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Highlights from

American College of Rheumatology

annual meeting 2018

Chicago, Illinois 19-24 October 2018

Upadacitinib shows clinically significant difference in response rate versus adalimumab in active RA

Take-home messages
  • Upadacitinib showed significantly greater improvement in signs and symptoms of RA than placebo and adalimumab, in patients with inadequate response to methotrexate
  • Upadacitinib 15 mg once daily showed better clinical outcomes, physical function and radiographic inhibition versus placebo
  • Rates of serious adverse events were similar between arms
“I think this is a very important clinically significant result. This study suggests that a patient who is a methotrexate incomplete responder, can start either upadacitinib or adalimumab but there will be more patients who respond to upadacitinib.”

Professor Roy Fleischmann Rheumatologist and Study Lead from the University of Texas Southwestern, US

Upadacitinib, an investigational oral Janus kinase 1 (JAK1)-selective inhibitor, showed significantly greater improvement in signs and symptoms of rheumatoid arthritis (RA) than placebo and adalimumab in patients with inadequate response to methotrexate.

“I think this is a very important, clinically significant result,” asserted Professor Roy Fleischmann, Rheumatologist and Study Lead from the University of Texas Southwestern, US, who presented the results at the 2018 American College of Rheumatology/ Association of Rheumatology Health Professionals (ACR/ARHP) Annual Meeting.

“This study suggests that a patient who is a methotrexate incomplete responder can start either upadacitinib or adalimumab but there will be more patients who respond to upadacitinib.”

“Upadacitinib at 15 mg once daily was associated with significantly greater improvement in clinical outcomes, physical function and radiographic inhibition versus placebo,” reported Professor Fleischmann. “Compared to adalimumab, upadacitinib was superior for ACR responses, multiple definitions of low disease activity [LDA], remission and multiple patient-reported outcomes. Safety [profile] was generally similar to adalimumab,” he continued.

The SELECT-COMPARE trial, which is one trial in a global SELECT phase III clinical programme, compared upadacitinib with placebo and adalimumab for efficacy and safety in patients with active RA and inadequate response to methotrexate, but who were on stable background methotrexate.

Inhibition of radiographic progression was assessed for upadacitinib versus placebo, and the trial was designed and powered to assess non-inferiority and superiority of upadacitinib compared with adalimumab.

The double-blind study was carried out over 48 weeks, and 1,629 patients were randomised in a 2:2:1 ratio to placebo, upadacitinib (15 mg once daily), and adalimumab (40 mg every other week), (n=651, 651 and 327, respectively) and treated for 12 weeks. Rescue was allowed from adalimumab to upadacitinib and vice versa, and from placebo to upadacitinib until week 26. This will allow a later analysis of whether non-responders on one drug respond to the alternative.

The primary endpoint was the proportion of patients showing an ACR20 response at week 12, and those achieving clinical remission based on disease activity score-28 (DAS28) and C-reactive protein (CRP; <2.6).

Secondary endpoints included the proportion of participants with no radiographic progression at week 26 (radiographic progression defined as a change from baseline modified total Sharp score that is greater than 0); change in health assessment questionnaire (HAQ-DI); and proportion of subjects achieving LDA based on clinical disease activity index (CDAI) among multiple other endpoints.

At week 14, completion rates were 95.2%, 95.2% and 91.7% for placebo, upadacitinib and adalimumab, respectively. By week 26, the percentage of completers changed to 91.4%, 92.2% and 88.1%, respectively. Baseline characteristics included around 79% women, a mean age of approximately 54 years, and a mean RA duration of 8 years. Participants were taking approximately 17 mg methotrexate/ week, around 10% had used disease-modifying anti-rheumatic drugs (DMARDs) previously, and 60% had used oral glucocorticoids. Approximately 88% were rheumatoid-factor positive or anti-CCP (anti-cyclic citrullinated peptide) positive.

“At week 12, ACR20 was met by 71% on upadacitinib versus 36% on placebo [p<0.001 vs placebo]. This is statistically significant, and for DAS28-CRP ≤2.6, the results were 29% on upadacitinib versus 6% on placebo, again a statistically significant difference [p<0.001 vs placebo],” reported Professor Fleischmann. “On adalimumab, 63% of patients achieved ACR20 and 18% DAS28-CRP <2.6, meaning that upadacitinib was statistically superior to adalimumab.”

ACR50 was achieved by 15%, 45%, and 29% for placebo, upadacitinib and adalimumab respectively; ACR70 by 5%, 25%, and 13%.

“If we look at the DAS28-CRP ≤3.2, again, upadacitinib is statistically superior to adalimumab (45% vs 29%, p<0.001), and again for CDAI [≤10], upadacitinib was statistically superior (40% vs 30%, p<0.01),” added Professor Fleischmann.

“Over time, the response (DAS28-CRP ≤3.2) was very quick, within 2 weeks, and statistically different to adalimumab at week 4. You’d expect adalimumab to catch up but it never did,” he added. A similar pattern was seen in favour of upadacitinib for CDAI ≤2.8, simple disease activity index (SDAI) ≤3.3, Boolean remission, HAQ-DI and pain, he continued. “With SF-36, upadacitinib was superior to adalimumab. With radiographic inhibition, upadacitinib is superior to placebo, and there is a clinically non-significant difference between upadacitinib and adalimumab, with about 85% experiencing no progression.”

“In terms of efficacy, upadacitinib at 15 mg, the lower dose in addition to methotrexate is superior to adalimumab,” he concluded.

In terms of adverse events, the rates of serious adverse events were similar, if slightly less with upadacitinib (3.7%) compared with adalimumab (4.3%). Discontinuations of study drug were seen in 3.5% versus 6.1% in upadacitinib and adalimumab respectively. “So, in terms of safety [profile], upadacitinib is at least as good as adalimumab.” Infections were all low in number, he said, with rates of serious infection at 0.8%, 1.8% and 1.5% for placebo, upadacitinib and adalimumab respectively. Herpes zoster was as expected, he pointed out, at 0.8% and 0.3% for upadacitinib and adalimumab. Incidences of venous thromboembolism (VTE) were 1, 2, and 3 with placebo, upadacitinib and adalimumab respectively, reported Professor Fleischmann. “The VTE has occurred in all three groups.”

Based on Fleischmann R, Pangan A L et al. A phase 3, randomized, double-blind study comparing upadacitinib to placebo and to adalimumab, in patients with active rheumatoid arthritis with inadequate response to methotrexate (abstract 890). Presented on Sunday 21 October 2018.

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