4 ± 8.3	29.4 ± 4.1	60	59.1	54.8
	Lorecivivint 0.23 mg	116	58.5 ± 9.0	28.5 ± 4.4	52.6	54.3	54.3
	Placebo	116	60.1 ± 9.0	28.6 ± 4.3	55.2	62.1	52.6
	Sham	117	59.0 ± 8.0	29.0 ± 3.8	59.8	49.6	53
OA-10	Lorecivivint	231	61.0 ± 8.7	29.94 ± 3.81	58.9	51.9	35.5
(Yazici 2025)	Placebo	239	61.0 ± 7.9	29.67 ± 3.98	61.9	51.9	28.9
OA-11	Lorecivivint	248	60.8 ± 8.0	31.66 ± 4.55	66.5	50	32.3
(Yazici 2025)	Placebo	253	61.0 ± 8.7	31.41 ± 4.83	64.4	47	32.4

3.4. Efficacy outcomes

3.4.1. WOMAC pain

3.4.1.1. At week 12

Three studies (OA-10, Yazici 2017, and Yazici 2021) evaluated WOMAC pain at week 12. The pooled analysis showed a statistically significant improvement with lorecivivint compared with placebo (SMD = -0.20, 95% CI: -0.30 to -0.09, I²= 0%, p = 0.004). No significant improvement was witnessed with each of the doses of 0.03 mg (SMD = -0.09, 95% CI: -0.26 to 0.07, I²= 0%, p = 0.95), 0.07 mg (SMD = −0.17, 95% CI: −0.36 to 0.01, I²= 0%, p = 0.87), or 0.23 mg (SMD = -0.37, 95% CI: −0.60 to -0.15, I²= 0%, p = 0.93). As illustrated in (Figure 4).

Figure 4.

Forest plot for the subgroup analysis of WOMAC pain at week 12.

3.4.1.2. At week 24

A pooled analysis of three studies (OA-10, Yazici 2017, and Yazici 2021) evaluating different doses of lorecivivint demonstrated a modest but statistically significant improvement in WOMAC pain scores at week 24 compared with placebo. Overall, treatment with lorecivivint was associated with a significant reduction in pain (SMD = −0.16, 95% CI: −0.25 to −0.07; p = 0.004), with no observed heterogeneity among studies (I²= 0%). There was no significant difference between dose subgroups (P = 0.56). As observed in (Figure 5).

Figure 5.

Forest plot for the subgroup analysis of WOMAC pain at week 24.

3.4.2. WOMAC function

3.4.2.1. At week 12

Four studies (OA-10, OA-11, Yazici 2017, and Yazici 2021) evaluated WOMAC function at week 12. The pooled analysis showed no statistically significant improvement with lorecivivint compared with placebo (SMD = -0.12, 95% CI: -0.26 to 0.03, I²= 0.0%, p = 0.10). However, subgroup analysis based on dose demonstrated no significant effect for 0.03 mg (SMD −0.18, 95% CI: −0.54 to 0.19), 0.07 mg (SMD = −0.06, 95% CI: −0.34 to 0.22), or 0.23 mg (SMD = −0.33, 95% CI: −1.06 to 0.40). As demonstrated in (Figure 6).

Figure 6.

Forest plot for the subgroup analysis of WOMAC function at week 12.

3.4.2.2. At week 24

A pooled analysis of four studies (OA-10, OA-11, Yazici 2017, and Yazici 2021) demonstrated no statistically significant improvement in WOMAC function at week 24 compared with placebo. Overall, treatment with lorecivivint was not associated with a statistically significant improvement in WOMAC function compared with control (SMD = −0.08, 95% CI: −0.21 to 0.04; p = 0.14), with no observed heterogeneity among studies (I²= 0%). There was no significant difference between dose subgroups (P = 0.40). As presented in (Figure 7).

Figure 7.

Forest plot for the subgroup analysis of WOMAC function at week 24.

3.4.2.3. At week 52

Two studies (OA-11 and Yazici 2021) evaluated WOMAC function at week 52 for the 0.07 mg dose of lorecivivint. The pooled analysis demonstrated no statistically significant difference between placebo and lorecivivint groups in WOMAC function, (SMD = -0.03, 95% CI: -1.39 to 1.34, I²= 24%, p = 0.84). As observed in (Supplementary Figure 1).

