Conference Coverage

Jakinib explosion for RA: Where do they fit in clinical practice?



– A measure of clarity regarding how the emerging class of oral Janus kinase inhibitors might fit into clinical practice for treatment of rheumatoid arthritis was supplied by a fusillade of five consecutive strongly positive phase 3 trials presented during a single session at the annual meeting of the American College of Rheumatology.

Dr. Roy M. Fleischmann

Dr. Roy M. Fleischmann

The session featured three randomized, double-blind, phase 3 trials of the Janus kinase inhibitor (JAKi) upadacitinib in more than 3,200 participants in three different clinical scenarios, known as the SELECT-COMPARE, SELECT-EARLY, and SELECT-MONOTHERAPY trials, along with two Japanese phase 3 trials of peficitinib, a JAK1 and -3 inhibitor, in a total of more than 1,000 rheumatoid arthritis patients.


SELECT-COMPARE: Roy M. Fleischmann, MD, presented the findings of this trial in which 1,629 patients with active RA inadequately responsive to methotrexate were randomized 2:2:1 to 26 weeks of once-daily oral upadacitinib at 15 mg, placebo, or 40 mg of adalimumab (Humira) by subcutaneous injection every 2 weeks, all on top of background stable doses of methotrexate.

Upadacitinib, a JAK1 selective agent, was the clear winner, trouncing placebo, unsurprisingly, but more importantly also proving statistically superior to adalimumab – the current go-to drug in patients with an insufficient response to methotrexate – in terms of across-the-board improvement in RA signs and symptoms, quality-of-life measures, and physical function. This result, coupled with the similarly positive findings of a trial of oral baricitinib (Olumiant) versus adalimumab in inadequate responders to methotrexate alone, and a third positive trial of oral tofacitinib (Xeljanz), have altered Dr. Fleischmann’s treatment philosophy.

“I think that these studies have changed the treatment paradigm. And I think if access – that is, costs – were the same, given a choice, if it were me, I would actually use a JAK inhibitor before I would use adalimumab, based on the results of these multiple studies in different populations,” said Dr. Fleischmann, a rheumatologist at the University of Texas Southwestern Medical Center, Dallas.

The two coprimary endpoints in SELECT-COMPARE were the week 12 American College of Rheumatology–defined 20% level of response (ACR 20) and a 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP). The ACR 20 response rate was 70.5% with upadacitinib 15 mg, significantly better than the 63% rate with adalimumab and the 36.4% rate with placebo. Similarly, the ACR 50 rate at 12 weeks was 45.2% with upadacitinib versus 29.1% with adalimumab, and ACR 70 rates were 24.9% and 13.5%, respectively.

“These are not small differences,” the rheumatologist observed. “That ACR 70 rate is almost doubled with upadacitinib.”

The rate for DAS28-CRP less than 2.6 at week 12 was 28.7% with upadacitinib, compared with 18% with adalimumab.

Improvements in pain scores and the Health Assessment Questionnaire Disability Index were also significantly greater with the JAKi, both at weeks 12 and 26.

As in the other two SELECT phase 3 trials presented at the meeting, the response to upadacitinib was quick: The JAKi was superior to placebo on the efficacy endpoints by week 2, and superior to adalimumab by week 4.

The week-12 Boolean remission rate, a stringent measure, was 9.8% in the upadacitinib group, more than twice the 4% rate with adalimumab. At week 26, the rates were 18.1% and 9.8%, respectively, a finding Dr. Fleischmann deemed “very impressive.”

Radiographic disease progression as measured by change in modified total Sharp score (mTSS) at week 26 was 0.92 with placebo, 0.24 with upadacitinib, and slightly better at 0.1 with adalimumab. Adalimumab was also slightly better than baricitinib by this metric in a separate randomized trial. But that’s not a deal breaker for Dr. Fleischmann.

“It’s a 0.1–Sharp unit difference over 6 months. So by the time a patient would be able to tell the difference clinically, if my calculation is correct they’ll be 712 years old,” he quipped.

Serious infection rates through 26 weeks were similar in the upadacitinib and adalimumab study arms, with both being higher than placebo. Venous thromboembolism occurred in one patient on placebo, two on upadacitinib, and three on adalimumab.

Dr. Ronald van Vollenhoven

SELECT-EARLY: This trial involved 947 methotrexate-naive patients with moderately to severely active RA deemed at baseline to be at high risk for disease progression. They were randomized to upadacitinib at 15 or 30 mg once daily or to methotrexate monotherapy. The markers utilized for high-risk disease were positive serology, an elevated CRP, and/or erosions at baseline, explained Ronald van Vollenhoven, MD, PhD, professor of rheumatology at the University of Amsterdam.

The coprimary endpoints were the week 12 ACR 50 and DAS28-CRP-less-than-2.6 response rates. ACR 50 was achieved in 28.3% of patients on methotrexate, 52.1% on the lower dose of upadacitinib, and 56.4% on upadacitinib 30 mg. The corresponding week 24 rates were 33.4%, 60.3%, and 65.6%.

The week 12 DAS28-CRP-less-than-2.6 rates were 13.7%, 35.6%, and 40.8%. By week 24, the rates had improved to 18.5%, 48.3%, and 50%.

Other functional, clinical, and quality-of-life endpoints followed suit. There was no radiographic progression over the course of 24 weeks in 77.7% of patients on methotrexate, 87.5% on upadacitinib 15 mg, and 89.3% on the JAKi at 30 mg.

The safety profile of upadacitinib was generally similar to that of methotrexate. Decreases in hemoglobin and neutrophils were more common in the high-dose upadacitinib group, while increased transaminase levels and reduced lymphocytes occurred more often with methotrexate.

Asked if the SELECT-EARLY results will lead to a change in the major guidelines for treatment of early RA, Dr. van Vollenhoven replied: “The advent of JAKis is changing the treatment of RA. Right now the positioning of JAKis is a big point of discussion: Should they be second or third or even fourth line? But it’s clear that methotrexate stands undisputed as the first-line treatment for RA in clinical practice. That has to do in part with lots and lots of experience, the fact that some patients do well with methotrexate, the convenience, but also the pricing.”

The goal in SELECT-EARLY was to test an individualized approach in which JAKis, which are clearly more effective than methotrexate, might be reserved as first-line therapy for the subgroup of patients with compelling markers for worse prognosis, and who are therefore less likely to turn out to be methotrexate responders.

“The markers we used aren’t good enough yet to engage in individualized treatment with a very specific drug, but we’re all trying very hard to find out who needs which treatment at which point in time,” the rheumatologist said.

SELECT-MONOTHERAPY: This trial randomized 648 patients with active RA and insufficient response to methotrexate to double-blind monotherapy with once-daily upadacitinib at 15 or 30 mg or to continued methotrexate.

Dr. Josef S. Smolen

Once again, upadacitinib achieved all of its primary and secondary endpoints. The week 14 ACR 20 rates for methotrexate and low- and high-dose upadacitinib were 41.2%, 67.7%, and 71.2%, respectively, with DAS28-CRP-less-than-or-equal-to-3.2 rates of 19.4%, 44.7%, and 53%. Remission as defined by a Clinical Disease Activity Index (CDAI) score of 2.8 or less was achieved in 1% of patients on methotrexate, 15% on upadacitinib 15 mg, and nearly 20% with upadacitinib 30 mg, reported Josef S. Smolen, MD, professor of medicine and chairman of rheumatology at the Medical University of Vienna.

Next Article: