LONDON – An investigational nerve growth factor inhibitor, fulranumab, showed promising efficacy and safety as a pain reliever for patients with hip or knee osteoarthritis in 12-week results from a phase II study of 466 patients.

Further study of fulranumab in osteoarthritis had been on hold. The Food and Drug Administration issued a moratorium last December that halted clinical testing of fulranumab and most other investigational agents in the anti–nerve growth factor class, following reports that some of these drugs appeared to trigger episodes of rapid progression of hip or knee osteoarthritis (OA) that led to joint replacement and possible osteonecrosis. The FDA lifted that moratorium on research with fulranumab in cancer pain this month. The moratorium on research involving OA pain remains in place, according to investigators.

Whether or not osteoarthritis progressed rapidly in any patient treated with fulranumab remains unknown. "Cases of joint replacement reported during the entire trial are under investigation, and will be reported in a future publication," Dr. John Thipphawong said at the annual European Congress of Rheumatology.

The safety data Dr. Thipphawong presented for 12 weeks of treatment showed a well-tolerated profile, compared with placebo. Specifically, serious adverse events occurred in 1% of patients treated with fulranumab, compared with 2% of those on placebo. Adverse events led to discontinuation of the assigned drug in 2% of fulranumab recipients and 1% of those on placebo. Adverse events that occurred more often in fulranumab-treated patients were paresthesia, with a 6%-10% rate in the higher fulranumab dosage subgroups, compared with a 3% rate for patients on placebo, and a hypoesthesia rate of 5%-6% in the higher dosage fulranumab subgroups, compared with a 1% rate with placebo. The fulranumab-treated patients also had no significant changes in laboratory values, ECG, or vital signs at 12 weeks after treatment began.

The study enrolled patients with documented hip or knee osteoarthritis who met the diagnostic criteria of the American College of Rheumatology and showed radiographic evidence of the disease, with a Kellgren-Lawrence grade of 2 or greater. All patients also reported moderate to severe pain, with a painscore of at least 5 on a 0-10 numerical rating scale despite treatment with an opioid, a nonsteroidal anti-inflammatory drug, or both.

The study randomized patients to receive fulranumab or placebo once every 4 or 8 weeks as a subcutaneous injection in addition to standard pain medications. The protocol tested five different fulranumab dosages: 1 mg every 4 weeks, 3 mg every 4 weeks, 3 mg every 8 weeks, 6 mg every 8 weeks, or 10 mg every 8 weeks. Fulranumab is a fully human, recombinant monoclonal antibody that neutralizes the biological actions of human nerve growth factor. About 78 patients entered each of the five active-treatment arms as well as a placebo arm. The study’s primary efficacy end point was the change in average pain score from baseline to the end of week 12 of the study.

The patients’ average age was 61 years, 58% were women, and two-thirds were white. Their average body mass index was 32 kg/m², and 60% weighed at least 85 kg. Knee OA predominated as the affected joint, in 77% of patients.

At 12 weeks after the start of treatment, average pain reduction with fulranumab significantly surpassed the placebo group in the 3 mg every 4 weeks, 6 mg every 8 weeks, and 10 mg every 8 weeks subgroups. In these three groups, pain scores fell by an average of 3.05, 2.64, and 2.65 points, respectively, compared with an average drop of 1.91 points in the placebo group, reported Dr. Thipphawong, who is senior director of clinical development, Johnson & Johnson Pharmaceutical Research & Development.

The study also included several secondary efficacy measures. The three highest-dosage subgroups, as well as the 3 mg every 8 weeks subgroup, showed statistically significant declines, compared with placebo after 12 weeks in the average levels of the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) subscales for pain and global function. For the WOMAC subscales of physical function and stiffness, all five fulranumab dosage subgroups showed significant reductions, compared with placebo.

On the Brief Pain Inventory-Short Form, patients in the 3 mg every 4 weeks and 10 mg every 8 weeks subgroups had significant average reductions, compared with the placebo group for the subscales of pain intensity and pain interference with activities. The three highest-dosage subgroups also produced average drops in patient global assessment of disease status that were statistically significant, compared with the placebo group’s average.

In a separate poster at the meeting, Dr. Thipphawong and his associates also reported that several of the fulranumab subgroups showed statistically significant average improvements, with placebo in several subscale measures on the Short From-36, specifically bodily pain, vitality, and physical component. The four highest-dosage subgroups also had significant average improvements in pain interference with sleep, compared with placebo, and all five fulranumab dosage subgroups had significant average improvements in sleep adequacy, compared with the placebo group.

Dr. Thipphawong and several of his associates are employees of Johnson & Johnson, the company developing fulranumab.

Fulranumab Shows Efficacy for Osteoarthritis Pain