There were 703 patients enrolled from the parent phase 2a and 2b trials (Fig. 1), of which 495 patients (mean age 60.5 [± 8.5] years, BMI 29.1 [± 4.4] kg/m2, female 61.2%, Black 13.9%, Asian 3.8%, WPI 1.8, KL grade 3 61.2%) received LOR treatment and 208 (mean age 61.3 [± 8.7] years, BMI 28.9 [± 4.0] kg/m2, female 60.6%, Black 16.8%, Asian 3.8%, WPI 1.8, KL grade 3 61.1%) were controls (i.e., patients that received either PBO or sham injection) in the parent trial. Demographics, other baseline characteristics and concomitant medication usage appeared similar across treatment groups for the ITT/SAS (Table 1) and ad hoc unilateral mITT analysis set (Supplementary Table S1).

Extension trial participant disposition. Flow chart of subject distribution and dropout in the extension trial. All patients must have completed one of the two lorecivivint (LOR) parent phase 2 trials to be enrolled/consented in this trial. The non-active control group included patients who were given an intra-articular (IA) vehicle placebo (placebo and other placebo groups) injection and patients given an IA dry-needle sham injection (Sham group). The extension study was terminated by the sponsor prior to its intended 60-month duration after it was determined that no new relevant safety data could be captured

All SAEs, any knee related AE, and AEs that were newly diagnosed chronic conditions requiring treatment (e.g., hypertension or diabetes) were collected for the SAS (495 LOR-treated, 208 control patients) (Table 2). In total, 237 AEs were reported by 137 (19.5%) patients.

Across all LOR treatment groups, 63 SAEs were reported in 33 (6.7%) patients, while five SAEs were reported in five (2.4%) patients amongst the control groups. No SAEs were considered to be related to prior study treatments. The overall incidence of SAEs was higher in the LOR-treated than the PBO patients, although this difference was mainly attributable to three patients in which single events unrelated to the trial drug generated 23 SAEs (one LOR 0.03 mg subject was involved in a motor vehicle accident accounting for four SAEs; one LOR 0.23 mg subject in was also involved in a motor vehicle accident accounting for 14 SAEs; one LOR 0.15 mg subject experienced four SAEs due to complications post-total knee replacement). Further, there was no identifiable relationship observed between LOR doses and SAE incidence. There was one death in the trial in the sham-injection group.

Of 169 AEs in 110 (15.6%) patients, four (reported by three [0.6%] patients) were considered related to LOR treatment by investigator: one patient reported one AE of mild joint swelling at 23.3 months after treatment, one reported two AEs of moderate OA in target and non-target knees at 33.4 months after treatment, and one reported one AE of moderate OA in the target knee at 40 months after treatment. The most commonly reported AEs were osteoarthritis (33 AEs reported by 28 [4.0%] patients) and arthralgia (27 AEs reported by 25 [3.6%] patients), with similar incidences for both LOR and control groups. Onset of metabolic disorders (e.g., diabetes mellitus, hypercholesterolemia, hyperlipidemia) was similar between LOR [nine subjects (1.8%) with 10 AEs] and control groups [five subjects (2.4%) with six AEs].

Regarding target-knee related SAEs, the overall incidence during this trial was 1.3%. There were nine SAEs of “worsening OA” that resulted in knee arthroplasty (eight [1.6%] LOR-treated patients and one [0.5%] control patient. There was one additional SAE of worsening target knee pain in LOR group that required hospitalization > 24 h. No dose dependence was apparent, and none of the events were considered related to the trial drug by the investigators.

The most commonly reported target knee AE was osteoarthritis with 14 AEs reported in 14 LOR-treated patients (2.8%), and four AEs in the control groups’ patients (1.9%). Next was arthralgia with 12 AEs in 12 LOR-treated patients, and four AEs in four control groups’ patients (1.9%) (Table 2).

The percentage of patients who had a knee replacement in the target knee was similar across treatment groups [2.6% in the LOR-treated patients (n = 13), 2.1% in the PBO group (n = 3) and 1.6% in the Sham group (n = 1)].

Compared with PBO, patients in the LOR 0.07 mg unilateral mITT analysis set showed a statistically significant improvement in WOMAC Pain (Fig. 2a) at month 6 (treatment difference estimate of − 8.16, 95% CI [− 15.60, − 0.71], P = 0.032) and month 12 (− 8.51 [− 15.17, − 1.85], P = 0.013). These patients also demonstrated a statistically significant improvement in WOMAC Function (Fig. 2b) compared with PBO at month 3 (− 9.47 [− 17.09, − 1.84], P = 0.015), month 6 (− 8.72 [− 16.21, − 1.24], P = 0.023), and month 12 (− 9.62 [− 16.83, − 2.42], P = 0.009). Month 18 improvements in the 0.07 mg LOR group were not statistically significantly different from the PBO group in either WOMAC Pain (− 3.50 [− 11.16, 4.17], P = 0.369) or Function (− 4.05 [− 11.90, 3.79], P = 0.308).

