Further evidence for the benefits of upadacitinib in patients with RA
medwireNews: Results from two phase III trials presented at the EULAR 2018 meeting in Amsterdam, the Netherlands, suggest that treatment with the Janus kinase (JAK) inhibitor upadacitinib alone or in combination with conventional DMARDs may be beneficial for patients with rheumatoid arthritis (RA).
In the first study, SELECT-MONOTHERAPY, Josef Smolen (Medical University of Vienna, Austria) and co-investigators randomly assigned patients with active RA and an inadequate response to methotrexate to receive upadacitinib monotherapy at a dose of 15 mg or 30 mg once daily, or to continue with methotrexate treatment.
In all, 67.7% of the 217 patients who received upadacitinib at the 15 mg dose and 71.2% of 215 participants given the 30 mg dose achieved at least a 20% improvement in ACR criteria (ACR20) at week 14 – the primary endpoint requested by the US FDA – compared with 41.2% of 216 patients who continued with methotrexate, a significant difference.
Moreover, a significantly higher proportion of patients treated with upadacitinib 15 or 30 mg versus methotrexate achieved the EMA-defined co-primary endpoint of low disease activity (LDA), indicated by a Disease Activity Score at 28 joints based on C-reactive protein (DAS28-CRP) of 3.2 points or lower, at 44.7% and 53.0% versus 19.4%, respectively.
Smolen noted that patients receiving the 30 mg dose of upadacitinib experienced numerically greater efficacy outcomes, including improvements in DAS28-CRP score and Clinical Disease Activity index, than those given the 15 mg dose. Commenting from the audience, Roy Fleischmann (University of Texas Southwestern Medical Center and Metroplex Clinical Research Center, Dallas, USA) highlighted that the 30 mg dose appears be more efficacious than the 15 mg dose without compromising safety, but Smolen believes that these results could be “a play of chance.”
In the safety analysis, a comparable proportion of patients in the upadacitinib 15 and 30 mg and methotrexate arms experienced adverse events (AEs; 47.5, 48.8, and 47.2%, respectively). One patient in the upadacitinib 15 mg group and one in the methotrexate group experienced a serious infection, and a higher proportion of patients treated with upadacitinib 15 and 30 mg compared with methotrexate developed herpes zoster infection (1.4 and 2.8 vs 0.5%).
“The safety and tolerability profile was consistent with the phase II data and with other phase III upadacitinib studies in RA, and also with other JAK inhibitors,” said Smolen.
The second trial, SELECT-NEXT, was a comparison of upadacitinib with placebo among patients with active RA and an inadequate response to conventional DMARDs. Participants were randomly assigned to receive once-daily upadacitinib at 15 mg or 30 mg or placebo alongside continued treatment with conventional DMARDs.
Lead investigator Gerd Burmester, from Charité–Universitätsmedizin in Berlin, Germany, told delegates that the 221 patients treated with upadacitinib 15 mg and the 219 patients given the 30 mg dose were significantly more likely to achieve an ACR20 response at week 12 than the 221 patients in the placebo arm, with corresponding rates of 63.8% and 66.2% versus 35.7%.
“Importantly, we already noticed significant improvement after 1 week,” said Burmester, with significantly more upadacitinib- than placebo-treated patients achieving an ACR20 response by this timepoint.
Rates of LDA according to DAS28-CRP score at week 12 were also significantly higher among patients treated with upadacitinib 15 or 30 mg versus placebo (48.4 and 47.9 vs 17.2%), and those in the upadacitinib groups experienced significantly greater improvements in disease activity, morning stiffness, and fatigue.
A total of 56.6% and 53.9% of patients in the upadacitinib 15 mg and 30 mg arms, respectively, experienced AEs, compared with 48.9% of participants in the placebo arm.
There was also “no major difference” between the groups in rates of serious adverse events, serious infection, and herpes zoster infection, said Burmester, and he noted that no deaths occurred during the trial.
In accordance with the SELECT-MONOTHERAPY results, Burmester concluded that the safety profile of upadacitinib in combination with conventional DMARDs “was consistent with observations in the phase II studies.”
The SELECT-NEXT trial results are now published in The Lancet, along with the findings from SELECT-BEYOND, which were presented previously at the 2017 ACR/ARHP Annual Meeting in San Diego, California, USA.
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