Session Information
Date: Sunday, November 5, 2017
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Upadacitinib (UPA, ABT-494) is a selective, oral JAK-1 inhibitor studied in two phase 2 randomized controlled trials (RCTs) in patients (pts) with rheumatoid arthritis (RA). We assessed UPA safety and efficacy in BALANCE-EXTEND, an ongoing, combined open-label extension (OLE) of the phase 2 RCTs.
Methods: Pts completing the two 12-week RCTs (in TNF-IR and MTX-IR pts)1,2 could enter the OLE. Pts switched to 6 mg UPA from their RCT dose of UPA 3, 6, 12, 18 mg twice daily (BID), 24 mg once daily (QD) or Placebo. A dose increase to 12 mg BID was required for pts with <20% improvement in both SJC and TJC on 6 mg BID (at wk 6 or 12), and permitted for pts not meeting CDAI LDA. Pts without 20% improvement in SJC and TJC 6 wks after escalation, or at any 2 consecutive visits, were discontinued. The dose was decreased to 6 mg BID only in pts with a safety concern or intolerability. Pts are grouped as: Never-titrated (on 6 mg BID throughout); Titrated-up (from 6 to 12 mg BID); Titrated-up and back down (to 6 mg BID). After Jan 2017, the 6 and 12 mg BID doses were replaced by 15 and 30 mg QD extended-release equivalents currently being studied in phase 3. Data up to Jan 13 2017 are reported. Adverse events (AE) per 100 yrs of pt exposure (PY) are summarized starting from day 1 of OLE. Efficacy is assessed by ACR20/50/70 and LDA (by DAS28-CRP and CDAI), and observed data are presented upto Wk 72 of OLE due to sample size consideration.
Results: Out of 516 pts who completed the 2 RCTs, 494 entered the OLE, 493 were dosed, 328 (66.5 %) were never-titrated, 150 (30.4%) were titrated-up, and 15 (3%) were titrated-up and back down; 150 pts (30.4%) were discontinued [42 (8.5%) withdrew consent, 37 (7.5%) due to AE and 24 (4.9%) due to lack of efficacy]. Mean exposure to UPA was 525.4 ± 221.4 days (range 1-961 days), and cumulative exposure was 725.1 PY (Table 1). The E/100PY for any AE in the OLE (170.5) was lower than for the RCTs in TNF-IR (697.9, 48 PY) and MTX-IR (408.4, 54.6 PY). The E/100PY was 2.3 for serious infection, 3.7 for herpes zoster, 0.8 for malignancies excluding non-melanoma skin cancer, and 1.0 for adjudicated cardiovascular events. There were 2 deaths. Changes from baseline in laboratory parameters were consistent with observations from phase 2 RCTs. For those pts completing Wk 72, efficacy was maintained in pts on 6 mg BID UPA from day 1 of OLE (never-titrated); 55% pts met ACR70 and 83% were in LDA by DAS28-CRP and CDAI based on as observed data (Table 2).
Conclusion: No unexpected safety signals were observed during this OLE. Efficacy responses were maintained upto 72 wks in pts on 6 mg BID UPA in the OLE.
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Table 1. Summary of Adverse Events in Patients who Entered the OLE |
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As of Jan 13 2017 N=493, PYs=725.1 Events (E/100PY) |
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Any AE |
1236 (170.5) |
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Serious AE |
68 (9.4) |
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AE leading to discontinuation |
42 (5.8) |
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AE leading to death# |
2 (0.3) |
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Infections |
427 (58.9) |
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-Serious infections |
17 (2.3) |
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-Opportunistic infectionsδ |
3 (0.4) |
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Anemia |
19 (2.6) |
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Neutropenia |
10 (1.4) |
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Lymphopenia |
17 (2.3) |
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GI perforation |
0 |
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NMSCγ |
5 (0.7) |
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Malignancy other than NMSCϮ |
6 (0.8) |
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Herpes Zoster |
27 (3.7) |
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CPK elevationǂ |
36 (5.0) |
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Hepatic disorders§ |
37 (5.1) |
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Adjudicated cardiovascular events |
7 (1.0) |
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PY, patient years; E/100 PY, events/100 PY; AE, adverse events; NMSC, non-melanoma skin cancer; CPK, creatine phosphokinase #1 sudden death, likely due to cardiac disease (undetermined or unknown cause of death);1 death due to Hodgkin’s lymphoma (non-cardiovascular death). δ1 pt with coccidiomycosis (from an endemic area); 2 pts with oral candidiasis γ3 pts with basal cell carcinoma; 1 pt with 2 events of squamous cell carcinoma of skin Ϯ2 pts with breast cancer (1 pt had bilateral cancer); 2 pts with lymphoma; 1 pt with prostate cancer ǂNot symptomatic §All isolated elevations of ALT/AST or bilirubin; no Hy’s Law cases. |
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Table 2. Efficacy Measures at Week 72 in Patients who Entered the OLE, n/N (%) |
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Never-titrated
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Titrated-up
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Overall efficacy in OLEδ |
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ACR20 |
208/231 (90) |
78/99 (79) |
297/342 (87) |
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ACR50 |
172/230 (75) |
44/100 (44) |
224/342 (65) |
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ACR70 |
127/232 (55) |
22/101 (22) |
153/345 (44) |
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DAS28-CRP LDA |
194/233 (83) |
46/104 (44) |
250/349 (72) |
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CDAI LDA |
191/230 (83) |
42/104 (40) |
242/346 (70) |
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Observed data presented for pts completing Week 72. Efficacy data reflect attrition in the OLE. δ Includes pts who were never-titrated, titrated-up, and titrated-up and back down. ACR20/50/70: 20/50/70% improvement in American College of Rheumatology criteria; DAS28-LDA, 28-joint count disease activity score using C-reactive protein; CDAI, clinical disease activity index; LDA, low disease activity |
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Ref:
- Kremer et al. 2016, Arth & Rheum;68:2867
- Genovese et al. 2016, Arth & Rheum;68:2857
To cite this abstract in AMA style:
Genovese MC, Kremer J, Zhong S, Friedman A. Long-Term Safety and Efficacy of Upadacitinib (ABT-494), an Oral JAK-1 Inhibitor in Patients with Rheumatoid Arthritis in an Open Label Extension Study [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/long-term-safety-and-efficacy-of-upadacitinib-abt-494-an-oral-jak-1-inhibitor-in-patients-with-rheumatoid-arthritis-in-an-open-label-extension-study/. Accessed .« Back to 2017 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/long-term-safety-and-efficacy-of-upadacitinib-abt-494-an-oral-jak-1-inhibitor-in-patients-with-rheumatoid-arthritis-in-an-open-label-extension-study/