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SELECT COMPARE - MTX inadequate responder patients2

A comparison of RINVOQ+MTX to adalimumab + MTX and Placebo + MTX2

RINVOQ + MTX demonstrated significantly greater DAS28 (CRP) remission rates and low disease activity rates  than Placebo + MTX and adalimumab + MTX at 12 weeks2

Primary endpoint of DAS28-CRP < 2.6 RINVOQ + MTX vs Placebo + MTX at 12 weeks was met

Graph adapted from Fleischmann et al; 2019.

Remission is defined as DAS28-CRP <2.6 and LDA as DAS28-CRP ≤3.2.

*p≤0.001 vs placebo + MTX; †nominal p≤0.001 vs adalimumab + MTX. ‡p≤0.001vs adalimumab + MTX. 

CRP, C-reactive protein; DAS28, Disease Activity Score 28 joints; LDA, low disease activity; MTX, methotrexate.

RINVOQ + MTX demonstrated significantly greater ACR response rates vs Placebo + MTX and Adalimumab + MTX at 12 weeks

Primary endpoint of DAS28-CRP < 2.6 RINVOQ + MTX vs Placebo + MTX at 12 weeks was met

Graph adapted from Fleischmann et al; 2019.

*p≤0.001 vs placebo + MTX; nominal p≤0.05 vs adalimumab + MTX; nominal p≤0.001 vs adalimumab + MTX; nominal p≤0.001 vs placebo + MTX; #p≤0.001 vs adalimumab + MTX.

ACR20/50/70, American College of Rheumatology ≥20 %/50%/70% improvement; MTX, methotrexate.

RINVOQ + MTX inhibits radiographic progression over time

SELECT-COMPARE: Inhibition of structural joint damage progression at Week 267

SELECT-COMPARE: Inhibition of structural joint damage progression at Week 48 (linear extrapolation)7

Primary endpoint of DAS28-CRP < 2.6 RINVOQ + MTX vs Placebo + MTX at 12 weeks was met

Graph adapted from Fleischmann et al; 2019.

*nominal p<0.01 vs placebo + MTX

Results based on reading session 2

Treatment groups are by initial randomisation. For the placebo group, all data at Week 48 were imputed by linear extrapolation. X-ray data collected at treatment switching or at discontinuation of placebo (for patients who discontinued placebo) were used for extrapolation. Specifically, for placebo patients who switched to RINVOQ at Week 26, the Week 26 X-ray was used for extrapolation to impute the data at Week 48. For patients randomised to RINVOQ or adalimumab who were rescued, data at Week 48 were also imputed by linear extrapolation using X-ray data collected at treatment switching.

SELECT COMPARE Study design

A Phase 3 study investigating the efficacy and safety of RINVOQ + MTX compared with placebo + MTX and adalimumab + MTX for the treatment of moderate to severe RA in patients who had an inadequate response to MTX2,7

*Rescue criteria: At Weeks 14, 18, and 22, patients receiving adalimumab or placebo were switched to RINVOQ and patients receiving RINVOQ were switched to adalimumab if <20% improvement in tender joint count and swollen joint count vs baseline. At Week 26, all remaining placebo patients who were not rescued were switched to RINVOQ, and patients receiving RINVOQ or adalimumab were switched to adalimumab and RINVOQ, respectively, if CDAI >10.

Primary 

RINVOQ+MTX vs PBO+MTX at 12 weeks: DAS28(CRP) < 2.6

Key secondary 

RINVOQ+MTX vs PBO+MTX at 12 weeks: DAS28(CRP) ≤3.2, Change from baseline in DAS28(CRP), HAQ-DI, SF-36 PCS, CDAI≤10, Change in morning stiffness duration, Change in FACIT-F, ACR20

RINVOQ+MTX vs PBO+MTX at 26 weeks: Change in mTSS, % with mTSS≤0. 

RINVOQ+MTX vs Adalimumab+MTX at 12 weeks: DAS28(CRP)≤ 3.2 

 

  • Patients ≥18 years of age were eligible to participate. 
  • Diagnosis of RA for ≥3 months fulfilling the 2010 ACR/EULAR classification for RA with active disease (≥6 swollen joints of 66, ≥6 tender joints of 68 examined, hsCRP ≥5 mg/L), and at least one of the following at screening: ≥3 erosions on x-rays of hands and feet, or ≥1 erosion and positivity for RF or anti-CCP antibodies.
  • Patients must have had an inadequate response to MTX. 
  • Patients with prior exposure to at most 1 bDMARD (except adalimumab) were eligible (up to 20% of total study number of patients) if they had either limited exposure (<3 months) or had to discontinue the bDMARD due to intolerability.
  • Patients with inadequate response to prior bDMARDs or prior exposure to a JAK inhibitor were excluded.

