In early 2019, the US FDA expanded the indication of certolizumab pegol to include nonradiographic axial spondyloarthritis (axSpA) [1], initially approved in 2008 for rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, and moderate-to-severe plaque psoriasis [2]. This makes the tumor necrosis factor (TNF) inhibitor the first FDA-approved treatment for nonradiographic axSpA. The approval was based on the results of the C-axSpAnd trial, which demonstrated the efficacy of certolizumab pegol in 317 patients with nonradiographic disease [3].
In Europe, on the other hand, certolizumab pegol has been approved for nonradiographic axSpA since 2013, when the European Commission expanded the indication to include severe active axSpA without radiographic evidence of ankylosing spondylitis [4].
Here, medwireNews talks to Walter Maksymowych (University of Alberta, Edmonton, Canada), one of the investigators on the C-axSpAnd trial, and Marina Magrey (MetroHealth Medical Center, Cleveland, Ohio, USA), a rheumatologist with a special interest in spondyloarthritis, about what the recent FDA approval of certolizumab pegol means for treating nonradiographic axSpA and why the approval happened so much later in the USA than in Europe.
A new disease indication
There were no approved treatments for nonradiographic axSpA in the USA until the approval of certolizumab pegol because “up to this point the FDA did not even recognize this [as] being a new indication,” says Walter Maksymowych. He explains that “it’s only in the past decade that we’ve been able to detect this very early form of spondyloarthritis,” because diagnosis relied mainly on X-rays in the past, which “detect a relatively late stage of disease.”
Indeed, ankylosing spondylitis, also known as radiographic axSpA, has long been recognized as a disease entity according to the presence of radiographic changes in the sacroiliac joints, together with clinical criteria, as specified by the modified New York criteria [5]. Nonradiographic axSpA was officially recognized by the Assessment of SpondyloArthritis international Society (ASAS) in 2009, when the new criteria included patients with clinical features of axSpA but without radiographic sacroiliitis – ie, those with nonradiographic axSpA – as well as patients with radiographic disease [6].
We now “have the means to detect the disease and conduct clinical trials of patients with nonradiographic spondyloarthritis,” says Maksymowych, noting that recent technology like magnetic resonance imaging (MRI) “has allowed us to detect the disease with confidence before it becomes apparent on an X-ray.”
The importance of MRI
Despite the technological advances, Maksymowych considers that understanding MRI results still remains a very important unmet need in axSpA.
I’m not aware of any rheumatologist specialty training program anywhere in the world that includes basic training in the assessment of MRI
Despite this, he points out that “a lot of rheumatologists still rely on radiography, and there is both overdiagnosis and failure to diagnose because the X-ray is unreliable,” and, “conversely, many rheumatologists are simply not familiar [enough] with MRI” to have an informed discussion with radiologists.
“I’m not aware of any rheumatologist specialty training program anywhere in the world that includes basic training in the assessment of MRI,” and “you simply cannot manage a patient effectively in 2019” without this understanding, stresses Maksymowych.
“Radiologists see very little of this disease in routine practice and most radiologists will have very little exposure to spondyloarthritis, so to assume that radiologists are going to understand the interpretation of MRI for spondyloarthritis is a big mistake.”
He emphasizes: “I think there is an exceptionally important need for educational programs for physicians to help them to understand MRI.”
Regulatory differences of opinion
So why did the first drug approval for this nonradiographic axSpA happen so much earlier in Europe than in the USA?
Marina Magrey believes that this could be due to differences in uptake of the term “nonradiographic axSpA” across different geographic settings. The term was first established by a set of classification criteria developed in 2009 by ASAS, and was “mainly developed for the approach to clinical trial design and the assessment of therapeutic efficacy,” she notes.
“I think our European colleagues and other people easily accepted this concept,” whereas “in the USA over time when more data became available about the clinical course and progression of the disease, the term started to register better,” says Magrey.
The first treatment to be approved for nonradiographic axSpA in Europe was adalimumab in 2012. The EMA said that patients with nonradiographic disease and an inadequate response to nonsteroidal anti-inflammatory drugs did not have alternative treatments available, despite having similar signs and symptoms to those with ankylosing spondylitis [7]. The agency approved adalimumab based on the findings of ABILITY-1, a phase 3 randomized trial demonstrating that the TNF inhibitor improved disease activity, inflammation, and quality of life relative to placebo in this patient population [8]. By contrast, the US FDA denied the approval of adalimumab for nonradiographic axSpA in 2013 due to uncertainty surrounding the disease definition.
The FDA felt that the natural history of axSpA was not well defined, and the other concern was that some of the classification criteria for nonradiographic axSpA could easily be fulfilled by patients with fibromyalgia, says Magrey.
“It took a little bit more time for people to understand the concept [of nonradiographic axSpA]” in the USA, she adds.
Maksymowych notes that another explanation for the delayed US approval could be that the FDA “considered that this was a condition that could spontaneously remit” when nonradiographic axSpA was first proposed as a new indication to the FDA in 2013.
“This was an obstacle [to new approvals] because the argument could be made that patients got better in clinical trials simply because this is a condition that can get better on its own,” he says.
The C-axSpAnd trial
Maksymowych says that this concept of spontaneous remission in nonradiographic axSpA was refuted by the results of C-axSpAnd, the pivotal trial supporting the FDA approval of certolizumab pegol for this indication.
