In a phase 3 randomized, controlled clinical trial, upadacitinib (Rinvoq) proved superior to placebo and adalimumab (Humira) for improving signs and symptoms of rheumatoid arthritis (RA) in patients, according to an article published in Arthritis & Rheumatology.1 Upadacitinib is a once-daily, oral Janus kinase inhibitor (jakinib) approved by the U.S. Food & Drug Administration in August 2019 to treat adults with moderate to severe RA who are intolerant to, or have had an inadequate response to, methotrexate.
The results of the SELECT-COMPARE study, which was supported by AbbVie, focused on the noninferiority and superiority of upadacitinib, both clinically and functionally, to placebo and adalimumab.
The Study
In the study, all patients were adults who had been diagnosed with RA for at least three or more months and had active disease and a high-sensitivity C-reactive protein level of 5 mg/L or greater. Additionally, participants had at least three erosions or more on hand and foot X-rays, or one or more erosions and were positive for rheumatoid factor (RF) or anti-cyclic citrullinated protein (anti-CCP) antibodies. All patients had taken methotrexate for at least three months and were on a stable 15–25 mg weekly dose for at least four weeks before receiving the first study treatment.
Up to 20% of patients exposed to one biologic disease-modifying anti-rheumatic drug (bDMARD)—not including adalimumab—could be included if they had fewer than three months of exposure or had discontinued taking it due to intolerance. Patients with an inadequate response to a prior bDMARD or jakinib were excluded from the study.
The study’s 1,629 patients were seen at 286 sites in 41 countries. Forty-four percent of study patients were from Eastern Europe, 27% from South or Central America, 19% from North America, 6% from Western Europe, 3% from Asia and 6% from other regions. Patients had active disease with a mean RA duration of approximately eight years. Nearly 88% of patients were positive for RF and/or anti-CCP antibodies. The mean methotrexate dose was 17 mg per week, and 9.3% of patients had prior bDMARD exposure.
Patients were randomized in a doubleblind, 2:2:1 ratio to receive 15 mg of upadacitinib once daily, 40 mg of adalimumab every other week or placebo. Patients also continued their oral or parenteral methotrexate at a stable dose. Stable doses of non-steroidal anti-inflammatory drugs, acetaminophen or oral steroids were also permitted.
Patients on placebo without an improvement of 20% or greater in tender and swollen joint counts from baseline were rescued at weeks 14, 18 and 22: placebo to upadacitinib, upadacitinib to adalimumab, and adalimumab to upadacitinib.
As the primary endpoints, researchers measured the proportion of patients who achieved an ACR20 response (i.e., an improvement of 20% in the number of tender and number of swollen joints, and a 20% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure, visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein) and achieved a Disease Activity Score for 28 joints (DAS28-CRP) of less than 2.6 vs. placebo at week 12. Researchers also examined inhibition of radiographic progression at week 26, and at week 14 in rescued patients.
Physical exams, vital signs, electrocardiogram and lab tests were monitored during the study for safety assessment. Data on investigator-reported adverse events were also collected and summarized through week 26. Additionally, Rheumatology Common Toxicity Criteria v.2.0 were used to grade adverse events and lab changes other than creatine phosphokinase and creatinine. An independent, external cardiovascular adjudication committee blindly adjudicated reported cardiovascular events.
Results
Seventy-one percent of upadacitinibtreated patients achieved an ACR20 response by week 12, compared with 36% of placebo-treated patients and 63% of adalimumab-treated patients. Compared with the placebo and adalimumab groups, the upadacitinib group had statistically better ACR50 and ACR70 responses. A significantly larger proportion of upadacitinib-treated patients achieved DAS28-CRP of 3.2 or less and a Clinical Disease Activity Index (CDAI) of 10 or less vs. placebo-treated patients.
At week 26, upadacitinib also demonstrated other advantages, such as low disease activity and remission, greater improvements for quality of life and reduced radiographic progression.
While on the original, randomized study treatment, the proportion of patients who experienced adverse events was higher in the adalimumab and upadacitinib groups compared with placebo. Similar proportions of patients had serious infections with upadacitinib (1.8%) and adalimumab (1.5%). Nine patients had opportunistic infections (placebo: 0.6%; upadacitinib: 0.6%; adalimumab: 0.3%). Five reported adjudicated major adverse cardiovascular events—none with upadacitinib, two with adalimumab and three with placebo. Eight patients had cases of herpes zoster, a greater number in the upadacitinib group than in the placebo and adalimumab groups.
Six patients experienced venous thromboembolic events (VTEs), one with placebo, two with upadacitinib and three with adalimumab. All six patients had preexisting risk factors.
Four deaths were reported: none with upadacitinib; two with placebo related to cardiovascular health and Pneumocystis jirovecii pneumonia; and two on adalimumab linked to craniocerebral injury in a car accident and cardiovascular death related to left ventricular failure.
The long-term safety assessments from upadacitinib’s phase 3 RA program will help better characterize rare safety events with the drug, write the authors.
According to the authors, one limitation of the study is that the duration of the placebo-controlled period was 26 weeks, with rescue treatment administered at week 14. “[Because] rescue treatment was provided starting at week 14 for ethical reasons, not all patients remained on their randomized treatment assignment for the entire six months,” they write.
A Closer Look
Because upadacitinib is newly available—the third jakinib approved for RA—it’s important for rheumatologists to reflect on the results of studies like this one.
The study’s evidence that upadacitinib is as effective as adalimumab to treat RA is notable, says study author Roy Fleischmann, MD, MACR, co-medical director, Metroplex Clinical Research Center, and clinical professor of medicine, UT Southwestern Medical Center, Dallas. “This is the third agent in the [jakinib] class that has been shown to be at least as effective—if not more so—[as] a bDMARD,” he says.
The similar adverse events seen in both the upadacitinib and adalimumab patients was an interesting result. “This riskbenefit profile raises the question, [because jakinibs] are oral, whether they should be used prior to a bDMARD in a methotrexate incomplete responder,” Dr. Fleischmann says.
Because of the concern with VTEs occurring in jakinib-treated patients, Elena Schiopu, MD, associate professor, Division of Rheumatology, Michigan Medicine, Ann Arbor, is more diligent about monitoring for additional risk factors associated with VTEs, such as obesity, estrogen use, history of malignancies and immobility. However, the major risk factors are prior VTEs and use of a COX2 inhibitor. Like tofacitinib and baricitinib, upadacitinib has a boxed warning about VTEs on its label.
Vanessa Caceres is a medical writer in Bradenton, Fla.
Reference
- Fleischmann R, Pangan AL, Song I-H, et al. Upadacitinib vs. placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a phase 3, double-blind, randomized controlled trial. Arthritis Rheumatol. 2019 Nov;71(11): 1788–1800. Epub 2019 Aug 28.
