Proposed axial spondyloarthritis indication for certolizumab divides FDA panel

SILVER SPRING, MD. – A Food and Drug Administration advisory panel split its vote on whether to recommend the approval of certolizumab as a treatment for axial spondyloarthritis, based on a study of 325 patients with ankylosing spondylitis or nonradiographic axial spondyloarthritis.

At a July 23 meeting, the FDA’s Arthritis Advisory Committee voted 7-6, with one abstention, to recommend approval of the tumor necrosis factor (TNF) blocker for the manufacturer’s proposed indication: treatment of "active axial spondyloarthritis, including patients with ankylosing spondylitis."

Certolizumab, a TNF blocker, was approved in 2008 for treating Crohn’s disease and in 2009 for treating rheumatoid arthritis (RA). It is marketed as Cimzia by UCB and is administered by subcutaneous injection every 4 weeks for Crohn’s disease and every other week or every 4 weeks for RA, as maintenance therapy. Currently, four other TNF inhibitors are approved for ankylosing spondylitis (AS) but none are approved for treating nonradiographic axial spondyloarthritis (nr-axSpA).

The pivotal study compared two dosing regimens of certolizumab against placebo in patients with active axial spondyloarthritis who had an inadequate response to NSAIDs or a contraindication to NSAIDs (178 patients with AS, and 147 patients with nr-axSpA). The dosing regimens were the same as those currently approved for rheumatoid arthritis: a loading dose of 400 mg in weeks 0, 2, and 4, followed by either 200 mg every 2 weeks (Q2W) or 400 mg every 4 weeks (Q4W). Requirements for enrollment included chronic back pain for at least 3 months; onset before age 45 years; and imaging criteria that included sacroiliitis (on MRI or X-ray) with at least one spondyloarthritis feature, such as inflammation, back pain, arthritis, uveitis, or dactylitis.

At 12 weeks, 58% of patients on the Q2W regimen and 64% on the Q4W regimen had achieved an ASAS (Assessment of SpondyloArthritis international Society) 20 response, the primary endpoint, compared with 38% of those on placebo, both of which were statistically significant differences. The differences remained significant at 24 weeks. ASAS20 responses in the two subpopulations, those with AS and those with nr-axSpA, also favored those treated with certolizumab.

Treatment with certolizumab also resulted in significant improvements in function and spinal mobility, with similar responses at both dosage regimens, compared with placebo, as well as improvements in spinal and sacroiliac joint inflammation, productivity, and health-related quality of life, according to UCB.

The rates of serious adverse events were similar in the certolizumab-treated and placebo groups, the safety profile of certolizumab was consistent with the known safety profile of TNF inhibitors, and no new safety signals were identified. The rate of serious infections, a known risk, was higher among those on certolizumab.

The main issue raised by the FDA was whether the data from this study were adequate to support the indication, especially for patients with nr-axSpA, which would be a new indication for an approved treatment, according to Dr. Janet Maynard, acting clinical team leader in the FDA’s Division of Pulmonary, Allergy, and Rheumatology Products. But the FDA’s analysis of the data did not suggest that the efficacy results were driven by any subgroup, and the efficacy data for AS "appear reasonable," she said at the meeting.

The panel had no substantial safety concerns – voting 13-1 that the safety profile of certolizumab was adequate to support approval of the new indication – and agreed there was evidence of efficacy. Those voting against approval, however, thought that the indication was too broad and had concerns that included the small number of patients for a new indication (nr-axSpA), the lack of a clear definition of active disease in the indication, and the possibility that primary care physicians would prescribe the biologic drug for patients with low back pain.

Panelists supporting approval said that adequate prescribing information would result in appropriate use for patients with active disease in clinical practice.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting; occasionally, a panelist might be given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel split its vote on whether to recommend the approval of certolizumab as a treatment for axial spondyloarthritis, based on a study of 325 patients with ankylosing spondylitis or nonradiographic axial spondyloarthritis.

At a July 23 meeting, the FDA’s Arthritis Advisory Committee voted 7-6, with one abstention, to recommend approval of the tumor necrosis factor (TNF) blocker for the manufacturer’s proposed indication: treatment of "active axial spondyloarthritis, including patients with ankylosing spondylitis."

Certolizumab, a TNF blocker, was approved in 2008 for treating Crohn’s disease and in 2009 for treating rheumatoid arthritis (RA). It is marketed as Cimzia by UCB and is administered by subcutaneous injection every 4 weeks for Crohn’s disease and every other week or every 4 weeks for RA, as maintenance therapy. Currently, four other TNF inhibitors are approved for ankylosing spondylitis (AS) but none are approved for treating nonradiographic axial spondyloarthritis (nr-axSpA).

The pivotal study compared two dosing regimens of certolizumab against placebo in patients with active axial spondyloarthritis who had an inadequate response to NSAIDs or a contraindication to NSAIDs (178 patients with AS, and 147 patients with nr-axSpA). The dosing regimens were the same as those currently approved for rheumatoid arthritis: a loading dose of 400 mg in weeks 0, 2, and 4, followed by either 200 mg every 2 weeks (Q2W) or 400 mg every 4 weeks (Q4W). Requirements for enrollment included chronic back pain for at least 3 months; onset before age 45 years; and imaging criteria that included sacroiliitis (on MRI or X-ray) with at least one spondyloarthritis feature, such as inflammation, back pain, arthritis, uveitis, or dactylitis.

