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29-03-2019 | Rheumatoid arthritis | Feature | Article

Updated April 2019

JAK inhibitors in RA: A round-up of the phase III trials

A number of Janus kinase (JAK) inhibitors have been evaluated in rheumatoid arthritis (RA) patients, with tofacitinib and baricitinib now approved in the USA and Europe, and other agents including filgotinib and upadacitinib showing promising results in clinical trials. Here, we round up the results from phase III trials of JAK inhibitors in RA patients that have been reported to date and summarize the ongoing studies.

Tofacitinib (JAK1/3 inhibitor; approved)

Findings from the seven ORAL (Oral Rheumatoid Arthritis triaL) studies, which investigated the selective JAK1/JAK3 inhibitor tofacitinib in various populations of RA patients, are outlined in this article.

Baricitinib (JAK1/2 inhibitor; approved)

The five phase III trials of the selective JAK 1 and 2 inhibitor baricitinib in RA – RA-BEACON, RA-BUILD, RA-BEGIN, RA-BEAM, and RA-BEYOND – along with earlier phase II studies, are summarized in this article.

Upadacitinib (selective JAK1 inhibitor; under investigation)


SELECT BEYOND

Patient population

Treatment groups

Status

Active RA and an inadequate response to biologic DMARDs

Upadacitinib 15 mg, upadacitinib 30 mg, or placebo, given once daily alongside conventional DMARDs

Published

https://clinicaltrials.gov/ct2/show/NCT02706847

The SELECT BEYOND trial, published in The Lancet in June 2018, showed significantly higher ACR20 response rates at week 12 among participants treated with upadacitinib 15 or 30 mg compared with placebo (65% and 56% vs 28%, respectively).


This is a “really tremendous response rate,” and “we’ve never seen a trial that’s had [ACR20 response rates] in the 60s for this population.”

Click here for our report of the SELECT BEYOND trial from the 2017 ACR/ARHP Annual Meeting, including comments from lead author Mark Genovese


Rates of low disease activity, defined as DAS28-CRP of 3.2 points or lower, were also significantly greater in the upadacitinib 15 mg and 30 mg versus placebo groups (43% and 42% vs 14%, respectively).

SELECT NEXT

Patient population

Treatment groups

Status

Patients with moderate-to-severe active RA and an inadequate response to conventional DMARDs

Upadacitinib 15 mg, upadacitinib 30 mg, or placebo, given once daily alongside continued treatment with conventional DMARDs

Published

https://clinicaltrials.gov/ct2/show/NCT02675426

The SELECT NEXT trial was also published in The Lancet in June 2018. The trial demonstrated that participants who were treated with upadacitinib 15 mg or 30 mg alongside conventional DMARDs had significantly greater ACR20 response rates at week 12 than those given placebo plus DMARDs, at 63.8% and 66.2% versus 35.7%, respectively. The proportion of patients with low disease activity was also significantly higher in the upadacitinib 15 mg and 30 mg versus placebo groups (48.4 and 47.9 vs 17.2%).

The investigators noted that “upadacitinib showed a favourable benefit-to risk profile” overall, but patients in the upadacitinib 15 mg and 30 mg groups were more likely to experience infections than those given placebo (29 and 32 vs 21%, respectively).

Related news story: Further evidence for the benefits of upadacitinib in patients with RA

Video interview: Expert commentary with Roy Fleischmann

SELECT MONOTHERAPY

Patient population

Treatment groups

Status

Patients with moderate-to-severe active RA and an inadequate response to methotrexate

Upadacitinib monotherapy 15 or 30 mg once daily, or placebo

Primary results announced; not published

https://clinicaltrials.gov/ct2/show/NCT02706951

Editor's recommendation
medwireNews@EULAR2018

Expert commentary: Trial results on upadacitinib for the treatment of RA

Roy Fleischmann comments on the results of the SELECT-MONOTHERAPY and SELECT-NEXT trials, which provide further evidence for the benefits of upadacitinib in patients with RA (6:18).

Although not yet published, the results of the SELECT MONOTHERAPY trial were presented at the EULAR 2018 meeting in Amsterdam, the Netherlands, and demonstrated significantly higher rates of ACR20 response and low disease activity among patients treated with the 15 and 30 mg doses of upadacitinib versus placebo.

Related news story: Further evidence for the benefits of upadacitinib in patients with RA

SELECT CHOICE

Patient population

Treatment groups

Status

RA patients on a stable background of conventional DMARDs with an inadequate response or intolerance to biologic DMARDs

Upadacitinib or abatacept given alongside a stable dose of conventional DMARDs (specific dosing information not currently available)

Ongoing

https://clinicaltrials.gov/ct2/show/NCT03086343

SELECT CHOICE is a noninferiority trial comparing upadacitinib with abatacept in RA patients with moderate-to-severe disease activity and an inadequate response or intolerance to prior treatment with biologics. Data collection for the primary outcome of change in DAS28-CRP from baseline to week 12 is expected to be completed in February 2020, and the estimated study completion date is June 2022.

SELECT COMPARE

Patient population

Treatment groups

Status

Patients with moderate-to-severe active RA with an inadequate response to methotrexate

Upadacitinib 15 mg/day, placebo, or adalimumab 40 mg every 2 weeks, all given on a stable background of methotrexate

Primary results announced; not published

https://clinicaltrials.gov/ct2/show/NCT02629159

Findings from SELECT COMPARE have not yet been published, but a company press release from April 2018 announced that patients treated with upadacitinib had significantly higher ACR20 response rates – the primary endpoint – than those given adalimumab or placebo.

