Background/Purpose: This Phase 2a/b trial evaluated the safety and dose effectiveness of honeybee toxin (purified Apis melliferatoxin) injections to improve pain and physical function in patients with osteoarthritis (OA) of the knee.  

Methods: Eligible patients were ≥35 years (men and women), with OA in one or both knees (Grade 1-3) and with pain symptoms ≥4 on a visual analog scale (VAS) after medication washout. Eligible patients were randomized to histamine controls: 2.75 μg (n=4), 8.25 μg (n=3), or 27.5 μg (n=4); or to honeybee toxin: 100 μg (n=9), 300 μg (n=10) or 1000 μg (n=10). Patients received 10 intradermal injections (5 in each knee) with syringes randomly filled with control, toxin or saline depending on treatment assignment. Injection sites were randomly targeted to the OA knee because honeybee toxin has systemic effectiveness as well as local activity. Safety evaluated any significant adverse events (AEs) including immediate hypersensitivity reactions from treatment after a negative honeybee toxin skin test (50 μg). Efficacy endpoints were assessed at Predose (Day 1), and Follow-Up Visits (Day 7 and 14) for pain and physical function using subscores from the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Version LK 3.1, as well as for patient global assessment (PGA) and physician global assessment (PhGA).

Results: The majority of patients (33/40, 82.5%) reported at least one treatment-emergent adverse event (TEAE) that were primarily mild to moderate injection site reactions (discomfort, edema, induration, pain, pruritus, urticaria and warmth). All injection site reactions resolved by Day 14. There were no discontinuations or SAEs associated with the honeybee toxin doses, and there were no changes in laboratory parameters, vital signs, or electrocardiograms. At Day 7, WOMAC pain subscores showed an improvement in pain relative to control for all three honeybee toxin doses but not significantly; i.e., least square mean (LSM) difference from control: -2.23, -2.27 and ‑2.11, respectively, for the 100 µg, 300 µg and 1000 µg doses; p=0.2880. Physical function subscores, however, showed significant improvement versus control at Day 7: -11.27 (p=0.0374), -11.38 (p=0.0308) and -10.35 (p=0.0541), respectively, for the honeybee toxin doses. Further, at Day 7, a significant majority of all patients treated with honeybee toxin (66.5%; p=0.0177) assessed their condition (PGA) as being “very good or good” whereas 90% of patients in the control group perceived their condition as being “fair or poor.” The PhGA was generally consistent with the PGA. Regarding Day 14 efficacy assessments, most were consistent with Day 7, however, the improvements among the doses were not as significant.

Conclusion: The honeybee toxin regimens resulted in consistent improvement in pain, physical function, and global health perceptions in patients with knee OA. The safety profile raised no concerns or issues related to treatment. The results of this Phase 2 trial provide sufficient clinical evidence to justify investigating the safety and efficacy of honeybee toxin (purified Apis mellifera toxin) for treating patients with OA pain and inflammation in a Phase 3 trial.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-phase-2-multi-center-randomized-double-blind-active-controlled-parallel-group-study-to-evaluate-the-safety-and-dose-effectiveness-of-intradermal-injections-of-purified-apis-mellifera-toxin/