3.4.3. mJSW (Mean joint space width)

3.4.3.1. At week 24

Two studies (Yazici 2017 and Yazici 2021) evaluated mJSW at week 24 in both the lorecivivint and placebo groups at doses of 0.03, 0.07, and 0.23 mg. The pooled analysis demonstrated no statistically significant difference in mJSW with lorecivivint with a standardized mean difference of (SMD = 0.00, 95% CI: -0.17 to 0.18, I²= 0%, p = 0.97). Subgroup analysis by dose did not reveal significant differences between groups (P = 0.70). As reported in (Supplementary Figure 2).

3.4.3.2. At week 52

Two studies (Yazici 2020 and OA-11) evaluated mJSW at week 52 for the 0.07 mg dose of lorecivivint. The pooled analysis demonstrated a statistically insignificant increase in mJSW with lorecivivint as compared to placebo, (SMD = -0.02, 95% CI: -0.34 to 0.30, I²= 0%, p = 0.55). As reported in (Supplementary Figure 3).

3.4.4. Pain NRS

3.4.4.1. At week 12

Three studies (OA-10, OA-11, and Yazici 2021) evaluated pain NRS score at week 12 for the 0.07 mg dose of lorecivivint. The pooled analysis demonstrated no statistically significant difference between placebo and lorecivivint groups in Pain NRS (SMD = -0.12, 95% CI: -0.79 to 0.55, I²= 72.1%, p = 0.53) as demonstrated in (Supplementary Figure 4). Leave one out sensitivity analysis demonstrated that exclusion of OA-11 led to greatest decrease in heterogeneity while keeping the effect size (SMD = -0.26, 95% CI: -1.48 to 0.95, I²= 0%, p = 0.22). As noted in (Supplementary Figure 5).

3.4.4.2. At week 24

Three studies (Yazici 2021, OA-10, and OA-11) evaluated pain NRS score at week 24 for the 0.07 mg dose of lorecivivint. The pooled analysis demonstrated no statistically significant difference between placebo and lorecivivint groups in Pain NRS, (SMD = -0.11, 95% CI: -0.63 to 0.40, I²= 55.8%, p = 0.44) as interpreted in (Figure 8). Leave one out sensitivity analysis demonstrated that exclusion of OA-11 led to the greatest decrease in heterogeneity while keeping effect size of similar magnitude. As visualized in (Supplementary Figure 6).

Figure 8.

Forest plot for the 0.07 mg dose subgroup analysis of pain NRS at week 24.

3.4.5. PtGA score

3.4.5.1. At week 12

Three studies (OA-10, OA-11, and Yazici 2021) evaluated PtGA score at week 12 for the 0.07 mg dose of lorecivivint. The pooled analysis demonstrated no statistically significant difference between placebo and lorecivivint in PtGA score, (SMD = -2.50, 95% CI: -12.31 to 7.31, I²= 40.3%, p = 0.39) as observed in (Supplementary Figure 7). Leave one out sensitivity analysis demonstrated that exclusion of OA-11 led to greatest decrease in heterogeneity while keeping the effect size appropriate. As depicted in (Supplementary Figure 8).

3.4.5.2. At week 24

Three studies (OA-10, OA-11, and Yazici 2021) evaluated PtGA score at week 24 for the 0.07 mg dose of lorecivivint. The pooled analysis demonstrated no statistically significant difference between placebo and lorecivivint groups in PtGA score, (SMD = -3.46, 95% CI: -15.53 to 8.61, I²= 60%, p = 0.34) as shown in (Supplementary Figure 9). Leave-one-out sensitivity analysis indicated that removing OA-11 resulted in the most substantial reduction in heterogeneity without materially altering the overall effect size. As illustrated in (Supplementary Figure 10).

3.5. Safety outcomes

The pooled risk ratio for the occurrence of a serious adverse event associated with lorecivivint was not statistically significant (RR) 1.56 (95% CI: 0.69 to 3.55, I²= 0%, p = 0.18) as reflected in (Supplementary Figure 11). Similarly, the risk ratio for any Adverse event was also not statistically significant (RR) 1.08 (95% CI: 0.99 to 1.17, I²= 0%, p = 0.08) as displayed in (Supplementary Figure 12). The risk ratio for adverse events leading to discontinuation of study treatment did not yield any significant differences between groups (RR) 1.18 (95% CI: 0.63 to 2.20, I²= 0%, p = 0.37) as indicated in (Supplementary Figure 13).

