Upadacitinib improves signs, symptoms of ankylosing spondylitis, nonradiographic axSpA
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Upadacitinib significantly reduced signs and symptoms of both ankylosing spondylitis and nonradiographic axial spondyloarthritis, as well as improved physical function and disease activity, according to a pair of phase 3 studies from AbbVie.
Both studies from the SELECT-AXIS 2 clinical trial. In the first, upadacitinib (Rinvoq, AbbVie) met the primary endpoint of Assessment in Spondyloarthritis International Society (ASAS) 40 response and all ranked secondary endpoints at week 14. In all, 45% of patients who received upadacitinib achieved the ASAS40 response, compared with 18% in the placebo group (P < .0001).
In the second study, upadacitinib met the primary endpoint of ASAS40 response and most ranked secondary endpoints at week 14. As in the first study, “significantly more” patients who received the drug achieved the response at week 14, compared with placebo — 45% versus 23% (P < .0001) — according to an AbbVie press release.
“Ankylosing spondylitis is a debilitating disease that can cause severe pain, stiffness, restricted mobility and lasting structural damage impacting patients' everyday life,” Michael Severino, MD, vice chairman and president of AbbVie, said in the release. “AbbVie is committed to improving standards of care for patients with rheumatic diseases,” he added. “We are encouraged by these results that show Rinvoq was able to provide significant improvements in signs and symptoms, as well as other measures of disease activity, for patients living with ankylosing spondylitis who have already failed treatment with a biologic.”
In a second release, regarding the second study, Severino added that patients with nonradiographic axSpA “suffer from chronic inflammatory back pain and limited physical function that can be very debilitating.”
“These patients need treatments that help them improve their physical function and quality of life,” he said in the release. “We are encouraged by the potential of upadacitinib in helping to provide relief of these signs and symptoms through meaningful disease control.”
The SELECT-AXIS 2 trial was conducted as a master study protocol with two standalone studies, each with their own randomization, data collection, analysis and reporting, according to the press release. The aim of the trial was to examine the efficacy and safety of upadacitinib, compared with placebo, in reducing the signs and symptoms of, in study one, active axSpA, including AS in patients with an inadequate response to biologic disease-modifying antirheumatic drugs, and, in study 2, nonradiographic axSpA.
Study one enrolled 420 adults who were randomly assigned to receive upadacitinib for 104 weeks or placebo for 14 weeks followed by upadacitinib for 90 weeks. Meanwhile, study two enrolled 314 adults randomized to receive either upadacitinib for 104 weeks or placebo for 52 weeks followed by upadacitinib for 52 weeks.
According to AbbVie’s released findings for both studies, treatment with upadacitinib resulted in statistically significant reductions in the signs and symptoms of AS and nonradiographic axSpA, including back pain and inflammation, as well as improvements in physical function and disease activity, at week 14. Significantly more patients treated with upadacitinib achieved Ankylosing Spondylitis Disease Activity Score (ASDAS) Low Disease Activity, compared with those treated with placebo — 44% versus 10% in study one and 42% versus 18% in study two.
In addition, both studies demonstrated a statistically significantly greater improvement in MRI Spondyloarthritis Research Consortium of Canada (SPARCC) Score, as measured by the mean change from baseline, in the upadacitinib group compared with placebo — with –3.95 versus –0.04 in study one and –2.49 versus 0.57 in study two. Patients in both studies who received upadacitinib also demonstrated a significantly greater mean decrease from baseline in Patient's Assessment of Total Back Pain compared with placebo — at –3 versus –1.47 in study one and –2.91 versus –2 in study two — at week 14.
Lastly, patients in both studies treated with upadacitinib, compared with placebo, demonstrated significantly greater improvement in physical function, based on mean change from baseline in the Bath Ankylosing Spondylitis Functional Index (BASFI) — at –2.26 versus –1.09 in study one and –2.61 versus –1.47 in study two.
Safety data in both studies were consistent with SELECT-AXIS 1, previous phase 3 studies in other indications, and the drug’s known safety profile, with no new risks.
