Disease Burden and Current Treatment Landscape
In June 2020, upadacitinib hemihydrate (Rinvoq; AbbVie), an oral reversible JAK1 selective inhibitor received local regulatory approval for use in ‘moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs).’
RA is a chronic systemic inflammatory autoimmune disease that causes significant pain, disability, and progressive joint destruction. Overtime, if inadequately treated, irreversible joint damage and loss of function can result in disability, impaired quality of life and premature death. In Singapore, RA affects up to 1% of the population, commonly between 30-50 years of age, with women 3 times more likely to develop RA than men. The 2010 Singapore Disease of Burden Study ranked RA as the 7th leading cause of years lived with disability (YLD), accounting for 42% of the overall burden from musculoskeletal disease.
RA disease management is aimed at maintaining physical function and good quality of life, grounded on the key tenet of treating to a target of clinical remission or low disease activity. First-line pharmacological management involves conventional-synthetic disease-modifying antirheumatic drugs (csDMARDs) monotherapy, with oral methotrexate (MTX) as the preferred agent. However, approximately 30% of patients with RA respond inadequately to csDMARDs and guidelines acknowledge that further pharmacotherapy to achieve treatment goals may ultimately involve multiple csDMARDs, biological DMARDs and targeted synthetic DMARDs with different mechanisms of action.
Drug Profile: Upadacitinib (Rinvoq) and the SELECT Phase III Clinical Program
Upadacitinib (Rinvoq) is a once-daily, oral Janus kinase (JAK) inhibitor with increased selectivity for JAK1 over JAK2, JAK3, and tyrosine kinase 2 (TK2). It has demonstrated a high and rapid efficacy in the treatment of RA refractory to csDMARD and bDMARD therapies. Upadacitinib’s SELECT Phase III clinical programme comprised five pivotal trials that recruited over 4,400 patients with RA, including csDMARD-naïve patients and in inadequate responders to csDMARDs or bDMARDs. The drug is available in Singapore as an orally administered extended-release 15mg tablet and is dosed at 15mg once daily.
Its JAK-1 selectivity is postulated to provide a better safety profile compared to earlier JAK inhibitors tofacitinib and baricitinib, that target more than one JAK molecule. However, their comparative efficacy and safety for RA have not been evaluated in head-to-head clinical trials.
From a safety perspective, JAK inhibitors have been associated with several safety risks including herpes zoster, serious and opportunistic infections and thromboembolic events. An integrated safety analysis of the five key trials within the SELECT Phase III program support an acceptable safety profile of upadacitinib in the treatment of patients with RA, with no new safety risks compared with other JAK inhibitors. In general, the most common TEAEs were URTI, nasopharyngitis, UTI and for upadacitinib 30mg only, increased blood creatine phosphokinase (CPK). There were 22 treatment-emergent deaths reported with upadacitinib which translated to a consistent standardized mortality rate (SMR) of 0.58 when compared to the general population (95% CI; 0.37 to 0.85). Further, despite signals for an additional clinically meaningful benefit with the upadacitinib 30mg dose, the higher risk of AEs has led AbbVie to only seek market authorisation for the upadacitinib (Rinvoq) 15mg dose in RA treatment.
A brief overview of the five key trials within SELECT are described below.