Likewise, no significant differences were noted for several other adverse outcomes between the two groups including arthralgia (RR) 0.82 (95% CI: 0.32 to 2.07, I²= 56.2%, p = 0.60) as visualised in (Supplementary Figure 14), nasopharyngitis (RR) 0.69 (95% CI: 0.04 to 11.18, I²= 45.4%, p = 0.62) as shown in (Supplementary Figure 15), headache (RR) 0.56 (95% CI: 0.29 to 1.07, I²= 0%, p = 0.07) as illustrated in (Supplementary Figure 16), upper respiratory tract infection (RR) 0.84 (95% CI: 0.39 to 1.80, I²= 0%, p = 0.53) as depicted in (Supplementary Figure 17), contusion (RR 1.00, p = 0.92), back pain (RR 0.70, p = 0.62), COVID-19 (RR 1.30, p = 0.44), hypertension (RR 1.13, p = 0.86), joint swelling (RR 0.92, p = 0.84), osteoarthritis (RR 1.40, p = 0.42), sinusitis (RR 0.74, p = 0.59), and urinary tract infections (RR 1.10, p = 0.56), as illustrated in (Supplementary Figures 18-25) respectively. To reduce heterogeneity, a leave one out analysis was performed for arthralgia, back pain, and hypertension. For arthralgia Yazici Phase 1 was omitted, which reduced heterogeneity with an RR of 1.01, I²= 45.7% as reported in (Supplementary Figure 26). For back pain, OA-11 was omitted, which reduced heterogeneity with RR of 0.33, I²=0% as displayed in (Supplementary Figure 27). Similarly, for hypertension, OA-11 was omitted, which reduced heterogeneity with an RR of 1.82, I²= 4% as observed in (Supplementary Figure 28).

4. Discussion

In this meta-analysis of RCTs, Lorecivivint demonstrated modest improvements in WOMAC pain scores, whereas effects on pain NRS, PtGA, WOMAC function, and mean joint space width were generally not significant compared to placebo. Across different doses, no meaningful dose-dependent differences were observed for most outcomes, suggesting that higher doses do not necessarily confer additional benefit. Lorecivivint was generally well tolerated, with no significant increase in serious or overall adverse events, and sensitivity analyses, including leave-one-out approaches, confirmed the robustness of these findings. Although small improvements in pain were observed, the overall impact of lorecivivint on functional outcomes and structural progression appears limited. The presence of residual heterogeneity indicates that additional patient-level or study-level factors may influence treatment response, highlighting the need for further large-scale, high-quality trials to better define the clinical utility of lorecivivint and identify patient populations who may benefit most.

In comparison with established symptomatic treatments for knee osteoarthritis and emerging disease-modifying osteoarthritis drugs (DMOADs), the clinical profile of lorecivivint warrants thoughtful consideration. Lorecivivint (SM04690) is an intra-articular small-molecule inhibitor of CDC-like kinase 2 (CLK2) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), designed to modulate the Wnt signalling pathway implicated in cartilage homeostasis and inflammation. Preclinical studies demonstrated that lorecivivint inhibits Wnt-related kinases, promotes chondrogenesis, and reduces inflammatory mediators in vitro and animal models, suggesting potential disease-modifying activity in preclinical models only, which has not been replicated in clinical structural outcomes.¹⁸ In Phase II clinical trials, lorecivivint was associated with modest improvements in patient-reported outcomes such as pain and function compared with placebo, although results varied across endpoints and study populations. Among the doses evaluated, 0.07 mg showed the most consistent signals of potential benefit across symptomatic measures, although radiographic progression was not significantly altered in the overall population.⁶ Safety data indicate that lorecivivint is generally well tolerated with no significant increase in systemic adverse events, supporting its favourable tolerability profile in OA patients.¹⁹ Importantly, despite statistical improvements in symptomatic outcomes, the magnitude of benefit appears modest and is likely below established minimal clinically important difference (MCID) thresholds, indicating limited clinical relevance for many patients.

