LEVI-04 REDUCES BONE MARROW LESION AREA AND PRESENCE IN KNEE OSTEOARTHRITIS: RESULTS FROM A PHASE II RCT

Abstract

INTRODUCTION

Bone marrow lesions (BMLs), detectable on MRI as areas of ill-defined high signal intensity on fluid-sensitive sequences, are a common feature of osteoarthritis (OA), representing areas of increased bone turnover, oedema, and fibrosis. BMLs are prevalent in ∼80% of symptomatic knee OA patients, correlate with radiographic severity (Kellgren-Lawrence [KL] grade) and knee pain. Changes in BMLs are associated with fluctuations in knee pain. Excess neurotrophins (NTs) are implicated in OA pain. LEVI-04, a first-in-class p75NTR-Fc fusion protein that supplements endogenous p75NTR, provides analgesia primarily via inhibition of neurotrophin-3 (NT-3) activity. In this Phase II RCT, LEVI-04 demonstrated statistically significant and clinically meaningful improvements versus placebo for the primary endpoint (WOMAC pain) and secondary endpoints including WOMAC physical function and stiffness, patient global assessment (PGA) and pain on movement (StEPP) across all doses. LEVI-04 was generally well tolerated, with no increased incidence of SAEs, TEAEs, or AESIs concerning joint pathologies compared to placebo.¹

OBJECTIVE

This analysis investigated LEVI-04′s effects on BMLs in people with painful knee OA.

METHODS

518 participants with symptomatic knee OA (WOMAC pain ≥ 4/10, KL grade ≥ 2) were enrolled in a Phase II multicentre randomized double-blinded placebo-controlled trial. Participants received placebo or LEVI-04 (0.3, 1, or 2 mg/kg) every 4 weeks through week 16. BML area (mm²) was measured in a blinded fashion from coronal proton density-weighted fat-suppressed (PD-FS) sequences (slice thickness 3 mm, TE/TR 35/3000 ms) of the target knee at baseline and week 20. For each participant, the BML area was determined as the largest area within the MRI sequence of ill-defined high signal intensity of the subchondral bone marrow, and without presence of a fracture line. The perimeter of each BML was highlighted and the area measured electronically using IAG Dynamika Software™. For BML presence, participants were categorized as BML positive if one or more lesions were identified in the target knee. The presence of BML and change in BML area were assessed in response to LEVI-04.

RESULTS

BML area was greater in knees with higher KL grade (figure 1). The presence of BMLs at baseline was similar across treatment and placebo groups (74-79%). At week 20, there was a significant and dose-dependent reduction in the proportion of patients with BMLs in the LEVI-04 groups (figure 2). Furthermore, a statistically-significant, dose-dependent reduction in mean BML area from baseline to week 20 was observed in LEVI-04 groups compared to placebo (figure 3).

CONCLUSION

In this Phase II trial, a statistically significant and dose-dependent reduction in both the presence of BMLs and BML area was seen for all LEV-04 treatment groups compared with placebo following 20 weeks of treatment. These findings suggest LEVI-04 may have structure-modifying potential in addition to providing analgesia. LEVI-04 holds promise as potentially the first therapy to demonstrate modification of structure (BMLs) and symptoms of OA.