FDA panel votes against new AS indication for TNF-blocker

SILVER SPRING, MD. – Citing uncertainties about the efficacy data in a pivotal trial, the majority of a Food and Drug Administration advisory panel recommended against expanding the approval of adalimumab to include patients with axial spondyloarthritis who do not have radiographic evidence of ankylosing spondylitis.

At a July 23 meeting, the FDA’s Arthritis Advisory Committee voted 12-1, with 1 abstention, against recommending approval of adalimumab for the indication proposed by the manufacturer, AbbVie Inc.: reducing signs and symptoms in adults with active nonradiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation (elevated C-reactive protein or MRI findings) and who have had an inadequate response to, or are intolerant of nonsteroidal anti-inflammatory drugs.

Adalimumab is a monoclonal antibody against tumor necrosis factor (TNF) that was initially approved by the FDA in December 2002 as a treatment for rheumatoid arthritis in adults and was subsequently approved in 2006 for reducing the signs and symptoms of active ankylosing spondylitis (AS) in adults. It is also approved for psoriatic arthritis, juvenile idiopathic arthritis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. It is administered by subcutaneous injection every other week.

Axial spondyloarthritis (axial SpA) includes AS and nr-axSpA; there are no FDA-approved treatments for people with nr-axSpA.

The majority of the panel agreed that no new safety signals were seen in the pivotal study and that the safety profile of adalimumab would not be expected to be different in patients with nr-axSpA and those with RA and other approved indications. But the panel voted that the manufacturer’s data did not provide substantial evidence that the drug resulted in a "clinically meaningful beneficial effect" for these patients, the efficacy criteria needed for approval.

The study compared adalimumab to placebo in 192 patients with active nr-axSpA, who had an inadequate response to NSAIDs, could not tolerate NSAIDs, or had a contraindication to NSAIDs. Patients were able to continue treatment with DMARDs, including sulfasalazine and methotrexate. The primary endpoint used to evaluate clinical responses was the ASAS (Assessment of SpondyloArthritis International Society) 40 response, which is defined as an improvement of at least 40% and absolute improvement of at least two units from baseline in at least three of four domains with no deterioration in the remaining domain (pain, function, morning stiffness, and Patient’s Global Assessment of Disease Activity).

At 12 weeks, 36% of those on adalimumab at a dose of 40 mg every other week had achieved an ASAS40 response, compared with 15% of those on placebo, a statistically significant difference. About 20% of those on adalimumab were in clinical remission at week 12, and efficacy was maintained or improved further among those who continued adalimumab in the open-label period through 68 weeks, according to the company. Adverse events were similar to those associated with the use of adalimumab in patients with AS, psoriatic arthritis, and rheumatoid arthritis.

But based on patient x-rays read at a central facility, a substantial proportion of patients in the trial had radiographic evidence of AS, an approved indication for adalimumab, which the FDA reviewer said may have affected the efficacy results. The FDA’s analysis of ASAS40 responses identified a markedly greater beneficial effect among those who had AS and had positive findings on x-rays, compared with those who had negative x-ray results and had nr-axSpA. In addition, the estimated effect of treatment in the nr-axSpA patients was described as "modest" by the FDA.

Panelists said that there is an unmet need for treatments in patients with this group, and encouraged the company to conduct another, better-designed study.

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.

In July 2012, adalimumab was approved in the European Union for nr-axSpA.

[email protected]

SILVER SPRING, MD. – Citing uncertainties about the efficacy data in a pivotal trial, the majority of a Food and Drug Administration advisory panel recommended against expanding the approval of adalimumab to include patients with axial spondyloarthritis who do not have radiographic evidence of ankylosing spondylitis.

At a July 23 meeting, the FDA’s Arthritis Advisory Committee voted 12-1, with 1 abstention, against recommending approval of adalimumab for the indication proposed by the manufacturer, AbbVie Inc.: reducing signs and symptoms in adults with active nonradiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation (elevated C-reactive protein or MRI findings) and who have had an inadequate response to, or are intolerant of nonsteroidal anti-inflammatory drugs.

Adalimumab is a monoclonal antibody against tumor necrosis factor (TNF) that was initially approved by the FDA in December 2002 as a treatment for rheumatoid arthritis in adults and was subsequently approved in 2006 for reducing the signs and symptoms of active ankylosing spondylitis (AS) in adults. It is also approved for psoriatic arthritis, juvenile idiopathic arthritis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. It is administered by subcutaneous injection every other week.

Axial spondyloarthritis (axial SpA) includes AS and nr-axSpA; there are no FDA-approved treatments for people with nr-axSpA.

The majority of the panel agreed that no new safety signals were seen in the pivotal study and that the safety profile of adalimumab would not be expected to be different in patients with nr-axSpA and those with RA and other approved indications. But the panel voted that the manufacturer’s data did not provide substantial evidence that the drug resulted in a "clinically meaningful beneficial effect" for these patients, the efficacy criteria needed for approval.