The broader therapeutic landscape places these findings into clearer context. Traditional OA therapies, such as NSAIDs or intra-articular corticosteroids, primarily address pain and inflammation but do not alter underlying disease pathways, while newer agents aiming at cartilage regeneration and structure-modifying effects are actively under investigation. Lorecivivint’s targeted Wnt pathway modulation represents an innovative mechanism distinct from symptomatic management alone. Subgroup analyses suggest that patients with less advanced structural damage may derive more symptomatic benefit, indicating that baseline joint status could influence therapeutic response.²⁰ However, these subgroup findings should be interpreted as exploratory only, as the small number of studies and participants limits statistical power and reliability. Although the magnitude of clinical benefit observed to date appears modest, lorecivivint remains among the more advanced intra-articular DMOAD candidates currently undergoing late-phase clinical evaluation. Continued research into optimal patient selection, dose refinement, and longer-term structural outcomes may further define its role in OA treatment and help bridge the gap between symptom control and true disease modification.

The safety profile of lorecivivint observed in our analysis appears comparable with placebo and consistent across multiple clinical studies in knee osteoarthritis. In large, randomized trials, the incidences, severity, and relationship of treatment-emergent adverse events (AEs) and serious adverse events (SAEs) were similar between lorecivivint and placebo groups, with no meaningful increases in systemic or treatment-related SAEs reported by investigators.^21,22 Pooled safety analyses from earlier phase studies also demonstrated that overall AE rates and categories of AEs were similar between lorecivivint and control subjects, with joint-related symptoms such as arthralgia being among the most commonly reported events but occurring at comparable frequencies.²³ Unlike systemic agents where gastrointestinal effects and other class-specific toxicities can limit tolerability, intra-articular lorecivivint did not show evidence of dose-dependent systemic adverse effects in the analysed trials. Collectively, these findings suggest that lorecivivint is generally well tolerated, with a safety profile that is not associated with a significant increase in serious harm compared with placebo, supporting its continued evaluation in osteoarthritis populations.

5. Limitations

Despite the insights gained from this meta-analysis, several limitations should be acknowledged. Most participants in the included trials had mild-to-moderate knee osteoarthritis, which limits generalizability to patients with severe or end-stage disease. Additionally, variations in study design, including differences in dosing regimens, follow-up durations, and outcome measures, introduced heterogeneity that may affect the precision of pooled estimates. Reporting of structural outcomes, such as mean joint space width, and certain patient-reported outcomes was inconsistent across studies, further limiting comprehensive evaluation. In addition, subgroup and dose-response analyses were based on a small number of trials per category, limiting statistical reliability and increasing uncertainty; therefore, these findings should be considered exploratory rather than confirmatory. Finally, because no head-to-head trials comparing lorecivivint with other intra-articular or disease-modifying osteoarthritis therapies are available, direct comparative conclusions cannot be drawn. Larger, longer, and more diverse trials will be essential to fully define the efficacy, structural benefits, and long-term safety profile of lorecivivint in knee osteoarthritis populations.

6. Conclusion

In summary, lorecivivint demonstrates modest improvements in pain outcomes for patients with knee osteoarthritis, while effects on function and structural progression remain limited. The therapy is generally well tolerated, with no significant increase in serious adverse events compared with placebo. Although statistically significant, the observed symptomatic benefit appears to be of limited clinical relevance when considered against MCID thresholds. Although current evidence supports its potential as a targeted intra-articular therapy, further large-scale, long-term trials are needed to clarify its clinical utility, optimal dosing, and patient populations most likely to benefit.

Supplemental material

Supplemental material - Efficacy and safety of lorecivivint for the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials

Supplemental material for Efficacy and safety of lorecivivint for the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials by Syed Ahmed Ali Shah, Divesh Sunil Sachdev, Zain Ul Abideen Shahid, Muhammad Hassan, Hassan Abdul Aziz Dhedhi, Talha Aamir, Ahmed Nawaz, MBBS, Muhammad Hussain, Sheikh Muhammad Maier, Hasibullah Aminpoor in Journal of Orthopaedic Surgery

Footnotes

Acknowledgements

The authors have no acknowledgments to declare.

ORCID iDs

Syed Ahmed Ali Shah

Ahmed Nawaz

Ethical considerations

This study is a systematic review and meta-analysis conducted using previously published data.

Consent to participate

Although human participants were involved in the original studies, no new data were collected, and no patient-identifiable information was used. Therefore, ethics approval and consent to participate were not required.