He explains that that the FDA-stipulated study design required the placebo-controlled part of the trial to last for 1 year to “permit the assessment as to whether the disease would remit or not in patients on placebo.”
Maksymowych and co-investigators found that the primary endpoint of major improvement in ASDAS – defined as a reduction of 2.0 points or more from baseline or achievement of the lowest possible score of 0.6 points – was met by 47.2% of 159 patients randomly assigned to receive certolizumab pegol but just 7.0% of the 158 patients given placebo, leading them to conclude that nonradiographic axSpA does not spontaneously remit without biologic treatment in the majority of patients [3].
Spontaneous remission “proved to be a false prediction” and a substantial proportion of patients required rescue treatment with open-label biologic,” he says.
Maksymowych says that the second main finding from the C-axSpAnd trial was that active treatment with certolizumab pegol “was effective in reducing disease activity in these patients, and the differences between those patients on active treatment and those patients on placebo were highly statistically significant,” thereby supporting use of the TNF inhibitor as a treatment option.
Impact of the approval
Certolizumab pegol will be “transformational” in many parts of the world where nonradiographic axSpA patients previously did not have access to biologic treatment, people for whom “treatment options are really quite limited,” believes Maksymowych.
He stresses that “it's important that we have agents available for the full spectrum of spondyloarthritis,” especially early disease.
“This is very important because treatment responses are very much larger early in the disease course; the sooner you diagnose and recognize the condition and the sooner you implement treatment the better the outcome and this is very much the case in spondyloarthritis,” he adds.
Magrey agrees, noting that “in the current paradigm, both nonradiographic and radiographic axSpA are believed to represent a continuum of the same disease.” She says that there have been some longitudinal studies demonstrating progression from nonradiographic to radiographic axSpA, with varying rates of progression. For example, a study of 95 patients with nonradiographic disease showed that 11.6% developed ankylosing spondylitis over 2 years of follow-up [9], while a 5-year analysis of data from the DESIR cohort demonstrated that 5.1% of 416 patients progressed from nonradiographic to radiographic disease[10]. And a population-based study of 83 people with nonradiographic disease found that 19.3% progressed to ankylosing spondylitis [11].
getting [certolizumab pegol] approved by the FDA gives some authenticity to what we were already doing
Magrey points out that despite there being no FDA-approved treatments for nonradiographic disease until recently, many “clinicians were using it off-label” because “disease burden is equal in both radiographic and nonradiographic disease,” with many studies showing that patients from both groups suffer similar levels of pain and impairments in physical function.
She feels that “getting [certolizumab pegol] approved by the FDA gives some authenticity to what we were already doing,” and that the approval should facilitate discussions with patients about treatment options.
How about other biologics?
Magrey believes that the approval of other biologics in the USA will “definitely” follow the approval of certolizumab pegol.
“I don't know about the TNF inhibitors, but other classes of biologics such as IL [interleukin]-17 inhibitors are currently being studied; some have even completed studies, and some companies will soon be approaching the FDA for approval for other medications,” she says. For example, she notes that clinical trials on the IL-17A inhibitor ixekizumab for nonradiographic axSpA have been completed, and Eli Lilly (Indianapolis, Indiana, USA) “will soon be approaching FDA for approval of ixekizumab for nonradiographic SpA.”
Findings from the ixekizumab trials in patients with nonradiographic disease have not yet been published, but a company press release issued in April 2019 reported that ixekizumab-treated patients had significantly higher ASAS40 response rates at weeks 16 and 52 than those given placebo in the phase 3 COAST-X study [12].
“Now whether one biologic is better than the other [for nonradiographic axSpA] we don’t know,” remarks Magrey. She notes that some of the biologics have restrictions in their use; etanercept, for example, requires caution in patients with inflammatory bowel disease or uveitis. For certolizumab pegol, she says there are general precautions about not prescribing the drug for people with active tuberculosis, invasive fungal infections, or a previous adverse reaction, but “to my knowledge there was no increased risk of any extra articular symptoms by using certolizumab that we would be cautioned about.”
The choice of biologic agent for nonradiographic disease will also likely be influenced by financial factors. Magrey explains that in the USA, “the prescription patterns are somewhat driven by the insurance companies because they are the ones who have to authorize these expensive medications.” She thinks that “it’s possible that [the insurance companies] will prefer certolizumab pegol over other biologics [at this time], since it’s the only FDA-approved drug for nonradiographic axSpA.”
Unanswered questions in axSpA
At present, “there’s a lot of stuff unanswered and we need to look into it,” says Magrey. She emphasizes that first and foremost, “we would love to know the predictors of response” to different agents.
“If I would know which patient would respond to which drug it would be easy for me and I could tell the patient that this one may be better for you than the other.”
Maksymowych also thinks that this is a key priority for future research, noting that “additional biomarkers that predict treatment response” are especially important with the emergence of different biologics with distinct mechanisms of action.
At present, “it's sort of a flip of the coin approach, and there's no way of predicting which treatment is going to work best,” and this is a challenge with “most of our biologics in the whole field of rheumatology,” he says.
Both experts feel that another key area for research is whether certolizumab pegol and other biologics are able to prevent progression of axSpA.
“Is there a window of opportunity in the treatment? If we treat [patients] early on in the disease course are we going to be able to withdraw the drug later?” asks Magrey.
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