The study compared adalimumab to placebo in 192 patients with active nr-axSpA, who had an inadequate response to NSAIDs, could not tolerate NSAIDs, or had a contraindication to NSAIDs. Patients were able to continue treatment with DMARDs, including sulfasalazine and methotrexate. The primary endpoint used to evaluate clinical responses was the ASAS (Assessment of SpondyloArthritis International Society) 40 response, which is defined as an improvement of at least 40% and absolute improvement of at least two units from baseline in at least three of four domains with no deterioration in the remaining domain (pain, function, morning stiffness, and Patient’s Global Assessment of Disease Activity).

At 12 weeks, 36% of those on adalimumab at a dose of 40 mg every other week had achieved an ASAS40 response, compared with 15% of those on placebo, a statistically significant difference. About 20% of those on adalimumab were in clinical remission at week 12, and efficacy was maintained or improved further among those who continued adalimumab in the open-label period through 68 weeks, according to the company. Adverse events were similar to those associated with the use of adalimumab in patients with AS, psoriatic arthritis, and rheumatoid arthritis.

But based on patient x-rays read at a central facility, a substantial proportion of patients in the trial had radiographic evidence of AS, an approved indication for adalimumab, which the FDA reviewer said may have affected the efficacy results. The FDA’s analysis of ASAS40 responses identified a markedly greater beneficial effect among those who had AS and had positive findings on x-rays, compared with those who had negative x-ray results and had nr-axSpA. In addition, the estimated effect of treatment in the nr-axSpA patients was described as "modest" by the FDA.

Panelists said that there is an unmet need for treatments in patients with this group, and encouraged the company to conduct another, better-designed study.

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.

In July 2012, adalimumab was approved in the European Union for nr-axSpA.

[email protected]

SILVER SPRING, MD. – Citing uncertainties about the efficacy data in a pivotal trial, the majority of a Food and Drug Administration advisory panel recommended against expanding the approval of adalimumab to include patients with axial spondyloarthritis who do not have radiographic evidence of ankylosing spondylitis.

At a July 23 meeting, the FDA’s Arthritis Advisory Committee voted 12-1, with 1 abstention, against recommending approval of adalimumab for the indication proposed by the manufacturer, AbbVie Inc.: reducing signs and symptoms in adults with active nonradiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation (elevated C-reactive protein or MRI findings) and who have had an inadequate response to, or are intolerant of nonsteroidal anti-inflammatory drugs.

Adalimumab is a monoclonal antibody against tumor necrosis factor (TNF) that was initially approved by the FDA in December 2002 as a treatment for rheumatoid arthritis in adults and was subsequently approved in 2006 for reducing the signs and symptoms of active ankylosing spondylitis (AS) in adults. It is also approved for psoriatic arthritis, juvenile idiopathic arthritis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. It is administered by subcutaneous injection every other week.

Axial spondyloarthritis (axial SpA) includes AS and nr-axSpA; there are no FDA-approved treatments for people with nr-axSpA.

The majority of the panel agreed that no new safety signals were seen in the pivotal study and that the safety profile of adalimumab would not be expected to be different in patients with nr-axSpA and those with RA and other approved indications. But the panel voted that the manufacturer’s data did not provide substantial evidence that the drug resulted in a "clinically meaningful beneficial effect" for these patients, the efficacy criteria needed for approval.

The study compared adalimumab to placebo in 192 patients with active nr-axSpA, who had an inadequate response to NSAIDs, could not tolerate NSAIDs, or had a contraindication to NSAIDs. Patients were able to continue treatment with DMARDs, including sulfasalazine and methotrexate. The primary endpoint used to evaluate clinical responses was the ASAS (Assessment of SpondyloArthritis International Society) 40 response, which is defined as an improvement of at least 40% and absolute improvement of at least two units from baseline in at least three of four domains with no deterioration in the remaining domain (pain, function, morning stiffness, and Patient’s Global Assessment of Disease Activity).

At 12 weeks, 36% of those on adalimumab at a dose of 40 mg every other week had achieved an ASAS40 response, compared with 15% of those on placebo, a statistically significant difference. About 20% of those on adalimumab were in clinical remission at week 12, and efficacy was maintained or improved further among those who continued adalimumab in the open-label period through 68 weeks, according to the company. Adverse events were similar to those associated with the use of adalimumab in patients with AS, psoriatic arthritis, and rheumatoid arthritis.

But based on patient x-rays read at a central facility, a substantial proportion of patients in the trial had radiographic evidence of AS, an approved indication for adalimumab, which the FDA reviewer said may have affected the efficacy results. The FDA’s analysis of ASAS40 responses identified a markedly greater beneficial effect among those who had AS and had positive findings on x-rays, compared with those who had negative x-ray results and had nr-axSpA. In addition, the estimated effect of treatment in the nr-axSpA patients was described as "modest" by the FDA.

Panelists said that there is an unmet need for treatments in patients with this group, and encouraged the company to conduct another, better-designed study.

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.

In July 2012, adalimumab was approved in the European Union for nr-axSpA.

[email protected]