Role of upadacitinib in addressing unmet needs in RA

Despite considerable advances in rheumatoid arthritis (RA) therapy over the past decades, remission rates remain suboptimal. In an interview with MIMS Doctor, Dr Tommy Tsang Cheung, Specialist in Rheumatology at the Hong Kong Sanatorium & Hospital, discussed common challenges in achieving optimal disease control and presented clinical data demonstrating superiority of the Janus kinase (JAK) inhibitor, upadacitinib, over the commonly used second-line biologic disease-modifying antirheumatic drug (bDMARD), adalimumab, in reaching RA treatment goals.

Current challenges in reaching treatment targets

“The European League Against Rheumatism [EULAR] guidelines recommend sustained clinical remission as the treatment goal in RA, and low disease activity if remission is not achievable,” said Cheung. “This is accomplished through a ‘treat-to-target’ strategy where treatment decisions are guided by ongoing disease activity. Remission can be measured using the Disease Activity Score [DAS] criteria, or the more stringent Simplified or Clinical Disease Activity Index [SDAI, CDAI], or the strictest Boolean-based criteria.” [Ann Rheum Dis 2020;79:685-699; Ann Rheum Dis 2016;75:3-15]

RA patients who achieve remission have less disability and better quality of life than those with persisting active disease. [BMC Rheumatol 2019;3:6] Furthermore, sustained remission is known to protect against radiographic joint damage. [J Rheumatol 2007;34:316-321]

A systematic review and meta-analysis of real-world observational studies involving >80,000 RA patients showed a trend of increasing remission rate with follow-up duration, but sustained remission was relatively rare. [Clin Rheumatol 2019;38:727-738]

“In general, only 40 percent of patients with an inadequate response to methotrexate [MTX] achieve DAS remission with bDMARDs monotherapy or bDMARDs combinations with conventional synthetic DMARDs,” highlighted Cheung. [Rheumatology 2019;58:481-491]

“One of the greatest unmet needs in achieving and maintaining remission with biologic therapy is progressive loss of efficacy, resulting from proliferation of antidrug antibodies,” noted Cheung. “Another concern is safety – the increased risk of infections, including upper respiratory tract and urinary tract infections, gastroenteritis, and occasionally opportunistic infections due to long-term immunosuppression. As a result, suboptimal tolerability may impact adherence.” [Rheumatology 2016;55:210-220; Rheumatology 2012;51:v38-v47; Ann Rheum Dis 2017;76:1101-1136]

On the other hand, JAK inhibitors are associated with a higher risk of herpes zoster (HZ) reactivation. [Arthritis Rheumatol 2014;66:2675-2684; Ann Rheum Dis 2020;79:1290-1297; Ann Rheum Dis 2020;0:1-17] “In my clinical experience, HZ reactivation from JAK inhibitor use tends to be more severe and less responsive to standard oral antiviral therapy among Asian patients, at times requiring hospitalization for more intensive antiviral treatment. Prophylactic HZ vaccination can be considered in patients at risk, but, with some exceptions, the use of live attenuated vaccines should be avoided in patients receiving bDMARDs or JAK inhibitors. The preferable time window for vaccination with live attenuated vaccines is 4 weeks prior to treatment initiation,” pointed out Cheung. [Ann Rheum Dis 2020;79:39-52]

“The risk of tuberculosis reactivation is of some concern in Asian countries, but is greatly reduced with vigilant screening and treatment of latent infection before initiating bDMARDs or JAK inhibitors,” he added.

JAK inhibitors improve treatment adherence

JAK inhibitors are the first oral, small-molecule targeted synthetic DMARDs developed for RA. Being small nonprotein substances, they lack the potential to generate an immune antidrug response and are therefore able to maintain a stable therapeutic effect. [Biomed Res Int 2018;2018:7492904]

“In contrast to frequent bDMARD injections, which can be associated with injection-site reactions, the convenience of once-daily oral administration of JAK inhibitors improves treatment adherence,” commented Cheung.“In addition, the gradual loss of efficacy and safety issues associated with bDMARDs are reflected in the progressive drop in treatment adherence.”

A meta-analysis of data from real-world registries and healthcare databases (n=>200,000) estimated that rates of discontinuation of tumour necrosis factor (TNF) inhibitors in RA were 21 percent at 6 months, 27 percent at 1 year, 37 percent at 2 years, 44 percent at 3 years, and 52 percent at 4 years. [Rheumatology 2016;55:523-534]

“JAK inhibitor therapy has demonstrated better medication persistence than TNF inhibitors in patients with RA in Hong Kong. The 2-year persistence rate with TNF inhibitor therapy is 41 percent, while it is 50 percent for JAK inhibitor therapy,” reported Cheung, citing unpublished analysis of data from Hong Kong Hospital Authority’s Clinical Data Analysis and Reporting System (CDARS).

Upadacitinib: Better disease control vs adalimumab

Upadacitinib is the latest JAK inhibitor approved in Hong Kong for treatment of moderate to severe active RA in adult patients with an inadequate response or intolerance to ≥1 DMARDs, as monotherapy or in combination with MTX. [Rinvoq Hong Kong Prescribing Information, March 2020]

In the SELECT-COMPARE trial, 1,629 RA patients with inadequate response to MTX were randomized to receive upadacitinib, placebo or adalimumab while continuing MTX therapy. [Arthritis Rheumatol 2019;71:1788-1800]

“A significantly higher proportion of patients achieved remission [ie, DAS-28 with C-reactive protein (DAS28-CRP) <2.6] with upadacitinib vs placebo and vs adalimumab [p≤0.001 for both],” noted Cheung. (Figure)

 

Upadacitinib also demonstrated superiority over adalimumab in terms of American College of Rheumatology (ACR) 50 response at week 12 (45 percent vs 29 percent; p<0.001), which was maintained at week 48 (49 percent vs 40 percent; p<0.01). [Arthritis Rheumatol 2019;71:1788-1800; Ann Rheum Dis 2019;78:1454-1462]

“In addition to improved disease control, upadacitinib was superior to adalimumab for the reduction in pain [-36.7 vs -32.1 on the 0–100 mm visual analogue scale; p<0.05] and physical functioning [mean improvements from baseline in Health Assessment Questionnaire-Disability Index, -0.73 vs -0.60; p<0.01] at week 48 vs adalimumab,” commented Cheung. [Ann Rheum Dis 2019;78:1454-1462]

The significant inhibition of radiographical progression (defined as mean change from baseline in mTSS) at week 48 was comparable between the upadacitinib and adalimumab groups. The safety profiles were also similar between the two groups, except for higher rates of HZ infection, lymphopenia, and elevations in creatine phosphokinase (CPK), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in patients receiving upadacitinib, while rates of serious adverse events (AEs) and AEs leading to discontinuation were the highest in the adalimumab group. [Ann Rheum Dis 2019;78:1454-1462]

Long-term results from the SELECT-COMPARE trial showed that upadacitinib maintained significantly higher levels of clinical response across multiple measures vs adalimumab through week 72. [Fleischmann R, et al, EULAR 2020, abstract THU0201]

Summary

Unmet needs exist in reaching treatment goals in RA with current therapies. JAK inhibitors, such as upadacitinib, can improve the standard of care in RA by enabling higher remission rates, better pain control and improved treatment adherence compared with bDMARDs.