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Psoriatic arthritis (PsA) affects approximately up to 30% of patients with a history of psoriasis. In addition to skin manifestations, other symptoms that can produce severe disability include inflammation of small joints, enthesitis, bone and axial skeleton involvement. Interleukin-17 (IL-17) is one of several cytokines involved with the pathogenesis of PsA. High levels of IL-17 receptors and IL-17 positive T-cells have been identified in the synovial fluid of these patients. Brodalumab is a novel antibody directed against one of the IL-17 receptors.
This phase 2 study compared brodalumab against placebo in patients with active PsA (both non-exposed and exposed to prior biologic therapy) to a primary endpoint of 20% improvement of American College of Rheumatology (ACR) criteria at week 12. However, beyond the primary endpoint, this study then became an open-label trial up to week 52. Patients previously exposed to another biologic in the past responded similarly (in terms of improvement in ACR criteria) as compared to those who were biologic-naïve in this study.
The study showed that treatment with brodalumab significantly improved signs and clinical symptoms associated with the disease, including tender and swollen joints, at 12 weeks as measured by a 20 percent improvement in the American College of Rheumatology response criteria (ACR20). The study also showed that many patients continued to improve, and that the improvements were sustained, through the first 52 weeks of the study reported in NEJM.
“Given our understanding of the role of the IL-17 receptor, we have developed a robust clinical program for brodalumab across the spectrum of inflammatory disease, including psoriasis, psoriatic arthritis and asthma,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “These encouraging psoriatic arthritis data showing that patients not only experienced improvements in clinical symptoms at week 12, but that those improvements continued over time and were sustained, were the basis for our decision to continue development of this molecule as a potential treatment for the many people who are looking to better control their disease.”
The study achieved its primary endpoint with both doses of brodalumab exhibiting superiority to placebo in ACR20 responses at week 12. These responses continued to improve through 24 weeks and were sustained through the first 52 weeks of the study.(1) ACR response criteria are a measure of improvement in tender and swollen joints, as well as patient and physician global assessments of disease activity, pain, disability and inflammatory markers. A 20 percent improvement from baseline in ACR response rates is known as ACR20, a 50 percent improvement from baseline is known as ACR50 and a 70 percent improvement from baseline is known as ACR70.
“We’re encouraged that treatment with brodalumab significantly reduced clinical signs and joint symptoms, compared to placebo, and that similar degrees of disease improvement were seen in biologic-treated and biologic-naive patients with psoriatic arthritis,” stated Philip Mease, M.D., lead investigator and study author, Swedish Medical Center and University of Washington. “These results add to the growing body of evidence indicating that the IL-17 receptor is a promising target for the treatment of inflammatory diseases, including psoriatic arthritis.”
Overall, adverse events were similar across groups with 3 percent of brodalumab-treated patients experiencing serious adverse events versus 2 percent of placebo recipients (four patients in total). Serious adverse events included skin infection (cellulitis, two cases), abdominal pain and inflammation of the gallbladder (cholecystitis). No clinically significant neutropenia (>Grade 2) was reported in this study.
“There is a significant need for new treatment options for people living with psoriatic arthritis for whom currently available treatments do not work. As an antibody targeting the IL-17 receptor, brodalumab is designed to work differently from existing treatment options,” said Briggs W. Morrison, M.D., executive vice president of Global Medicines Development at AstraZeneca. “We are encouraged by the efficacy and safety profile demonstrated in this study and are investigating the potential of brodalumab in Phase 3 trials for psoriatic arthritis.”
Amgen and AstraZeneca have initiated two Phase 3 studies of brodalumab in psoriatic arthritis, AMVISION-1 and AMVISION-2, which together will provide detailed information on the impact of brodalumab on improving clinical signs and symptoms in psoriatic arthritis, as well as its ability to prevent joint damage.
Study Design
The study was a Phase 2, randomized, double-blind, placebo-controlled trial designed to assess the efficacy and safety of brodalumab in psoriatic arthritis. Patients with active psoriatic arthritis were randomized to receive brodalumab (140 or 280 mg subcutaneously) or placebo at day 1 and weeks 1, 2, 4, 6, 8, and 10. At week 12, patients were offered open-label brodalumab 280 mg every two weeks.
Active psoriatic arthritis was defined by the Classification of Psoriatic Arthritis criteria (CASPAR)(2) with >3 tender and >3 swollen joints.
Detailed Results
At 12 weeks, 37 percent of patients treated with 140 mg of brodalumab (n=21/57) and 39 percent of patients treated with 280 mg of brodalumab (n=22/56) achieved an ACR20 response compared to 18 percent of patients treated with placebo (n=10/55) (p=0.03 and p=0.02, respectively).
After 12 weeks of treatment, all patients began receiving 280 mg of brodalumab every two weeks in an unblinded fashion. Improvements observed among brodalumab-treated patients in the first 12 weeks continued. At 24 weeks, 51 percent of patients treated in the first 12 weeks with 140 mg of brodalumab (n=24/47) and 64 percent of patients treated in the first 12 weeks with 280 mg of brodalumab (n=29/45) achieved ACR20 responses, compared to 44 percent of patients who switched from placebo to 280 mg of brodalumab at week 12 (n=20/46). Responses were sustained through 52 weeks.
At 12 weeks, 14 percent of patients in both groups treated with brodalumab [140 mg dose (n=8/57) and 280 mg dose (n=8/56)] achieved ACR50 responses compared to 4 percent of patients treated with placebo (n=2/55) (p=0.05 for 280 mg dose vs placebo). ACR70 responses were not significantly higher in brodalumab groups than placebo groups. At 24 weeks, 33 percent of patients in both groups initially treated with brodalumab for the first 12 weeks [140 mg dose (n=16/49) and 280 mg dose (n=15/45)], followed by 280 mg of brodalumab from weeks 12 to 24, achieved ACR50 responses compared to 20 percent of patients initially treated with placebo (n=9/46). ACR50 and ACR70 response rates continued to improve through the remainder of the study.
Safety endpoints included adverse events, which were overall similar across groups. Those most commonly reported in the combined brodalumab groups were upper respiratory tract infection (12 percent vs 7 percent for placebo), fatigue (7 percent vs 4 percent for placebo), diarrhea (6 percent vs 4 percent for placebo), and headache (6 percent vs 7 percent for placebo).
Agencies/Canadajournal
