FDA Panel Split on 2 Biologics for Axial Spondyloarthritis

Miriam E. Tucker

July 24, 2013

Silver Spring, MD — A federal advisory panel voted narrowly for the approval of certolizumab (Cimzia, UCB) for the treatment of axial spondyloarthritis (ax-SpA) but voted against expanding the current indication for adalimumab (Humira, AbbVie) for ax-SpA to include nonradiographic forms of the condition.

The US Food and Drug Administration's (FDA's) Arthritis Advisory Committee yesterday addressed separate applications for the treatment of ax-SpA with 2 different anti–tumor necrosis factor alpha drugs. In both cases, the debate surrounded the uncertainty regarding the definition of nonradiographic ax-SpA (nr-axSpA) and whether each of the respective manufacturers had provided sufficient evidence to support licensure in that patient subgroup.

Axial SpA includes both patients with ankylosing spondylitis (AS) and those with nr-axSpA. The 2 conditions share similar clinical, imaging, and laboratory features, but patients with nr-axSpA do not have radiographic sacroiliitis and are considered to have an earlier form of AS, although not all will progress if left untreated. There is currently no drug licensed for the treatment of nr-axSpA.

Panel members expressed concern that if the definition of nr-axSpA is too loose, both biologics, which are expensive and associated with adverse effects such as serious infections, might be inappropriately prescribed for people who actually have mechanical, rather than inflammatory, back pain.

Current criteria for nr-axSpA are not very specific, Sarah Yim, MD, associate director of the FDA's Division of Pulmonary, Allergy and Rheumatology Products, told Medscape Medical News, "We have a very vague notion of who these people are.... [F]or both sessions, the primary question was, 'In that [nr-axSpA] group, was there enough evidence?' "

Adalimumab Voted Down

In the morning, by a vote of 12 to 1 with 1 abstention, the panel voted down AbbVie's application for an expanded indication for adalimumab injection to include "adult patients with active nr-axSpA with objective signs of inflammation by elevated C-reactive protein [CRP] or magnetic resonance imaging [MRI], in patients who have had inadequate response to, or are intolerant to, nonsteroidal anti-inflammatory drugs [NSAIDs]."

Adalimumab is already FDA-approved for the treatment of active axSpA, rheumatoid arthritis, psoriatic arthritis, Crohn's disease, and other inflammatory conditions, and it is approved for nr-axSpA in 50 countries including the European Union, AbbVie Vice President John Medich, PhD, told the panel.

AbbVie's application for the expanded indication was based on a single trial of 185 patients with active nr-axSpA who had an inadequate response to NSAIDs or contraindications to their use. Patients were required to fulfill the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axSpA, but not the modified New York criteria for AS.

The patients were randomly assigned to receive adalimumab or placebo for 12 weeks and were then continued in an open-label phase for up to 68 weeks.

The primary endpoint was the ASAS40, defined as improvement of 40% or more and absolute improvement of 2 or more units from baseline in at least 3 of 4 domains, with no deterioration in the remaining domains of pain, function, morning stiffness, and Patient's Global Assessment of Disease Activity at 12 weeks. That endpoint was met, achieved by 36% of the 91 patients receiving adalimumab compared with just 15% of the 94 patients receiving placebo (P < .001).

All 9 prespecified secondary endpoints of disease activity and function scores were also met, Aileen Pangan, MD, senior medical director, Immunology Clinical Development, AbbVie, reported.

However, FDA reviewer Janet Maynard, MD, explained that a major problem was that 37% of the 102 patients who had initially been classified as nr-axSpA at screening, after subsequently having their X-rays centrally read on a post hoc basis, were later reclassified as fulfilling the radiographic modified New York Criteria for AS, leaving only 64 patients (33 receiving adalimumab, 31 receiving placebo) with nr-axSpA, according to central X-ray interpretation. Another 83 patients (43 receiving adalimumab, 40 receiving placebo) did not have their X-rays centrally read.

"While there are limitations to these analyses, they suggest that inclusion of patients with AS by central evaluation in the study appears to increase the apparent treatment effect of adalimumab in the overall study population," said Dr. Maynard, acting clinical team leader in the FDA Division of Pulmonary, Allergy and Rheumatology Products.

Panel members agreed. Irwin J. Russell, MD, PhD, who voted against the nr-axSpA indication, said "the post hoc central reading and post hoc analysis based on the central reading is leading to confusion, I think."

