Upadacitinib, a JAK1-selective inhibitor, for adults with moderately to severely active rheumatoid arthritis who fail to adequately respond or are intolerant to Methotrexate


Upadacitinib ( Rinvoq ) was developed as a JAK1-selective inhibitor by exploiting differences in the non-conserved domains outside the active sites of JAK1 and JAK2.
In cellular assays, Upadacitinib displays 60 and 100 fold selectivity for JAK1 over JAK2 and for JAK1 over JAK3, respectively.

Upadacitinib was approved by FDA ( Food and Drug Admnistration ) , and, more recently, by EMA ( European Medicines Agency ), at a dosage of 15 mg once daily, for adults with moderately to severely active rheumatoid arthritis ( RA ) who fail to adequately respond or are intolerant to Methotrexate ( MTX ).
Upadacitinib may be prescribed with or without Methotrexate.

The efficacy of Upadacitinib has been evaluated in two phase II trials ( BALANCE 1 and BALANCE 2 ), one phase IIb/III trial ( SELECT-SUNRISE ) and five phase III RCTs ( SELECT-NEXT, SELECT-BEYOND, SELECT-MONOTHERAPY, SELECT-EARLY, SELECT-COMPARE ).

The phase III trial SELECT-CHOICE, comparing Upadacitinib and Abatacept in RA patients with an inadequate response to c/bDMARDs is ongoing, and results have not published yet.

Results from BALANCE 1 and BALANCE 2, enrolling anti-TNF failing and Methotrexate-failing patients respectively, showed rapid, dose-dependent improvements in RA signs and symptoms, with a similar safety and tolerability profile to those of other JAK inhibitors ( JAKi ).

Phase III RCTs recruited patients with inadequate response to at least one cDMARD, including Methotrexate ( SELECT-NEXT, SELECT-MONOTHERAPY and SELECT-COMPARE ), and patients with inadequate response or intolerance to bDMARDs ( SELECT-BEYOND ).

Patients were randomly assigned to received once-daily extended-release formulations of Upadacitinib 15 or 30 mg or placebo for at least 12 weeks.
Overall, results of these studies showed a rapid statistically significant improvement in the ACR20 response as early as week 1, and in the ACR50 and ACR70 responses from week 2 onward with Upadacitinib 15 and 30 mg.
DAS28-CRP and CDAI scores were significantly improved with both the two Upadacitinib doses, with 40–50% of patients achieving low disease activity by week 12.
Quality of life, physical function, fatigue, severity, and duration of morning stiffness were also significantly improved in Upadacitinib arms regardless of the dose.

In the SELECT-BEYOND trial, recruiting 498 RA patients failing previous lines with biologics ( anti-TNF and anti-IL-6R agents ), the efficacy outcomes were achieved in the Upadacitinib arm versus placebo regardless of the number or kind of previously received treatments.

In the SELECT-MONOTHERAPY phase III RCT, Upadacitinib monotherapy led to statistically significant improvements in clinical and functional outcomes versus the continuation of Methotrexate in MTX-resistant patients.
A higher and statistically significant proportion of patients receiving both the two Upadacitinib doses achieved DAS28-CRP low disease activity or remission compared to those assigned to Methotrexate alone.

In the SELECT-COMPARE trial, Upadacitinib, at a dose of 15 mg once daily, outperformed Adalimumab in the achievement of ACR50, HAQ and DAS28-CRP responses at week 12 in Methotrexate-refractory RA patients.
Furthermore, a higher percentage of Upadacitinib-assigned patients were in low disease activity or remission at week 26 compared to the Adalimumab arm.

The safety profile of Upadacitinib was in line with that of non-selective JAKi. Adverse events in BALANCE 1 and 2 increased in a dose-dependent manner but were mostly mild and included infections ( the most common adverse events ), nausea, headache, transient increase in serum transaminases and in lipid levels ( both LDL and HDL with unchanged ratio ).
A dose-dependent decrease in the levels of hemoglobin ( grade 3 and 4 anemia ) was also noted, as well as a decrease in lymphocyte, NK cell and neutrophil count.
Serious infections occurred in the Upadacitinib 30 mg arms of the SELECT-NEXT and SELECT-BEYOND trials, but none had a fatal course.

An increased incidence of herpes zoster ( HZV ) reactivation was observed in all the Upadacitinib treatment arms across the five trials, with two serious cases in the Upadacitinib 30 mg group in the SELECT-BEYOND study.

Two malignancies and one major MACE occurred in the Upadacitinib 30 mg arm of the SELECT-NEXT trial, whereas four malignancies and two MACEs were reported in the SELECT-BEYOND trial in Upadacitinib arms.

Four cases of pulmonary embolism were also reported in the SELECT-BEYOND study, but all the patients had known additional risk factors.

In the SELECT-COMPARE trial an increase in serum creatine phosphokinase ( CPK ) was reported in subjects receiving Upadacitinib but not in those treated with the active comparator.

Upadacitinib is metabolized by CYP enzymes, including CYP3A, but it can be safely taken with other CYP3A-metabolized drugs, including statins, which might be co-prescribed due to the paradoxical effect of JAKi on lipid transport.
However, attention must be paid to the plausible synergistic effect of Upadacitinib and statins in inducing CPK elevation and skeletal muscle damage. ( Xagena )

Angelini J et al, Biomolecules 2020; 10(7):1002

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