Upadacitinib continues to improve RA symptoms in extension studies
The selective Janus kinase 1 inhibitor upadacitinib demonstrated sustained efficacy and safety beyond 12 weeks in patients with moderate-to-severe rheumatoid arthritis (RA) who had inadequate response or were refractory to disease-modifying antirheumatic drugs (DMARDs), according to the interim results of the ongoing extension phases of SELECT-NEXT* and SELECT-BEYOND** presented at EULAR 2019.
SELECT-NEXT participants who completed 12 weeks of treatment (n=611/661) entered the extension phase wherein upadacitinib recipients continued with their assigned dose (15 or 30 mg once-daily; same-therapy arm); while those on placebo switched to upadacitinib 15 or 30 mg (switcher arm) on a stable background of conventional synthetic (cs) DMARDs. [EULAR 2019, abstract FRI0132]
Patients in the same-therapy arm saw an increase in DAS28-CRP*** ≤3.2 response from week 12 to week 60 (from 48 percent to 75 percent for pooled results of both 15- and 30-mg doses).
Similar proportion of patients in the switcher arm also had DAS28-CRP ≤3.2 at week 60 (78 percent [upadacitinib 15 mg] and 68 percent [upadacitinib 30 mg]).
A majority of the population exhibited 20 percent clinical and functional improvement (ACR20# response, 85–90 percent across all patient subgroups). Favourable ACR70# response was also observed across patient subgroups, ranging from 46–51 percent.
Although ACR20 has been the preferred clinical endpoint in most RA trials, [Arthritis Rheum 1998;41:1564-1570] ACR50# and ACR70 are being favoured of late as a 20-percent improvement only represents a relatively modest change in RA parameters. [Ann Rheum Dis 2006;65:1602-1607; Ann Rheum Dis 2015;74:1691-1696]
Overall safety assessment revealed that patients on upadacitinib 30 mg had higher rates of serious adverse events (SAEs, 24.2 vs 16.3 events/100 patient-years [PY]), AEs leading to drug cessation (17.2 vs 8.4 events/100 PY), serious infections (7.5 vs 2.3 events/100 PY), and herpes zoster (7.5 vs 3.1 events/100 PY) than those receiving upadacitinib 15 mg.
In SELECT-BEYOND, 84 percent of participants (n=418/498) with active RA who failed prior biologic therapy and completed 24 weeks of treatment entered the extension phase. As in SELECT-NEXT, the extension phase entailed study drug continuation (same therapy arm) or transitioning from placebo to upadacitinib (switcher arm) on top of background csDMARD treatment. [EULAR 2019, abstract THU0172]
Clinical outcomes mirrored those in SELECT-NEXT given the improved DAS28-CRP ≤3.2 rates from week 12 to week 60 in the same-therapy arm (from 43 percent to 69 percent [upadacitinib 15 mg] and from 42 percent to 73 percent [upadacitinib 30 mg]). DAS28-CRP ≤3.2 rates in the switcher arm were comparable to those in the same-therapy arms (63 percent and 72 percent for placebo-upadacitinib 15 mg and placebo-upadacitinib 30 mg, respectively).
ACR20 and ACR70 responses across patient subgroups ranged from 77–84 percent and 33–42 percent, respectively.
Use of upadacitinib 30 mg also generated higher rates of SAEs (29.2 vs 17.9 events/100 PYs), AEs leading to discontinuation (15.1 vs 9.6 events/100 PYs), serious infections (8.3 vs 3.0 events/100 PYs), herpes zoster (8.9 vs 4.6 events/100 PYs), and hepatic disorders (8.3 vs 4.6 events/100 PYs) than upadacitinib 15 mg.
Overall, the risk-benefit ratio of upadacitinib in DMARD-refractory individuals remains favourable, noted the researchers. Despite the higher AE rates in the 30-mg arm, both upadacitinib doses continued to be effective in managing RA signs and symptoms and improving physical function, they added.
Taken together, the results support the efficacy and safety of both upadacitinib doses on a background of csDMARD therapy for over a year in DMARD-refractory RA patients. An integrated safety analysis is warranted to thoroughly explore the risk-benefit ratio of upadacitinib in this setting, said the researchers of both studies.