Authors’ Contributions

Syed Ahmed Ali Shah: Conceptualization, Data Extraction, Writing - original draft, Writing - review & editing, Formatting, Supervision, Visualization, Approval of the final draft.

Divesh Sunil Sachdev: Data Extraction, Data Analysis, Writing - original draft, Writing -review & editing.

Zain Ul Abideen Shahid: Conceptualization, Writing - original draft, Writing - review & editing, Supervision, Visualization, Approval of the final draft.

Muhammad Hassan: Writing - original draft, Writing - review & editing.

Hassan Abdul Aziz Dhedhi: Writing - original draft, Writing - review & editing.

Talha Aamir: Risk of Bias Assessment, GRADE Assessment.

Ahmed Nawaz: Writing - original draft, Writing - review & editing.

Muhammad Hussain: Writing - original draft, Writing - review & editing.

Sheikh Muhammad Maier: Writing - original draft, Writing - review & editing, Referencing, Visualization.

Hasibullah Aminpoor: Writing - original draft, Writing - review & editing.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

Data is available at the request of the corresponding author.*

Supplemental material

Supplemental material for this article is available online.

Appendix

References

Loeser

Goldring

Scanzello

, et al. Osteoarthritis: A disease of the joint as an organ. Arthritis Rheum 2012; 64: 1697–1707. https://doi.org/10.1002/art.34453

Pereira

Peleteiro

Araújo

, et al. The effect of osteoarthritis definition on prevalence and incidence estimates: A systematic review. Osteoarthritis Cartilage 2011; 19: 1270–1285. https://doi.org/10.1016/j.joca.2011.08.009

Steinmetz

Culbreth

Haile

, et al. Global, regional, and national burden of osteoarthritis, 1990-2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol 2023; 5: e508–e522. https://doi.org/10.1016/S2665-9913(23)00163-7

Salman

Ahmed

Dakin

, et al. Osteoarthritis: a narrative review of molecular approaches to disease management. Arthritis Research & Therapy 2023; 25(1): 27 2023;25-. https://doi.org/10.1186/s13075-023-03006-w

Vrouwe

JPM

Burggraaf

Kloppenburg

, et al. Challenges and opportunities of pharmacological interventions for osteoarthritis: A review of current clinical trials and developments. Osteoarthr Cartil Open 2021; 3: 100212. https://doi.org/10.1016/j.ocarto.2021.100212

Yazici

McAlindon

Gibofsky

, et al. A Phase 2b randomized trial of lorecivivint, a novel intra-articular CLK2/DYRK1A inhibitor and Wnt pathway modulator for knee osteoarthritis. Osteoarthritis Cartilage 2021; 29: 654–666. https://doi.org/10.1016/j.joca.2021.02.004

Yazici

McAlindon

Gibofsky

, et al. Lorecivivint, a Novel Intraarticular CDC-like Kinase 2 and Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitor and Wnt Pathway Modulator for the Treatment of Knee Osteoarthritis: A Phase II Randomized Trial. Arthritis and Rheumatology 2020; 72: 1694–1706. https://doi.org/10.1002/art.41315

Yazici

Tambiah

JRS

Swearingen

, et al. A Phase 3, 56-week, randomised, double-blind, placebo-controlled study (OA-11) utilising patient-reported and radiographic outcomes evaluating the efficacy and safety of a lorecivivint injection in patients with moderate to severe knee osteoarthritis. Clin Exp Rheumatol 2025; 43: 854–860. https://doi.org/10.55563/clinexprheumatol/hjt118

Yazici

Swearingen

Ghandehari

, et al. A Phase 3, 28-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial (OA-10) to Evaluate the Efficacy and Safety of a Single Injection of Lorecivivint Injected in the Target Knee Joint of Moderately to Severely Symptomatic Osteoarthritis S… n.d. https://acrabstracts.org/abstract/a-phase-3-28-week-multicenter-randomized-double-blind-placebo-controlled-trial-oa-10-to-evaluate-the-efficacy-and-safety-of-a-single-injection-of-lorecivivint-injected-in-the-target-knee-joint/ (accessed March 19, 2026).

10.