| Trial | Intervention/ Comparator | Primary Efficacy Outcome | Safety |
| SELECT-COMPARE
RA with inadequate response to MTX |
Intervention: upadacitinib 15mg (n=652) + MTX
Comparator: adalimumab (n=327) + MTX; or placebo (n=652) + MTX At Week 26: placebo patients were switched to upadacitinib |
|
AEs were comparable between the upadacitinib and adalimumab groups. The proportions of patients with serious AEs and AEs leading to discontinuation were highest in the adalimumab group; the proportions of patients with herpes zoster and those with CPK elevations were highest in the upadacitinib group. |
| SELECT-NEXT
RA with inadequate response to at least 1 csDMARD |
Intervention: upadacitib 15mg (n=221) or 30mg (n=219) + csDMARD
Comparator: placebo (n=221) + csDMARD After 12 weeks: placebo patients were switched to upadacitinib 15mg or 30mg once daily |
|
AEs were reported in 57% receiving upadacitinib 15mg and 54% of patients receiving upadacitinib 40mg, and 49% of patients receiving placebo. The most frequent reported AE in the upadacitinib groups were nausea, nasopharyngitis, URTI and infections. |
| SELECT-MONOTHERAPY
RA with inadequate response to MTX |
Intervention: upadacitinib monotherapy 15mg (n=217) or 30mg (n=215)
Comparator: MTX (n=216) Starting week 14: MTX patients were switched to 15mg/ 30mg upadacitinib |
|
AEs were reported in 47% of MTX patients, 47% of upadacitinib 15mg patients and 49% of upadacitinib 30mg tablets. Of note, herpes zoster occurred at a higher rate in the upadacitinib arms. |
| SELECT-BEYOND
RA with inadequate response to bDMARDs |
Intervention: upadacitinib 15mg (n=165) or 30mg (n=165) + csDMARD
Comparator: placebo + csDMARD (n=85) Starting Week 12: followed up by upadacitinib 15mg and 30mg |
|
Up to Week 12, overall AEs were similar between placebo (56%) and upadacitinib 15mg (55%), but higher in upadacitinib 30mg (67%). The most common AE reported in the treatment group (>5%) was URTI, nasopharyngitis, UTI and RA worsening. |
| SELECT-EARLY | Intervention: upadacitinib (n=303) + csDMARD
Comparator: IV abatacept (n=309) + csDMARD |
Change from baseline in DAS28-CRP at week 12:
-2.52 (upadacitinib) and -2.00 (abatacept); difference, -0.52 points 95% CI, -0.69 to -0.35; p<0.001 for superiority |
Serious AEs and serious infections were reported in 3.3% and 1.0% (upadacitinib); 1.6% and 0.3% (abatacept) respectively. |
Abbreviations: ACR20: 20% improvement in American College of Rheumatology criteria, DAS28[CRP]: 28-joint disease activity score using C-reactive protein, MTX: methotrexate
The Clinical Landscape
Evidence to date has provided compelling evidence for the promising JAK1 selective inhibitor. A long term extension study of the SELECT-COMPARE population observed that upadacitinib (Rinvoq) continued to maintain higher levels of clinical response, compared to adalimumab, in patients with RA through Week 72 with no new safety signals. Separately, to address the limitations surrounding direct comparative data for upadacitinib against other possible RA therapeutics, a network meta-analysis (NMA) by Cacciapaglia et al. (2021) pooled evidence from 11 RCTs evaluating 6,004 patients with active RA inadequately responding to previous csDMARDs. The analysis compared ACR50 response at 24 weeks to adalimumab originator/ biosimilars, abatacept, baricitinib, certolizumab pegol, tofacitinib or upadacitinib with MTX. The NMA concluded that upadacitinib ranked first among treatments with a 86.3% probability of being the agent more likely to induce ACR50 response.
UK NICE highlighted that csDMARDs are often ineffective for many with active RA and bDMARDs treatment often produces an inadequate response. Newer targeted DMARDs such as upadacitinib (Rinvoq) have revolutionised the treatment landscape, providing alternative tailored therapies for patients. The high direct and indirect costs associated with RA, coupled with substantial morbidity and mortality affecting millions of people globally, underscore the potential benefits of improved treatments for this chronic disease to patients, their families and society.
Upadacitinib (Rinvoq) has also gone on to receive local market authorisation for the treatment of psoriatic arthritis (PsA) and ankylosing spondylitis (AS) in November 2021. The use of upadacitinib for the latter indications are discussed separately. In the U.S. and EU, upadacitinib has most recently been approved for use in refractory, moderate to severe atopic dermatitis (Jan 2022). Phase 3 trials of upadacitinib in Crohn’s disease, ulcerative colitis, giant cell arteritis and Takayasu arteritis are ongoing.
