LEVI-04, A NOVEL NEUROTROPHIN-3 INHIBITOR, DEMONSTRATED SIGNIFICANT IMPROVEMENTS IN PAIN AND FUNCTION AND WAS NOT ASSOCIATED WITH DELETERIOUS EFFECTS ON JOINT STRUCTURE IN PEOPLE WITH KNEE OA IN A PHASE II RCT

Abstract

INTRODUCTION

Improvement in the symptoms of osteoarthritis (OA) remains a serious unmet medical need and new pharmacological treatments are urgently needed. Excess neurotrophins (NT) are implicated in OA and other painful conditions. Previous analgesic therapies selectively targeting NGF inhibition provided improvements in pain and function, but were dose-dependently associated with significant joint pathologies, including rapidly progressive OA (RPOA). LEVI-04 is a first-in-class fusion protein (p75NTR-Fc) that supplements the endogenous p75NTR binding protein, providing analgesia via inhibition of NT-3 activity. Here we present efficacy and safety data from the phase II RCT of LEVI-04 in people with knee OA.

METHODS

This was a PhII multicentre (Europe and Hong Kong) RCT in people with painful (≥4/10 WOMAC), radiographic (KL≥2) knee OA. Participants were randomised to baseline then 4-weekly IV placebo or 0.3, 1, or 2mg/kg LEVI-04 through week16. The primary efficacy endpoint was assessed at week 17, safety assessments were assessed to week 20, with a telephone safety follow-up at week 30. The primary endpoint was change in WOMAC pain to week 17, with additional outcomes including function, Patient Global Assessment (PGA), 50 and 70% pain responders, a novel pain on movement assessment (the Staircase-evoked Pain Procedure, StEPP) and daily NRS pain scores. Safety and tolerability, including Adverse Events of Special Interest (AESI) concerning joint pathologies, were key secondary endpoints. X-rays of 6 large joints and MRI of knees were utilised for inclusion/exclusion criteria at baseline, and safety evaluation at week 20. All safety events involving joints were escalated to an independent Adjudication Committee.

RESULTS

518 people with knee OA were enrolled (mean age 63.1–65.4 years, mean BMI 29.3–30.3, female participants 51.5–61.5%). LEVI-04 demonstrated significant differences to placebo for the primary endpoint for all doses (Figure 1). WOMAC function and stiffness, PGA, daily pain scores, and StEPP were all statistically different to placebo. LEVI-04 was well tolerated, with no increased incidence of SAEs, TEAEs (Table 1) or joint pathologies, including RPOA (Table 2), compared to placebo.

CONCLUSION

LEVI-04 demonstrated significant and clinically meaningful improvement in pain, function and other efficacy outcomes. LEVI-04 was well tolerated at all doses studied, supporting the concept of supplementing endogenous p75NTR as a treatment for OA and other pain conditions. Phase III trials are in planning.