"We have a study that...turned out to be inadequate and didn't leave us with enough information about the patient population we're dealing with to understand how to make a decision based on the data that's available," said Dr. Russell, director of Fibromylagia Research and Consulting, Arthritis & Osteoporosis Center of South Texas, San Antonio.

Other members said that the nr-axSpA criteria should require both elevated CRP and MRI evidence, rather than one or the other, and that the MRI criteria should have specified inflammation at the sacroiliac joint. In addition, several members noted that the sample size with confirmed nr-axSpA was too small to support a decision.

Robert Lahita, MD, PhD, chairman of medicine at Newark Beth Israel Hospital in New Jersey, said, "I voted no, because I feel [both] the CRP and the MRI should be included. I'm not sure about the [nr-axSpA], its progression, and its self-remitting character. I think all of that's undefined, and I'm worried about people with mechanical back problems being included in this large, nebulous subgroup."

Acting committee chair Tuhina Neogi, MD, PhD, associate professor of medicine and epidemiology at Boston University Schools of Medicine and Public Health in Massachusetts, also voted no, citing the small number of patients with nr-axSpA exposed to adalimumab as well as the ambiguity of the subgroup definition. "I struggled with the question.... I do acknowledge overall the study was positive, and I think there is a treatment effect there. I just am not comfortable yet that this trial has helped us identify that particular subgroup."

Narrow Vote for Certolizumab

In the afternoon, the same committee voted 7 to 6 with 1 abstention in favor of UCB's bid for licensure of certolizumab injection for the treatment of "active axial spondyloarthritis, including patients with ankylosing spondylitis."

Certolizumab is currently FDA-approved for the treatment of rheumatoid arthritis and Crohn's disease.

Victor S. Sloan, MD, vice president and head of immunology practice for UCB, presented the data for certolizumab vs placebo in 325 patients with "active" disease. All met the ASAS classification criteria and had objective evidence of active disease, including elevated CRP and/or MRI evidence of sacroiliitis. They also had to have disease duration of 3 months or longer and to have been intolerant to or failed at least a single NSAID.

Here, the primary endpoint was ASAS20 at week 12, which assesses 20% improvement on clinical symptoms and features of axSpA. The response was significantly greater for 2 doses of certolizumab compared with placebo, at 63.6% with 400 mg every other week and 57.7% with 200 mg every other week compared with just 38.3% for placebo (P < .001 for 400 mg and P = .004 for 200 mg vs placebo).

Significant early and sustained improvements were also seen in other signs, symptoms, function, and spinal mobility, Dr. Sloan said.

The panel agreed that the data supported the indication for AS, but they again differed regarding the evidence supporting efficacy for nr-axSpA. Similar to the case with adalimumab, post hoc central rereading of the X-rays in 282 of the patients resulted in reclassification of 30% of the patients from nr-axSpA to AS. "It's unclear if efficacy data for nr-axSpA are adequate to support the novel indication," Dr. Maynard told the panel.

However, she also said that in the case of certolizumab, the overall results did not appear to be driven by a single subgroup and that the trends were similar regardless of which X-ray assessment the researchers used to classify the subgroups.

Panel members expressed mixed feelings about the nr-axSpA definition, with several suggesting they would be more comfortable with more data and a more restrictive definition for the subgroup.

Nancy E. Lane, MD, director of the Center for Musculoskeletal Health and endowed professor of medicine and rheumatology at the University of California School of Medicine at Davis, voted against approval. "I voted no, not because I didn't think the data was compelling. It was, but...I'm really yet insecure about this nonradiographic group until I really see some data that's not equivocal that this is the group that's going to respond."

However, Donald Miller, PharmD, professor and chair of the Pharmacy Practice Department at North Dakota State University in Fargo, voted yes. "I think in this case there was some potential. I'm optimistic that they can negotiate an appropriate label. I think probably payers will look to that labeling for guidelines as to appropriate use, and hopefully that will provide appropriate use in practice."

G. Caleb Alexander, MD, associated professor of medicine and epidemiology at Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, said "I voted no, although I think for a more restrictive indication I would likely be comfortable with this approval.... I also think there are some interesting questions regarding how long therapy should be continued, particularly among the radiographically negative subjects. I don't think we have any clue about that."

Dr. Lahita was willing to take a chance. "I voted yes, with the presumption that the FDA and the sponsor are going to work this out."

FDA advisory panel members are vetted for conflicts of interest and are granted waivers for participation if necessary. No waivers were granted for this meeting.


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