Upadacitinib shows promise, toxicity issues give pause

In patients with rheumatoid arthritis (RA) refractory to biologic disease-modifying antirheumatic drugs (DMARDs), upadacitinib proved a double-edged sword—while the oral selective Janus kinase (JAK) inhibitor bested abatacept in reducing disease activity and achieving remission at week 12, upadacitinib therapy was associated with more serious side effects.

Studies showed that upadacitinib led to remission in roughly 30% of RA patients, regardless of previous treatment failures with synthetic or biologic DMARDs, Andrea Rubbert-Roth, MD, of the division of rheumatology at Cantonal Clinic St. Gallen in St. Gallen, Switzerland, and colleagues explained in The New England Journal of Medicine. Meanwhile, the T-cell costimulation modulator abatacept has proved its efficacy and safety in phase III trials involving patients with active RA with an inadequate response to methotrexate or other biologic DMARDs.

For the phase III, double-blind SELECT-CHOICE trial, Rubbert-Roth and colleagues pitted upadacitinib against abatacept — each in combination with stable background conventional synthetic DMARDs — in a cohort of RA patients who had an inadequate response to previous biologic DMARDs.

“Upadacitinib, when administered with stable conventional DMARDs, was superior to abatacept in the mean change from baseline in the [Disease Activity Score for 28 joints based on the C-reactive protein level] DAS28-CRP at week 12 (−2.52 vs −2.00), with a difference of −0.52 points (95% CI, −0.69 to −0.35),” they found. “Upadacitinib was also superior with regard to the percentage of patients having remission according to a DAS28-CRP of less than 2.6 at week 12.”

However, patients in the upadacitinib group experienced a higher rate of serious adverse events, including two venous thromboembolic events, one nonfatal stroke, and one treatment-emergent death, along with elevated hepatic aminotransferase levels, they added.

“By showing the superiority of upadacitinib over abatacept in difficult-to-treat patients with rheumatoid arthritis who had had an inadequate response to a biologic DMARD, Rubbert-Roth et al position JAK inhibitors in a treatment algorithm and help push JAK inhibitors to the forefront of treatment for rheumatoid arthritis,” Tore K. Kvien, MD, PhD, and Guro L. Goll, MD, PhD, both of the department of rheumatology at Diakonhjemmet Hospital in Oslo, Norway, wrote in an editorial accompanying the study. “In order to compete in the crowded field of targeted treatments for rheumatoid arthritis, JAK inhibitors not only have to prove that they are efficacious and safe — they also need to be less expensive than or clinically superior to biologic DMARDs.”

For their 24-week, phase III, double-blind, controlled trial, Rubbert-Roth and colleagues recruited 613 patients ages 18 years or older with a diagnosis of rheumatoid arthritis for at least 3 months — patients had moderate-to-severe active disease despite treatment for at least 3 months with at least one biologic DMARD or had had unacceptable side effects from at least one biologic DMARD. Patients were required to have received conventional synthetic DMARDs for at least 3 months and taken a stable dose of up to two conventional synthetic DMARDs for at least 4 weeks prior to randomization — patients were excluded if they had previously been exposed to a JAK inhibitor or abatacept, or if they had a history of inflammatory joint disease other than RA.

Patients were assigned in a 1:1 ratio to receive either 15 mg of extended release oral upadacitinib once daily or intravenous abatacept (at day 1 and weeks 2, 4, 8, 12, 16, and 20 [500 mg in patients with a body weight of <60 kg, 750 mg in those with a weight of 60 to 100 kg, and 1,000 mg in those with a weight of >100 kg]), each in combination with stable synthetic DMARDs, the study authors explained.

The primary endpoint was change from baseline in composite DAS28-CRP scores (range, 0 to 9.4, with higher scores indicating more disease activity) at week 12, assessed for non-inferiority; Secondary endpoints at week 12 were superiority of upadacitinib in change from baseline in DAS28-CRP score and the percentage of patients having clinical remission according to a DAS28-CRP of less than 2.6.

“A total of 303 patients received upadacitinib, and 309 patients received abatacept. From baseline DAS28-CRP values of 5.70 in the upadacitinib group and 5.88 in the abatacept group, the mean change at week 12 was −2.52 and −2.00, respectively (difference, −0.52 points; 95% confidence interval [CI], −0.69 to −0.35; P<0.001 for noninferiority; P<0.001 for superiority),” Rubbert-Roth and colleagues reported. “The percentage of patients having remission was 30.0% with upadacitinib and 13.3% with abatacept (difference, 16.8 percentage points; 95% CI, 10.4 to 23.2; P<0.001 for superiority).”

