First-in-human randomized clinical trials of the safety and efficacy of tanezumab for treatment of chronic knee osteoarthritis pain or acute bunionectomy pain

Abstract

Introduction: The neurotrophin nerve growth factor has a demonstrated role in pain transduction and pathophysiology.

Objectives: Two randomized, double-blind, placebo-controlled, phase 1 studies were conducted to evaluate safety, tolerability, and analgesic efficacy of single doses of tanezumab, a humanized anti-nerve growth factor monoclonal antibody, in chronic or acute pain.

Methods: In the first study (CL001), patients with moderate to severe pain from osteoarthritis (OA) of the knee received a single intravenous infusion of tanezumab (3-1000 μg/kg) or placebo in a dose-escalation (part 1; N = 42) or parallel-arm (part 2; N = 79) study design. The second study (CL002) was a placebo-controlled dose-escalation (tanezumab 10-1000 μg/kg; N = 50) study in patients undergoing bunionectomy surgery.

Results: Adverse event rates were generally similar across treatments. Most adverse events were generally mild to moderate in severity and no patients discontinued as a result of adverse events. Adverse events of abnormal peripheral sensation were more common with higher doses of tanezumab (≥100 μg/kg) than with placebo. These were generally mild to moderate in severity. Tanezumab provided up to 12 weeks of effective analgesia for OA knee pain, with statistically significant improvements at doses ≥100 μg/kg (P < 0.05). By contrast, no trend for analgesic activity was found when tanezumab was administered 8 to 16 hours before bunionectomy.

Conclusions: The demonstration of a favorable safety profile and clinical efficacy in OA pain supports clinical development of tanezumab as a potential treatment for chronic pain conditions.

Keywords: Analgesia; Bunionectomy; Nerve growth factor; Osteoarthritis; Safety; Tanezumab.

Figure 1.

CL001 study design (A) part 1 sequential, single-dose, dose-escalation, placebo-controlled, randomized study and (B) part 2 parallel-arm, placebo-controlled, randomized study.

Figure 2.

CL002 single-dose, dose-escalation, placebo-controlled, randomized study design.

Figure 3.

Patient disposition in study CL001 (A) part 1 and (B) part 2.

Figure 4.

Current index knee pain: mean change from baseline visual analogue scale (VAS) in study CL001, part 1. Overall, knee pain was measured on VAS 0 to 100 where higher scores equal greater pain.

Figure 5.

Patient disposition in study CL002.

Figure 6.

(A) Mean categorical pain intensity (0–48 hours) and (B) summed categorical pain intensity (days 4–12) after bunionectomy in study CL002.