Anti-CCP antibodies: anti-cyclic citrullinated protein; ACR: American College of Rheumatology; ACR20: American College of Rheumatology >20% improvement;  bDMARD: biological disease-modifying antirheumatic drug; CDAI: Clinical Disease Activity Index; DAS28 (CRP): disease activity score with 28 joint count (C-reactive protein); EOW: every other week; EULAR: European League Against Rheumatism; FACIT-F: Functional Assessment of Chronic Illness Therapy-Fatigue; HAQ-DI: Health Assessment Questionnaire without Didability Index; hsCRP: high-sensitivity C-reactive protein; mTSS: modified total sharp score; MTX: methotrexate; PBO: Placebo;QD: once daily; RF: rheumatoid factor; SF-36 PCS: PCS Short Form (36) Health Survey Physical Component Score.

Upadacitinib versus Placebo or Adalimumab in Patients with Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase 3, Double Blind, Randomised Controlled Trails. Fleischman et al. 

SELECT MONOTHERAPY  - MTX inadequate responder patients3

A comparison of RINVOQ to cMTX3

RINVOQ demonstrated significantly greater DAS28 (CRP) remission rate and Lower Disease Activity rate than cMTX at 14 weeks3

Primary endpoint of DAS28-CRP < 3.2 RINVOQ vs Placebo + cMTX was met at week 14

Graph adapted from Smolen et al; 2019

LDA is defined as DAS28-CRP ≤3.2 and remission as DAS28-CRP <2.6.

*p≤0.0001 vs cMTX. 

cMTX, continued methotrexate; CRP, C-reactive protein; DAS28, Disease Activity Score 28 joints; LDA, low disease activity.

RINVOQ demonstrated significantly greater ACR response rates vs cMTX at 14 weeks

Primary endpoint of DAS28-CRP < 3.2 RINVOQ vs Placebo + cMTX was met at week 14

Graph adapted from Smolen et al; 2019

*p≤0.0001 vs cMTX.

ACR20/50/70, American College of Rheumatology ≥20 %/50%/70% improvement; cMTX, continued methotrexate.

SELECT MONOTHERAPY Study design

A Phase 3 study investigating the efficacy and safety of RINVOQ monotherapy after switching from MTX compared with cMTX for the treatment of moderate to severe RA in patients who had an inadequate response to MTX2

*For the primary analysis at Week 14, comparisons of RINVOQ 15 mg and upadacitinib 30 mg vs cMTX were done by combining data from the two cMTX groups. 
† From Week 14, patients initially randomized to cMTX at baseline were switched to RINVOQ 15 mg or upadacitinib 30 mg per prespecified randomization assignment.

Primary

RINVOQ vs cMTX at 14 weeks: DAS28(CRP) ≤3.2

Key secondary

RINVOQ vs cMTX at 14 weeks: Change from baseline in DAS28(CRP), Change from baseline in HAQ-DI, Change from baseline in SF-36 PCS, DAS28(CRP) < 2.6, Change in morning stiffness duration, ACR20

  • Patients ≥18 years of age were eligible to participate. 
  • Diagnosis of RA for ≥3 months fulfilling the 2010 ACR/EULAR classification for RA with active disease (at least 6 swollen joints out of 66, at least 6 tender joints out of 68, and more than 3 mg/L hsCRP). 
  • Patients must have had an inadequate response to MTX. 
  • No prior exposure to a JAK inhibitor or bDMARD.

The approved dose of RINVOQ is 15 mg once daily. Upadacitinib 30 mg QD is not an approved dose.

ACR: American College of Rheumatology; ACR20: American College of Rheumatology >20% improvement; bDMARD: biological disease-modifying antirheumatic drug; cMTX: continued methotrexate; DAS28 (CRP): disease activity score with 28 joint count (C-reactive protein); EULAR: European League Against Rheumatism; HAQ-DI: Health Assessment Questionnaire without Didability Index; hsCRP: high-sensitivity C-reactive protein; JAK: Janus kinase; MTX: methotrexate;  QD: once daily; SF-36 PCS: PCS Short Form (36) Health Survey Physical Component Score.

SELECT NEXT - csDMARD inadequate responder patients4

A comparison of RINVOQ+csDMARD(s) to Placebo+csDMARD(s)4

RINVOQ + csDMARD(s) demonstrated a significantly greater DAS28 (CRP) remission rate and Lower Disease Activity rate than Placebo+csDMARD(s) at 12 weeks4

Primary endpoint of DAS28-CRP < 3.2 RINVOQ + csDMARD(s) vs Placebo + csDMARD(s) was met at 12 weeks

Graph adapted from Burmester et al; 2018

LDA is defined as DAS28-CRP ≤3.2 and remission as DAS28-CRP <2.6.