WOMAC Pain and Function scores over time after intra-articular lorecivivint (LOR) 0.07 mg or vehicle placebo (PBO) injection. Scores are described for the subgroup of the modified intent-to-treat population that reported unilateral pain in the target knee and no widespread pain and who underwent target knee radiography at month 18 post-injection. a WOMAC Pain and b WOMAC Function scores for the LOR 0.07 mg (blue), LOR 0.23 mg (orange), and placebo (PBO; gray) groups; data points represent time post-injection. Mean (± SE); 0.07 mg vs. PBO *P < 0.05, **P < 0.01, ***P < 0.001; 0.23 mg LOR vs PBO †P < 0.05, ††P < 0.01, †††P < 0.001; significance was determined by logistic regression. WOMAC Western Ontario and McMasters Universities Osteoarthritis Index

The unilateral mITT analysis set treated with LOR 0.07 mg showed statistically significant improvements in change from baseline in PtGA compared to PBO at month 3 (treatment difference estimate of − 11.35, 95% CI [(− 18.87, − 3.82)], P = 0.003); these changes approached but did not reach statistical significance at month 6 (treatment difference estimate of − 7.52, 95% CI [(− 15.16, 0.12)], P = 0.054)) and were not significant at month 18 (treatment difference estimates of − 2.94, 95% CI [(− 10.97, 5.09)], P = 0.470).

When compared with PBO (Supplementary Table S2), for the unilateral mITT analysis set, treatment with LOR 0.07 mg increased the odds of demonstrating 30%, 50% and 70% responses at all timepoints (3, 6, 12 and 18 months) for WOMAC Pain. Statistically significant increases in these ORs were noted at the following timepoints: a 30% threshold response in WOMAC Pain (Fig. 3a) at month 6 (OR = 2.62 [1.06, 6.52]; P = 0.037 and month 12 (OR = 3.48 [1.42, 8.52]; P = 0.006); a 50% threshold response at month 3 (OR = 2.14 [1.02, 4.46]; P = 0.044), month 6 (OR = 2.67 [1.28, 5.97]; P = 0.010), and month 12 (OR = 2.11 [1.02, 4.34]; P = 0.044).

Patients meeting 30%, 50%, and 70% response improvement thresholds in the WOMAC Pain and Function subscales. The subject population represented is a subgroup of the modified intent-to-treat population that reported unilateral pain in the target knee and no widespread pain and who underwent target knee radiography at month 18 post-injection. The percentage of patients in the lorecivivint (LOR, blue) and vehicle placebo (PBO, gray) groups achieving each threshold at 3, 6, 12, and 18 months post-injection are shown for a WOMAC Pain and b WOMAC Function subscales. Statistically significant comparisons between groups are identified by asterisks (*P < 0.05, **P < 0.01, ***P < 0.001); significance was determined by logistic regression. WOMAC Western Ontario and McMasters Universities Osteoarthritis Index

When compared with PBO (Supplementary Table S3), for the unilateral mITT analysis set, treatment with LOR 0.07 mg increased the odds of demonstrating 30%, 50% and 70% responses at all timepoints for WOMAC Function. Statistically significant increases in these ORs were noted at the following timepoints: a 30% threshold response in WOMAC Function (Fig. 3b) at month 3 (OR = 3.60 [1.56, 8.32]; P = 0.003) and month 6 (OR = 3.58 [1.40, 9.17]; P = 0.008); and a 50% threshold response at month 3 (OR = 2.68 [1.27, 5.68]; P = 0.010), month 6 (OR = 2.52 [1.16, 5.47]; P = 0.019), and month 12 (OR = 2.67 [1.29, 5.51]; P = 0.008); a 70% threshold response in WOMAC Function at month 6 (OR = 2.64 [1.26, 5.52]; P = 0.010) and month 12 (OR = 2.87 [1.37, 6.04]; P = 0.005).

When compared with PBO (Supplementary Table S4), for the unilateral mITT analysis set, treatment with LOR 0.07 mg increased the odds of meeting the OMERACT-OARSI responder criteria (defined in Efficacy Analyses) at most timepoints, with statistically significant increases in these ORs were noted at the following timepoints: at 3 months (OR = 3.58 [1.40, 9.16], P = 0.008), and at 6 months (OR = 2.94 [1.08, 8.03], P = 0.035) (Fig. 4a).

Patients meeting OMERACT-OARSI response improvement thresholds. The patient population represented is a subgroup of the unilateral modified intent-to-treat population that reported unilateral pain in the target knee and no widespread pain and who underwent target knee radiography at month 18 post-injection. The percentage of patients in the lorecivivint (LOR, blue) and vehicle placebo (PBO, gray) groups achieving each threshold at 3, 6, 12, and 18 months post-injection are shown for a responders (20% relative and 10-point absolute [scaled 0–100] in either WOMAC Pain, WOMAC Function, or Patient Global Assessment) and b strict responders (50% relative and 20-point absolute [scaled 0–100] improvement). Statistically significant comparisons between groups are identified by asterisks (*P < 0.05, **P < 0.01, ***P < 0.001); significance was determined by logistic regression. OMERACT-OARSI Outcome Measures in Rheumatology-Osteoarthritis Research Society International, WOMAC Western Ontario and McMasters Universities Osteoarthritis Index

When compared with PBO (Supplementary Table S4), for the unilateral mITT analysis set, treatment with LOR 0.07 mg increased the odds of meeting the OMERACT-OARSI strict responder criteria at all timepoints. Statistically significant increases in these ORs were noted at the following timepoints: 3 months (OR = 2.60 [1.22, 5.54], P = 0.013), 6 months (OR = 2.71 [1.24, 5.93], P = 0.013), and 12 months (OR = 2.11 [1.02, 4.34], P = 0.044) from baseline (Fig. 4b).

For the unilateral mITT analysis set, at month 12 post-injection, no significant changes in JSW were found in either the LOR 0.07 mg or PBO groups (LOR, 0.02 ± 0.69 mm; PBO, − 0.07 ± 0.70 mm). At month 18, both LOR and PBO groups appeared to show similar numerical decreases (LOR, − 0.07 ± 0.82 mm; PBO − 0.09 ± 0.75 mm) in medial JSW.