Yazici

Tambiah

Swearingen

McAlindon

. Radiographic and Pain Outcomes from a Phase 3 Trial (OA-07) Evaluating the Efficacy and Safety of Repeat Lorecivivint Injections over 3 Years in Subjects with Knee OA - ACR Meeting Abstracts n.d. https://acrabstracts.org/abstract/radiographic-and-pain-outcomes-from-a-phase-3-trial-oa-07-evaluating-the-efficacy-and-safety-of-repeat-lorecivivint-injections-over-3-years-in-subjects-with-knee-oa/ (accessed March 19, 2026).

11.

Kou

Qing

Zhao

, et al. Effect of lorecivivint on osteoarthritis: A systematic review and meta-analysis. Heliyon 2023; 9: e18682. https://doi.org/10.1016/j.heliyon.2023.e18682

12.

Kou

Qing

Zhao

, et al. Retraction notice to “Effect of lorecivivint on osteoarthritis: A systematic review and meta-analysis” [Heliyon 9 (2023) e18682] (Heliyon (2023) 9(8), (S2405844023058905), (10.1016/j.heliyon.2023.e18682)). Heliyon 2025; 11: e42831. https://doi.org/10.1016/j.heliyon.2025.e42831

13.

Page

McKenzie

Bossuyt

, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71. https://doi.org/10.1136/bmj.n71

14.

Shah

SAA

Sunil

Shahid

. PROSPERO n.d. https://www.crd.york.ac.uk/PROSPERO/view/CRD420261338621 (accessed March 19, 2026).

15.

Ouzzani

Hammady

Fedorowicz

Elmagarmid

. Rayyan-a web and mobile app for systematic reviews. (Published 2016 Dec 5 Syst Rev 2016; 5(1): 210. accessed March 19, 2026). https://doi.org/10.1186/s13643-016-0384-4.

16.

Sterne

JAC

Savović

Page

, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898. accessed March 19, 2026. Published 2019 Aug 28. https://doi.org/10.1136/bmj.l4898.

17.

Guyatt

Oxman

Akl

, et al. GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011; 64(4): 383-394. https://doi.org/10.1016/j.jclinepi.2010.04.026 (accessed March 19, 2026).

18.

Deshmukh

O’Green

Bossard

, et al. Modulation of the Wnt pathway through inhibition of CLK2 and DYRK1A by lorecivivint as a novel, potentially disease-modifying approach for knee osteoarthritis treatment. Osteoarthritis Cartilage 2019; 27: 1347–1360. https://doi.org/10.1016/j.joca.2019.05.006

19.

Yazici

McAlindon

Gibofsky

, et al. Lorecivivint, a Novel Intraarticular CDC-like Kinase 2 and Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitor and Wnt Pathway Modulator for the Treatment of Knee Osteoarthritis: A Phase II Randomized Trial. Arthritis Rheumatol 2020; 72: 1694–1706. https://doi.org/10.1002/art.41315

20.

Tambiah

Kennedy

Swearingen

, et al. Impact of structural severity on outcomes in knee osteoarthritis: an analysis of data from phase 2 and phase 3 lorecivivint clinical trials. Rheumatology (Oxford) 2025; 64: 2583–2590. https://doi.org/10.1093/rheumatology/keae610

21.

Swearingen

Tambiah

JRS

Simsek

, et al. Evaluation of Safety and Efficacy of a Single Lorecivivint Injection in Patients with Knee Osteoarthritis: A Multicenter, Observational Extension Trial. Rheumatol Ther 2025; 12: 157–171. https://doi.org/10.1007/s40744-024-00731-9

22.

Yazici

Tambiah

JRS

Swearingen

, et al. A Phase 3, 28-week, multicentre, randomised, double-blind, placebo-controlled trial (OA-10) to evaluate the efficacy and safety of a single injection of lorecivivint in the target knee joint of moderately to severely symptomatic osteoarthritis patients. Clin Exp Rheumatol 2025; 43: 847–853. https://doi.org/10.55563/clinexprheumatol/gskbin

23.

Samumed

LLC

. Samumed Presents Safety Data Analysis of Lorecivivint for Knee Osteoarthritis at the 2019 ACR Annual Meeting - BioSpace n.d. https://www.biospace.com/samumed-presents-safety-data-analysis-of-lorecivivint-for-knee-osteoarthritis-at-the-2019-acr-annual-meeting?utm_source=chatgpt.com (accessed March 19, 2026).

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

1.17 MB