*p≤0.0001 vs placebo + csDMARD(s). 

CRP, C-reactive protein; csDMARD, conventional systemic disease-modifying anti-rheumatic drug; DAS28, Disease Activity Score 28 joints; LDA, low disease activity.

RINVOQ+ csDMARD(s) demonstrated significantly greater ACR response rates vs Placebo+csDMARD(s) at 12 weeks

Primary endpoint of DAS28-CRP < 3.2 RINVOQ + csDMARD vs Placebo + csDMARD was met at 12 weeks

Graph adapted from Burmester et al; 2018

*p<0.0001 vs placebo + csDMARD(s). 

ACR20/50/70, American College of Rheumatology ≥20 %/50%/70% improvement; csDMARD, conventional systemic disease-modifying anti-rheumatic drug

SELECT NEXT Study Design

A Phase 3 study investigating the efficacy and safety of RINVOQ + csDMARDs compared to placebo + csDMARDs in patients with moderate to severe RA and an inadequate response to csDMARDs1

Permitted background csDMARDs were oral and parenteral MTX, sulfasalazine, hydroxychloroquine, chloroquine, and leflunomide; up to 2 concomitant background csDMARDs were allowed, with the exception of the combination of MTX and leflunomide.

*From Week 12 onward, patients initially randomized to placebo at baseline were switched to RINVOQ 15 mg or upadacitinib 30 mg per prespecified randomization assignment. Patients assigned to RINVOQ 15 mg or upadacitinib 30 mg continued their assigned dose.

Primary

RINVOQ+csDMARD(s) vs PBO+csDMARD(s) at 12 weeks: DAS28(CRP)≤ 3.2

Key secondary

RINVOQ+csDMARD(s) vs PBO+csDMARD(s) at 12 weeks: % of pts achieving DAS28(CRP) < 2.6, CDAI≤10, ACR20; Changes from baseline in DAS28(CRP), HAQ-DI, FACIT-F, SF-36 PCS, morning stiffness duration;

  • Patients ≥18 years of age were eligible to participate. 
  • Diagnosis of RA for ≥3 months fulfilling the 2010 ACR/EULAR classification for RA with active disease (at least 6 swollen joints out of 66, at least 6 tender joints out of 68, and hsCRP of 3 mg/L or more). 
  • Received csDMARDs for ≥3 months and on a stable dose for ≥4 weeks before study entry. 
  • Patients must have had an inadequate response to at least 1 prior csDMARD (MTX, sulfasalazine, or leflunomide). 
  • Patients with prior exposure to at most 1 bDMARD were eligible (up to 20% of total study number of patients) if they had either limited exposure (<3 months) or had to discontinue the bDMARD due to intolerability. 
  • No prior exposure to a JAK inhibitor or prior inadequate response to bDMARDs.

The approved dose of RINVOQ is 15 mg once daily. Upadacitinib 30 mg QD is not an approved dose.

ACR: American College of Rheumatology; ACR20: American College of Rheumatology >20% improvement; bDMARD: biological disease-modifying antirheumatic drug; CDAI: Clinical Disease Activity Index; csDMARD: conventional synthetic disease-modifying antirheumatic drug; DAS28 (CRP): disease activity score with 28 joint count (C-reactive protein); EULAR: European League Against Rheumatism; FACIT-F: Functional Assessment of Chronic Illness Therapy-Fatigue; HAQ-DI: Health Assessment Questionnaire without Didability Index; hsCRP high-sensitivity C-reactive protein; JAK: Janus kinase; MTX: methotrexate; PBO: Placebo; QD: once daily; SF-36 PCS: PCS Short Form (36) Health Survey Physical Component Score.

SELECT BEYOND  - bDMARD inadequate responder patients5

A comparison of RINVOQ+csDMARD(s) to Placebo+csDMARD(s)5

RINVOQ + csDMARD(s) demonstrated a significantly greater DAS28 (CRP) remission rate and Lower Disease Activity rate than Placebo+csDMARD(s) at 12 weeks5,6

Primary endpoint of DAS28-CRP < 3.2 RINVOQ + csDMARD vs Placebo + csDMARD(s) was met at week 12

Graph adapted from Genovese et al: 2018

LDA is defined as DAS28-CRP ≤3.2 and remission as DAS28-CRP <2.6.

*p≤0.001 vs placebo + csDMARD(s), #nominal p<0.001vs placebo + csDMARD(s). 

CRP, C-reactive protein; csDMARD, conventional systemic disease-modifying anti-rheumatic drug; DAS28, Disease Activity Score 28 joints; LDA, low disease activity.

