Upadacitinib Superior to Adalimumab in Methotrexate Refractory RA Save

Upadacitinib, a JAK1-selective inhibitor, was studied head to head against adalimumab (ADA) and placebo (PBO) in rheumatoid arthritis after an inadequate response to methotrexate, and shown to be superior to ADA and PBO in ACR20 and DAS remission level responses. 

A total of 1629 patients were randomized once-daily upadacitinib (UPA) 15mg, PBO or ADA 40mg, every other week while remaining on background methotrexate. Primary endpoints were ACR20 and DAS28CRP<2.6 versus placebo at Week12 and inhibition of radiographic progression was evaluated at Week26. 

UPA was superior to ADA and PBO at Week12:

• ACR20: UPA 71% vs. ADA 64% vs. PBO 36%  (p≤0.001 UPA vs PBO; p< 0.5 UPA vs ADA).
• DAS28CRP<2.6  UPA 29% vs. ADA 18% vs PBO 6%.
• ACR50: UPA 45% vs. ADA 29% vs. PBO 15%
• ACR70: UPA 25% vs. ADA 13% vs. PBO 5%
• DAS28CRP≤3.2 (LDAS): UPA 71% vs. ADA 64% vs. PBO 36%

Radiographic progression was less and observed in fewer patients receiving upadacitinib versus placebo (mTSS PBO +0.92 vs UPA +0.24 vs. ADA +0.1 p≤0.001 UPA & ADA vs PBO).

There were no surprises with regard to adverse events (AEs) being similar between groups.

• Serious infections UPA 1.8% vs ADA 1.5% vs PBO 0.8%.
• There were more discontinuations in those on ADA vs UPA
• Herpes zoster (UPA 0.8%; ADA 0.3%; PBO 0.5%)
• CPK elevations were higher for UPA treated patients
• Venous thromboembolic events: a total of 6 were reported [PBO 1; UPA 2; ADA 3]
• Others: 3 malignancies, 5 MACE, and 4 deaths were reported, none on UPA.

In this short term trial UPA was more clinically effective than ADA and PBO and equally comparable to ADA in radiographic inhibition. As expected of a Janus kinas inhibitor there were more cases of herpes zoster and CPK elevations on UPA.