Perspective
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Charles Pritchard, MD, FACP, FACR, RhMSUS
There is a clear rationale for using JAK inhibitors in ankylosing spondylitis. The JAK pathway sits at the crossroads of both key innate and adaptive immune cell populations involved in SpA pathogenesis. Another JAK inhibitor, tofacitinib, has already shown effectiveness in a phase 3 trial of AS.
The first study of phase 3 SELECT-AXIS 2 of upadacitinib among patients with AS who had failed or did not tolerate biologic DMARDs met the primary endpoint of ASAS40 at week 14 vs. placebo (45% compared to 18%). Results of the second study among patients with non-radiographic AS are also positive.
Both studies show positive secondary endpoint results including ASDAS low disease activity, SPARCC MRI score, total back pain and BASFI. Additionally, the safety data was consistent with what was seen in the SELECT-AXIS 1 trial consistent with the known safety profile of upadacitinib.
This will be the first and only oral option approved for AS patients who have had a poor response to NSAIDs or biologic DMARDs. Enthusiasm for this medication may be somewhat dampened by the results of the Oral Surveillance study, which showed some increased risk of MACE and malignancy among rheumatoid arthritis patients with one cardiovascular risk factor.
Given the very positive clinical results with a drug in which rheumatologists have much experience, I suspect we will adopt this new use quickly. This will be a positive addition to our clinical armamentarium that already includes anti-TNF and anti-IL-17 medications; patient will like having a once-a-day oral drug option with a very tolerable safety profile.
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Atul Deodhar, MD
Upadacitinib will be the first JAK inhibitor that has done a study in nonradiographic axial SpA. Although Pfizer did a successful phase 3 study in ankylosing spondylitis with tofacitinib (Xeljanz, Pfizer), they have not done a study in nonradiographic axSpA, and I’m not sure if they will do one. Filgotinib (Gilead Sciences/Galapagos NV) only had a phase 2 study in ankylosing spondylitis, and did not pursue a phase 3 study for that, let alone for nonradiographic axSpA. Baricitinib (Olumiant, Eli Lilly & Co.) has not conducted any study at all for these indications.
AbbVie is the only group that has done a phase 3 study in AS for patients with an inadequate response to TNF inhibitors, and now also in nonradiographic axSpA. This is a positive, because there are no oral drugs outside of NSAIDs to treat patients with axSpA. JAK inhibitors will be the first oral agent, which is very convenient from the patient’s point of view — you won’t have to put them in the refrigerator, etc.
The SELECT-AXIS 2 results look very robust. There is no head-to-head comparison here, but you really make up your mind by looking at the active drug vs. the placebo and that looks very good for nonradiographic axSpA.
Another thing is that, in nonradiographic axSpA, HLA-B27 prevalence is generally lower than in ankylosing spondylitis, and there are more females compared to males. Male sex and HLA-B27 are, in fact, prognostic indicators and these patients respond better, at least in the TNF inhibitor and IL-17 classes of drugs. In nonradiographic axSpA, the prevalence of HLA-B27 and male sex are lower – compared to similar studies in ankylosing spondylitis – so one would have expected a lower response for their drug, but the response looks very good.
However, one cannot discuss JAK inhibitors without mentioning the risks regarding these drugs. ORAL Surveillance, a post-marketing safety clinical trial ordered by the FDA when it first approved tofacitinib for rheumatoid arthritis in 2012, required participants to be at least 50 years of age and have at least one additional cardiovascular risk factor. It was a noninferiority study, but tofacitinib failed to show noninferiority to TNF inhibitors. As a result, the FDA has called a black box warning on tofacitinib and extended that warning to upadacitinib because it’s in the same class of drugs. These results have made all of us take a more careful look at JAK inhibitors.
Patients with non-radiographic axSpA are generally younger, and they have less cardiovascular risk factors, compared with patients with psoriatic arthritis, for example, who tend to be heavier and more obese. Although this study is very positive, this should be a matter for shared decision-making with the patient. I should also mention that in the upadacitinib study on nonradiographic axSpA, there were no cases of major cardiovascular events or venous thromboembolism.
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