RINVOQ+csDMARD(s) demonstrated significantly greater ACR 20 and ACR 50 repsonse rates vs Placebo + csDMARD(s) at 12 weeks

Primary endpoint of DAS28-CRP < 3.2 RINVOQ + csDMARD vs Placebo + csDMARD(s) was met at week 12

Graph adapted from Genovese et al: 2018

*p<0.0001 vs placebo + csDMARD(s); not significant vs Placebo + CSDMARD(s)

ACR20/50/70, American College of Rheumatology ≥20 %/50%/70% improvement; csDMARD, conventional systemic disease-modifying anti-rheumatic drug.

SELECT BEYOND  study design

A Phase 3 study investigating the efficacy and safety of RINVOQ + csDMARDs compared to placebo + csDMARDs in patients with moderate to severe RA and an inadequate response to bDMARDs1

Patients continued stable csDMARD therapy for the first 24 weeks of the study, restricted to oral or parenteral MTX, chloroquine, hydroxychloroquine, sulfasalazine, or leflunomide. Patients could be taking a maximum of 2 background csDMARDs, except the combination of MTX and leflunomide, which was not allowed.

*Randomisation was stratified by prior failed bDMARDs (1-2 with same mechanism of action vs ≥3 with the same mechanism of action or at least 2 biologics with different mechanisms of action).

Primary

RINVOQ+csDMARD(s) vs PBO+csDMARD(s) at 12 weeks: DAS28(CRP) ≤3.2

Key secondary

RINVOQ+csDMARD(s) vs PBO+csDMARD(s) at 12 weeks: % pts achieving, ACR20; Change from baseline in DAS28(CRP), HAQ-DI, SF-36 PCS,

  • Patients ≥18 years of age were eligible to participate. 
  • Diagnosis of RA for ≥3 months fulfilling the 2010 ACR/EULAR classification for RA with active disease (at least 6 swollen joints out of 66, at least 6 tender joints out of 68, and hsCRP of 3 mg/L or more). 
  • Patients must have had an inadequate response for at least 3 months with at least one bDMARD or an intolerance or toxicity to bDMARDs. 
  • Patients were on csDMARD therapy for at least 3 months and on stable doses for at least 4 weeks before study entry. 
  • No previous exposure to a JAK inhibitor.

 

The approved dose of RINVOQ is 15 mg once daily. Upadacitinib 30 mg QD is not an approved dose.

ACR: American College of Rheumatology; ACR20: American College of Rheumatology >20% improvement; bDMARD: biological disease-modifying antirheumatic drug; csDMARD: conventional synthetic disease-modifying antirheumatic drug; DAS28 (CRP): disease activity score with 28 joint count (C-reactive protein); EULAR: European League Against Rheumatism; HAQ-DI: Health Assessment Questionnaire without Didability Index; hsCRP: high-sensitivity C-reactive protein; JAK: Janus kinase; MTX: methotrexate; PBO: Placebo; QD: once daily; SF-36 PCS: PCS Short Form (36) Health Survey Physical Component Score.

References

  1. RINVOQ (Upadactinib) SmPC.
  2. Fleischmann R, Pangan AL, Song IH, et al. Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase III, double-blind, randomized controlled trial [published online July 9, 2019]. Arthritis Rheumatol. doi:10.1002/art.41032.
  3. Smolen JS, Pangan AL, Emery P, et al. Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase III study. Lancet. 2019;393(10188):2303-2311. doi:10.1016/S0140-6736(19)30419-2.
  4. Burmester GR, Kremer JM, Van den Bosch F, et al. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase III trial. Lancet. 2018;391(10139):2503-2512. doi:10.1016/S0140-6736(18)31115-2.
  5. Genovese MC, Fleischmann R, Combe B, et al. Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase III trial. Lancet. 2018;391(10139):2513-2524. doi:10.1016/S0140-6736(18)31116-4.
  6. Genovese CM, Fleischmann R, Combe B, et al. Upadacitinib (ABT-494) in Patients With Active Rheumatoid Arthritis and Inadequate Response or Intolerance to Biological DMARDs: A Phase 3 Randomized, Placebo-Controlled, Double-Blind Study of a Selective JAK-1 Inhibitor. 2017. Poster presented at the ACR Annual Meeting, November 3–8, 2017, San Diego, California, United States.
  7. Fleischmann RM, Genovese MC, Enejosa JV, et al. Safety and effectiveness of upadacitinib or adalimumab plus methotrexate in patients with rheumatoid arthritis over 48 weeks with switch to alternate therapy in patients with insufficient response [published online July 30, 2019]. Ann Rheum Dis. doi:10.1136/annrheumdis-2019-215764.
  8. NICE (2020) Upadacitinib for treating severe rheumatoid arthritis; Technology Appraisal Guidance; TA665. Accessed at: https://www.nice.org.uk/guidance/ta665 [last accessed December 2020] 

UK-UPAD-200350. Date of preparation: December 2020

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