However, over the 24-week trial period, “the incidences of serious adverse events, adverse events leading to discontinuation of the trial drug, and severe adverse events were numerically higher with upadacitinib than with abatacept,” they added.

Serious adverse events were reported in 10 patients (3.3%) receiving upadacitinib and in 5 patients (1.6%) receiving abatacept. In terms of specific adverse events:

  • Serious infections: 3 patients (1.0%) in the upadacitinib group and 1 patient (0.3%) in the abatacept group.
  • Opportunistic infections: 4 patients in the upadacitinib group (3 patients with oral candidiasis and 1 patient with esophageal candidiasis) and 1 in the abatacept group (oral candidiasis).
  • Herpes zoster: 4 patients in each treatment group.
  • Hepatic disorders: 23 patients (7.6%) in the upadacitinib group and 5 patients (1.6%) in the abatacept group.

In addition, in the upadacitinib group, one patient with a history of cerebrovascular accident experienced a non-fatal stroke, and two patients experienced venous thromboembolic events (deep-vein thrombosis in a patient with hypertension and obesity; pulmonary embolism in a patient with previous pulmonary embolism). And, while three deaths occurred — two in the upadacitinib group and one in the abatacept group — only one death in the upadacitinib group was deemed treatment-emergent.

In their editorial, Kvien and Goll noted the study authors’ choice to use abatacept as the comparator for upadacitinib rather than a more widely used TNF-α–blocking agent as a potential limitation, as well as the choice to use intravenous abatacept rather than the more commonly used subcutaneous formulation, though they added that, “on the basis of previous work, it is likely that the results of the current trial can be extrapolated from intravenous to subcutaneous abatacept.”

The real question, they noted, is whether the benefits of upadacitinib outweigh the risks.

“Our understanding of JAK inhibitors, particularly regarding the risk of thromboembolic events, is evolving,” they wrote. “A 24-week trial may be too short to detect meaningful long-term efficacy and safety. By 24 weeks in the current trial, there were more serious adverse events in the upadacitinib group than in the abatacept group. Rheumatologists will be looking hard at future data to assess whether improved treatment outcomes justify an increased risk of adverse events. This requires data from a longer-term trial and the use of robust outcome measures independent of the CRP level and the erythrocyte sedimentation rate.”

The study authors reached the same conclusion, noting that “additional data from longer and larger trials are needed to better understand long-term outcomes and safety of upadacitinib as compared with other drugs for the treatment of rheumatoid arthritis.”

  1. In patients with rheumatoid arthritis refractory to biologic disease-modifying antirheumatic drugs (DMARDS), the oral selective Janus kinase (JAK) inhibitor upadacitinib was superior to the biologic DMARD abatacept in reducing disease activity and achieving remission at week 12, but it also came with more serious adverse events.

  2. Additional data from larger and longer trials are needed to determine whether the improved treatment outcomes with upadacitinib outweigh the increased risk of adverse events.

John McKenna, Associate Editor, BreakingMED™

The trial was supported by AbbVie.

Rubbert-Roth reported receiving fees for reviewing newsletters, advisory board fees, lecture fees, consulting fees, and fees for completing a review from AbbVie, fees for meeting organization, lecture fees, and consulting fees from AbbVie Deutschland, lecture fees and consulting fees from Amgen, Eli Lilly, and Sanofi Pasteur, lecture fees, fees for attending a meeting, and advisory board fees from Bristol-Myers Squibb, consulting fees, advisory board fees, and lecture fees from F. Hoffmann–La Roche, consulting fees from Chugai Pharmaceutical, Gilead Sciences, and Novartis, and lecture fees from Janssen Global Services.

Kvien reported personal fees from AbbVie, grants from BMS, grants from MSD, personal fees from Hospira/Pfizer, personal fees from Roche, grants from UCB, personal fees from Eli Lilly, personal fees from Hikma, personal fees from Sanofi, personal fees from Celltrion, personal fees from Sandoz, personal fees from Biogen, personal fees from Amgen, personal fees from Egis, personal fees from Ewopharma, personal fees from Mylan, and personal fees from Evapharma outside the submitted work.

Lovik Goll reported personal fees from AbbVie, personal fees from Pfizer, personal fees from Eli Lilly, personal fees from Novartis, personal fees from Roche, personal fees from Boehringer Ingelheim, personal fees from Sandoz, and personal fees from Orion Pharma outside the submitted work.

Cat ID: 158

Topic ID: 90,158,192,158,68,920,925