Upadacitinib vs adalimumab or placebo in patients with an inadequate response to non-biological therapy: Week 56 results from the SELECT-PsA 1 study

Psoriatic arthritis (PsA) is an inflammatory disease that can present with multiple clinical manifestations, including psoriasis, peripheral arthritis, dactylitis, enthesitis, spondylitis, quality of life, physical function, pain, and fatigue.¹ Treatment strategies focus on maximizing patient outcomes by controlling inflammation and preventing irreversible joint damage and disability. Currently, treatment options for PsA include several disease-modifying antirheumatic drugs (DMARDs), yet <1/3 of patients with PsA achieve minimal disease activity (MDA) in most placebo-controlled trials so new treatment options are needed.¹

Upadacitinib, an oral, reversible, Janus associated kinase (JAK) inhibitor, is approved in Europe for the treatment of rheumatoid arthritis, PsA, and ankylosing spondylitis.² The SELECT-PsA 1 trial (NCT03104400) is investigating the effect of upadacitinib compared with adalimumab (standard of care treatment) or placebo in adult patients with active PsA and an inadequate response or intolerance to ≥1 non-biological DMARD. Results of the 56-week efficacy and safety analysis were published by Iain McInnes et al.¹ in the journal Rheumatic & Musculoskeletal Diseases Open. A summary of these results is provided below.

Study design and patient characteristics

This was a phase III, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of upadacitinib (15 mg or 30 mg once daily) compared with adalimumab (40 mg every other week) or placebo in 1,705 adult patients (≥18 years of age) with active PsA and inadequate response or intolerance to ≥1 non-biological DMARD. The study design can be seen in Figure 1.

Figure 1. Study design*

ADA, adalimumab; D, day; DMARD, disease-modifying antirheumatic drug; EOW, every other week; PsA, psoriatic arthritis; QD, once daily; SJC, swollen joint count; TCJ, tender joint count; UPA, upadacitinib; W, week.
*Data from McInnes et al.^1
†Data from ClinicalTrials.gov.^3
‡One patient in the UPA 15 mg cohort did not receive study drug.
^§Compared with baseline at two consecutive visits.

Baseline characteristics were well balanced across all cohorts (Table 1).

Table 1. Baseline characteristics*

Results

In total, 83.2% of the patients enrolled in the trial completed 56 weeks of treatment. The most common reasons for discontinuation were withdrawal by the patient and lack of efficacy.

Efficacy

The proportions of patients achieving ≥20%/50%/70% improvement in American College of Rheumatology response criteria (ACR20/50/70) response were maintained from Week 24 to Week 56 across all treatment groups. A greater proportion of patients originally randomized to upadacitinib achieved ACR20/50/70 compared with those randomized to adalimumab at Week 56 (non-responder imputation analysis: nominal p ≤ 0.05 for 15 mg upadacitinib vs adalimumab for ACR50/70; nominal p ≤ 0.05 for 30 mg upadacitinib vs adalimumab for ACR20/50/70). ACR70 responses can be seen in Figure 2.

Figure 2. Percentage of patients achieving ACR70*

ACR70, 70% improvement in American College of Rheumatology response criteria; ADA, adalimumab; UPA, upadacitinib; PBO, placebo.

*Adapted from McInnes, et al.¹

All ACR components were improved from baseline across all cohorts. Patients who switched from placebo to upadacitinib had comparable results to those originally randomized to upadacitinib (Table 2).

Table 2. ACR components and patient-reported outcomes at 56 weeks*

• In all treatment groups, the proportion of patients achieving Psoriatic Arthritis Response Criteria (PsARC) was also maintained from Week 24 to Week 56.