At 12 weeks, 58% of patients on the Q2W regimen and 64% on the Q4W regimen had achieved an ASAS (Assessment of SpondyloArthritis international Society) 20 response, the primary endpoint, compared with 38% of those on placebo, both of which were statistically significant differences. The differences remained significant at 24 weeks. ASAS20 responses in the two subpopulations, those with AS and those with nr-axSpA, also favored those treated with certolizumab.

Treatment with certolizumab also resulted in significant improvements in function and spinal mobility, with similar responses at both dosage regimens, compared with placebo, as well as improvements in spinal and sacroiliac joint inflammation, productivity, and health-related quality of life, according to UCB.

The rates of serious adverse events were similar in the certolizumab-treated and placebo groups, the safety profile of certolizumab was consistent with the known safety profile of TNF inhibitors, and no new safety signals were identified. The rate of serious infections, a known risk, was higher among those on certolizumab.

The main issue raised by the FDA was whether the data from this study were adequate to support the indication, especially for patients with nr-axSpA, which would be a new indication for an approved treatment, according to Dr. Janet Maynard, acting clinical team leader in the FDA’s Division of Pulmonary, Allergy, and Rheumatology Products. But the FDA’s analysis of the data did not suggest that the efficacy results were driven by any subgroup, and the efficacy data for AS "appear reasonable," she said at the meeting.

The panel had no substantial safety concerns – voting 13-1 that the safety profile of certolizumab was adequate to support approval of the new indication – and agreed there was evidence of efficacy. Those voting against approval, however, thought that the indication was too broad and had concerns that included the small number of patients for a new indication (nr-axSpA), the lack of a clear definition of active disease in the indication, and the possibility that primary care physicians would prescribe the biologic drug for patients with low back pain.

Panelists supporting approval said that adequate prescribing information would result in appropriate use for patients with active disease in clinical practice.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting; occasionally, a panelist might be given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel split its vote on whether to recommend the approval of certolizumab as a treatment for axial spondyloarthritis, based on a study of 325 patients with ankylosing spondylitis or nonradiographic axial spondyloarthritis.

At a July 23 meeting, the FDA’s Arthritis Advisory Committee voted 7-6, with one abstention, to recommend approval of the tumor necrosis factor (TNF) blocker for the manufacturer’s proposed indication: treatment of "active axial spondyloarthritis, including patients with ankylosing spondylitis."

Certolizumab, a TNF blocker, was approved in 2008 for treating Crohn’s disease and in 2009 for treating rheumatoid arthritis (RA). It is marketed as Cimzia by UCB and is administered by subcutaneous injection every 4 weeks for Crohn’s disease and every other week or every 4 weeks for RA, as maintenance therapy. Currently, four other TNF inhibitors are approved for ankylosing spondylitis (AS) but none are approved for treating nonradiographic axial spondyloarthritis (nr-axSpA).

The pivotal study compared two dosing regimens of certolizumab against placebo in patients with active axial spondyloarthritis who had an inadequate response to NSAIDs or a contraindication to NSAIDs (178 patients with AS, and 147 patients with nr-axSpA). The dosing regimens were the same as those currently approved for rheumatoid arthritis: a loading dose of 400 mg in weeks 0, 2, and 4, followed by either 200 mg every 2 weeks (Q2W) or 400 mg every 4 weeks (Q4W). Requirements for enrollment included chronic back pain for at least 3 months; onset before age 45 years; and imaging criteria that included sacroiliitis (on MRI or X-ray) with at least one spondyloarthritis feature, such as inflammation, back pain, arthritis, uveitis, or dactylitis.

At 12 weeks, 58% of patients on the Q2W regimen and 64% on the Q4W regimen had achieved an ASAS (Assessment of SpondyloArthritis international Society) 20 response, the primary endpoint, compared with 38% of those on placebo, both of which were statistically significant differences. The differences remained significant at 24 weeks. ASAS20 responses in the two subpopulations, those with AS and those with nr-axSpA, also favored those treated with certolizumab.

Treatment with certolizumab also resulted in significant improvements in function and spinal mobility, with similar responses at both dosage regimens, compared with placebo, as well as improvements in spinal and sacroiliac joint inflammation, productivity, and health-related quality of life, according to UCB.

The rates of serious adverse events were similar in the certolizumab-treated and placebo groups, the safety profile of certolizumab was consistent with the known safety profile of TNF inhibitors, and no new safety signals were identified. The rate of serious infections, a known risk, was higher among those on certolizumab.

The main issue raised by the FDA was whether the data from this study were adequate to support the indication, especially for patients with nr-axSpA, which would be a new indication for an approved treatment, according to Dr. Janet Maynard, acting clinical team leader in the FDA’s Division of Pulmonary, Allergy, and Rheumatology Products. But the FDA’s analysis of the data did not suggest that the efficacy results were driven by any subgroup, and the efficacy data for AS "appear reasonable," she said at the meeting.

The panel had no substantial safety concerns – voting 13-1 that the safety profile of certolizumab was adequate to support approval of the new indication – and agreed there was evidence of efficacy. Those voting against approval, however, thought that the indication was too broad and had concerns that included the small number of patients for a new indication (nr-axSpA), the lack of a clear definition of active disease in the indication, and the possibility that primary care physicians would prescribe the biologic drug for patients with low back pain.

Panelists supporting approval said that adequate prescribing information would result in appropriate use for patients with active disease in clinical practice.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting; occasionally, a panelist might be given a waiver, but not at this meeting.

[email protected]