C-AXSPAND Study in nr-axSpA

Transcript: Sergio Schwartzman, MD: Atul, there’s only 1 biologic that’s been approved for nonradiographic axial spondyloarthritis. It’s been studied in 2 separate studies, the most recent being the C-AXSPAND study. Can you please summarize that study for us?

Atul Deodhar, MD, MRCP: The C-AXSPAND study was a study done on certolizumab pegol, and you’re right: That’s the only anti—TNF [tumor necrosis factor] approved in the United States. There are 4 anti-TNF approved in the European Union for the use of nonradiographic axial spondyloarthritis. The C-AXSPAND study is special because it was the first time we did the study with a 52-week placebo control, which is the high bar that the FDA had. They said that we are not really sure about the natural history of this condition, which was incompletely characterized. There was concern that these patients might spontaneously remit, which is the reason they wanted to do this 52-week placebo-controlled study.

The patients were randomized from all over the world—North America, Asia, Australia, and Europe. They were given either certolizumab pegol, and that’s the usual dose that we use—400 mg at baseline at week 2 and week 4, followed by 200 mg every 2 weeks—which is how we would be using certolizumab even in rheumatoid arthritis, compared with placebo. One important thing is that the study was done in patients who had definitive objective signs of inflammation.

By that, I mean they had to have either high C-reactive protein, or they had to have a positive MRI [magnetic resonance imaging] scan. Patients were allowed to continue the background medications that they were taking. In fact, they were allowed to even change the background medications after week 12. This was added by the FDA to make it more ethical, so patients wouldn’t really be on placebo for the entire year. The first 12 weeks, that was discouraged. The primary end point in this study was something called ASDAS [Ankylosing Spondylitis Disease Activity Score] major improvement.

The major improvement means an improvement of 2 or more at week 52. There were 317 patients in that study, and what they found out was 47% of the patients on the active drug—compared with only 7% in the placebo—got the primary end point, so it was definitely successful. Not only that, but 61% of the patients who were on placebo just couldn’t stay on the placebo and had to switch to open-label treatment. That happened in only about 12% of the patients—the 12% of patients who were on certolizumab.

Both ways it showed that certolizumab improved the quality of life and that ASDAS, the disease activity score, had major improvement in patients who receive the drug compared with placebo. This was the first 52-week placebo-controlled study, and that’s the reason the FDA approved it. There are other anti-TNF drugs that have done studies on this, though they are not 52 weeks. But they are enough for the European Union to accept them, and those drugs are Enbrel [etanercept], Humira [adalimumab], and Simponi [golimumab].

Remicade, which is infliximab, is not really approved but is in daily practice. There is no reason to believe that other anti-TNF drugs will not really work.

Sergio Schwartzman, MD: What you think are some of the unique features of C-AXSPAND study? You mentioned the 52-week primary end point as 1. Were there any other things that struck you about the study?

Atul Deodhar, MD, MRCP: I was very struck about how positive the study was. It was conducted very well. A 52-week placebo-controlled study is not easy to conduct. They allowed change in the background medication in patients who were on placebo, so it was kept ethical. At the same time, it was continued for 52 weeks. As I said, they used the ASAS [Assessment in SpondyloArthritis international Society] classification criteria, but they added that patients had to have objective signs of active inflammation. The MRI scans and the x-rays were all centrally read, so overall, I would say it was a well-done study.

Sergio Schwartzman, MD: The other thing that struck me about that study was the very low placebo response. The outcome measure was different from other studies’. I was very impressed by the fact that it had such a low placebo response, which made this study very believable.

Atul Deodhar, MD, MRCP: Yes, the problem is with the other studies, where the placebo responses are very high. One of the reasons we’re discussing that is that patients believe that biologics are going to work because of their familiarity with this class of drug overall. That makes people believe that, “Oh, I must be. There is a 50% chance I’m on biologics.” They start feeling better. Placebo responses are higher because our expectations have changed.

Sergio Schwartzman, MD: Thank you.

The rheumatic diseases in general—or a significant portion of the rheumatic diseases—affect young people, many of whom are in their childbearing years. One of the concerns that’s frequently expressed when we meet our patients who have rheumatic disease is, “How is the rheumatic disease going to affect my fertility and my ability to have children?” It comes not only from women but men.

Some of the medications we give can affect male fertility. Certolizumab is a unique therapy in the TNF class because it’s a PEGylated Fab fragment that lacks an Fc portion. We know that transport during pregnancy across the placenta is Fc mediated to a large extent. It is the only anti-TNF agent that we have that does not have an Fc portion. It has actually been studied in pregnancy, which is unusual for many of the therapies that we utilized to treat patients with rheumatic diseases.

What has been found is that compared with other Fc-bearing therapies, transport across the placenta for certolizumab is minimal. It’s also been studied in breast milk, and it’s not expressed in the breast milk of women who are breastfeeding. This unique feature of certolizumab is now well known in the rheumatic disease community. Not only is it well-known in the rheumatic disease community, but many patients are aware of this as well. It’s the niche that exists that is supported by data and is actually part of the package insert for certolizumab across all its indications.

Sergio Schwartzman, MD: Thank you.

Transcript Edited for Clarity