• • At Week 56, more patients achieved PsARC response with upadacitinib 30 mg compared with adalimumab (nominal p ≤ 0.05).
• Based on linear extrapolation at Week 56, mean changes from baseline in radiographic endpoints were comparable between both upadacitinib cohorts and the adalimumab cohort.
• MDA responses can be seen in Figure 3.
  • For those originally randomized to upadacitinib or adalimumab, the proportion of patients achieving MDA were maintained from Week 24 to Week 56.
  • Overall, more patients in the upadacitinib 30 mg cohort achieved MDA compared with the adalimumab cohort (nominal p ≤ 0.05).
  • For the placebo cohorts, the percentage of patients achieving MDA increased when they were switched to upadacitinib.
• Improvements in the skin outcomes Psoriasis Area and Severity Index (PASI75/90/100) and Static Investigator Global Assessment of Psoriasis of 0 or 1 (sIGA 0/1) response rates were maintained over time.
  • After patients switched to upadacitinib from placebo, the proportion of patients achieving PASI75/90/100 and sIGA 0/1 increased and were similar to the upadacitinib cohorts by Week 36.

Figure 3. Percentage of patients achieving MDA (NRI)*^†

ADA, adalimumab; MDA, minimal disease activity; NRI, non-responder imputation; PBO, placebo; UPA, upadacitinib.
*Adapted from McInnes, et al.^1
†NRI with additional rescue handling was used, where patients rescued at Week 16 are imputed as non-responders.

Patient-reported outcomes

Improvements in Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue, Short Form Health Survey questionnaire (SF-36), Physical Component Summary (PCS) and Mental Component Summary (MCS), patients’ assessment of pain, Patients’ Global Assessment of Disease Activity (PtGA), and Work Productivity and Activity Impairment (WPA) were maintained from Week 24 to Week 56.

Patient reported outcomes at Week 56 are detailed in Table 2.

Safety

• At Week 56, treatment-emergent adverse event (TEAE) rates were highest in the 30 mg upadacitinib cohort (333.9 events/100 patient years vs 281.1 [UPA 15 mg] and 265.9 [ADA]).
• The most frequent AEs were upper respiratory tract infection and blood creatine phosphokinase elevations.
• Exposure-adjusted event rates of TEAEs at Week 56 can be seen in Table 3.
  • Of note, patients in the UPA 30 mg cohort had higher rates of infection.
• Event rates of malignancy were similar across the upadacitinib and adalimumab treatment groups; no notable malignancy patterns or types were observed.

Table 3. Exposure-adjusted event rates of treatment-emergent AEs at Week 56.

• Deaths were reported in
  • two patients in the upadacitinib 15 mg cohort (due to metastatic lung cancer and lower respiratory tract infection);
  • two patients in the upadacitinib 30 mg cohort (due to coronavirus infection and interstitial lung disease);
  • one patient in the adalimumab cohort (due to a traffic accident); and
  • one patient in the placebo group (due to an unspecified emergency while driving).

Conclusion

The 56-week efficacy data across various domains of PsA support the benefit of continued upadacitinib therapy in patients with active PsA and inadequate response or intolerance to ≥1 non-biological DMARD. Moreover, the 56-week safety data were comparable to findings from Week 24. However, a major limitation of this trial includes the lack of axial imaging to assess for psoriatic spondylitis. As the diagnosis was made on presumptive criteria, patients without true spondylitis may have been included. Furthermore, the study was not powered or designed to include a prespecified statistical comparison for efficacy between the upadacitinib arms and adalimumab arm through to Week 56.

Despite its limitations, the results of this trial along with those of the SELECT-PSA 2 trial lead the National Institute for Health and Care Excellence (NICE) to recommend upadacitinib alone or in combination with methotrexate as a treatment option for adult patients with active PsA whose disease has not responded well enough to DMARDs or those that cannot tolerate them. This recommendation was published earlier this year and is only for patients who have peripheral arthritis with ≥3 tender joints and ≥3 swollen joints and

• have had two conventional DMARDs and ≥1 biological DMARD; or
• where TNF-alpha inhibitors are contraindicated.²