SELECT EARLY

Patient population

Treatment groups

Status

Methotrexate-naïve patients with moderate-to-severe active RA

Upadacitinib 15 mg/day, upadacitinib 30 mg/day, or methotrexate, all given as monotherapy

Primary results announced; not published

https://clinicaltrials.gov/ct2/show/NCT02706873

The SELECT EARLY results have also not yet been published, but according to a company press release issued in June 2018, the coprimary endpoints of ACR50 response rates and the proportion of patients achieving remission (DAS28-CRP<2.6) were significantly greater among those treated with upadacitinib versus methotrexate.

NCT02955212

Patient population

Treatment groups

Status

Patients with moderate-to-severe RA and an inadequate response to conventional DMARDs

Upadacitinib or placebo (specific dosing information not currently available)

Recruiting

https://clinicaltrials.gov/ct2/show/NCT02955212

This trial aims to compare the safety and efficacy profiles of upadacitinib versus placebo in patients from China and other selected countries. The primary endpoint is ACR20 response at week 12, after which time all participants will be switched to upadacitinib for a 1-year open-label extension study. It is estimated that all data for the primary outcome will be collected by July 2019.

Filgotinib (selective JAK1 inhibitor; under investigation)


FINCH 1

Patient population

Treatment groups

Status

Active RA and an inadequate response to methotrexate

Filgotinib, placebo, or the active comparator adalimumab, all in combination with methotrexate

Primary results announced; not published

https://clinicaltrials.gov/ct2/show/NCT02889796

Although the findings of the FINCH 1 trial have not yet been published, initial results were announced in a press release in March 2019. The investigators demonstrated that a significantly higher proportion of patients treated with filgotinib versus placebo achieved an ACR20 response at week 12.

FINCH 2

Patient population

Treatment groups

Status

Active RA and an inadequate response to biologic DMARDs

Filgotinib or placebo in combination with conventional DMARDs

Primary results announced; not published

https://clinicaltrials.gov/ct2/show/NCT02873936

Although the findings of the FINCH 2 trial have not yet been published, data outlined in a press release and presented at the 2018 ACR/ARHP Annual Meeting indicated that patients treated with filgotinib had significantly better ACR20, ACR50, and ACR70 responses at weeks 12 and 24, as well as higher rates of low disease activity and remission, than those given placebo.

FINCH 3

Patient population

Treatment groups

Status

Biologic-naïve patients with moderate-to-severe active RA and limited or no prior exposure to methotrexate

Filgotinib, methotrexate, or a combination of both agents

Primary results announced; not published

https://clinicaltrials.gov/ct2/show/NCT02886728

The FINCH 3 results have also not been published, but were announced in a press release in March 2019. ACR20 response rates at week 24 were significantly higher among patients treated with filgotinib in combination with methotrexate compared with methotrexate alone.

FINCH 4

Patient population

Treatment groups

Status

RA patients who have completed FINCH 1, 2, or 3

Filgotinib or placebo

Recruiting

https://clinicaltrials.gov/ct2/show/NCT03025308

The FINCH 4 study will investigate the long-term safety and tolerability profiles of filgotinib in patients who participated in one of the previous FINCH trials. It is expected that the study will be complete in May 2022.

Peficitinib (under investigation)


RAJ3

Patient population

Treatment groups

Status

RA patients from Japan, Korea, or Taiwan with an inadequate response to DMARDs

Peficitinib 100 mg/day, peficitinib 150 mg/day, placebo, or etanercept

Completed; not published

https://clinicaltrials.gov/ct2/show/study/NCT02308163

Results from the RAJ3 trial, presented at the 2018 ACR/ARHP Annual Meeting, demonstrated that patients treated with peficitinib were significantly more likely to achieve an ACR20 response at week 12 than those given placebo.

Related news story: Peficitinib may be a promising treatment option for RA

RAJ4

Patient population

Treatment groups

Status

Japanese RA patients with an inadequate response to methotrexate

Peficitinib 100 mg/day, peficitinib 150 mg/day, or placebo, all given in combination with methotrexate

Completed; not published

https://clinicaltrials.gov/ct2/show/NCT02305849

Findings from this trial were also reported at the 2018 ACR/ARHP Annual Meeting. The trial investigators demonstrated significantly higher ACR20, 50, and 70 response rates among patients treated with peficitinib versus placebo.

Related news story: Peficitinib may be a promising treatment option for RA

NCT03660059

Patient population

Treatment groups

Status

RA patients from Japan, Korea, or Taiwan with an inadequate response or intolerance to methotrexate

Peficitinib or placebo given alongside DMARDs (specific dosing information not currently available)

Recruiting

https://clinicaltrials.gov/ct2/show/NCT03660059

The study will investigate the efficacy of peficitinib in combination with methotrexate or other DMARDs in patients from Japan, Korea, or Taiwan with a prior inadequate response or intolerance to methotrexate. The trial is currently recruiting, and data collection for the primary outcome (ACR20 response rate at week 24) is expected to be completed in June 2020.

NCT01638013

Patient population

Treatment groups

Status

RA patients who completed the phase III RAJ3 or RAJ4 trials, or the phase IIb RAJ1 study

Peficitinib

Ongoing

https://clinicaltrials.gov/ct2/show/NCT01638013

This open-label extension study aims to evaluate the long-term safety and efficacy profiles of peficitinib. The estimated completion date is March 2020.

By Claire Barnard

medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group

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