Upadacitinib

Unassigned

New Medicines

Rheumatoid arthritis (RA) with inadequate response to either methotrexate or TNF inhibitors

Information

New molecular entity
AbbVie
AbbVie

Development and Regulatory status

Pre-registration (Filed)
Pre-registration (Filed)
Pre-registration (Filed)

Mar 19: A new market research report identifies upadacitinib for RA as one of seven new drugs it believes will hit sales of $1 billion or more, the so-called “blockbuster” mark, by 2023 [15].


Dec 18: New Drug Application (NDA) submitted to the U.S. Food and Drug Administration (FDA) and a marketing authorization application (MAA) to the European Medicines Agency (EMA) in adults with moderate-severe rheumatoid arthritis [14].


Jan 17: INN allocated; multi-national PIII trial programme (SELECT) now recruiting [4].


Jan 16: P3 trial programme announced by AbbVie; currently only in US [3].

Category

Janus kinase inhibitor
The incidence of the condition is low, with around 1.5 men and 3.6 women developing RA per 10,000 people per year. [2]
Rheumatoid arthritis (RA) with inadequate response to either methotrexate or TNF inhibitors
Oral

Further information

Yes
To be confirmed

Trial or other data

May 19: Results of PIII SELECT-MONOTHERAPY RCT (NCT02706951; n=648) are published in the Lancet; the authors report that upadacitinib monotherapy showed statistically significant improvements in ACR20 and DAS28 (CRP) versus continuing methotrexate (MTX) in patients with an inadequate response to MTX with no new safety concerns. The following results were reported at 14 weeks: - ACR20 response was achieved by more patients in the upadacitinib group vs MTX group (68% for 15mg and 71% for 30mg vs 41%; p<0.0001 for both doses vs MTX);- DAS28(CRP) 3·2 or lower was met by more patients in the upadacitinib group vs MTX group (45% for 15mg and 53% for 30mg vs 19%; p<0.0001 for both doses vs MTX);- adverse events of interest for which a potential dose relationship was observed include herpes zoster [16].


Oct 18: Abbvie announce topline data from PIII SELECT-MONOTHERAPY study. At 14 weeks, 69% patients on 30mg and 65% on 15mg dose reported improvements in physical function vs. 45% on methotrexate (p<0.001) [13].


Jun 18: Results of PIII SELECT-BEYOND (NCT02706847) study (n=499) published in The Lancet. CR20 was achieved by 106 (65%) of 164 patients on upadacitinib 15 mg and 93 (56%) of 165 patients on 30 mg compared with 48 (28%) of 169 patients on placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of ≤3·2 was achieved by 71 (43%) of 164 patients on 15 mg and 70 (42%) of 165 patients receiving 30 mg versus 24 (14%) of 169 patients on placebo (p<0·0001 for each dose vs placebo) [12].


Jun 18: Results of PIII SELECT-NEXT (NCT02675426) study (n=661) published in The Lancet. At week 12, ACR20 was achieved by 141 (64%) of 221 patients receiving upadacitinib 15 mg and 145 (66%) of 219 patients receiving upadacitinib 30 mg, compared with 79 (36%) of 221 patients receiving placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of ≤3·2 met by 107 (48%) patients on upadacitinib 15 mg and 105 (48%) patients on 30 mg, compared with 38 (17%) patients receiving placebo (p<0·0001 for each dose vs placebo) [11].


Apr 18: Abbvie announce further results from PIII SELECT-COMPARE study. At 12 weeks, upadacitinib met primary endpoints of ACR20 response (71% on 15 mg/d vs. 36%) and clinical remission vs. placebo. All ranked secondary endpoints were also achieved vs placebo or adalimumab (40 mg every other week) [9].


Mar 18: PIII SELECT-COMPARE clinical trial found that after 12 weeks, upadacitinib (15 mg daily) met the primary endpoints of ACR20 and clinical remission versus placebo. Primary and secondary endpoints were also better than placebo or adalimumab (40 mg every other week) [8].


Sept 17: initial topline results from the SELECT-BEYOND study (NCT02706847) are positive, according to AbbVie, with primary and major secondary efficacy endpoints being met after 12 weeks. There may be some concern over two deaths in the study, one resulting from heart failure and presumed pulmonary embolism and the cause for the other being unknown: the FDA recently declined to approve a similar drug, baracitinib, due to concerns over increased numbers of potentially dangerous blood clots in trials [7].


Jun 17: AbbVie announces upadacitinib created a statistically significant cut in symptoms in pretreated patients vs. placebo in a 12-week, phase 3 test. Around half of patients saw a low disease activity at both doses (48% of patients receiving either dose of upadacitinib, compared to 17% of patients on placebo) hitting its primary endpoint, with around 30% achieving clinical remission across both doses, compared to 10% for placebo. Safety also seemed to be promising [6].


Jan 17: SELECT trial programme now recruiting with estimated primary completion dates between June 17 and July 18: SELECT-NEXT (NCT02675426, inadequate response to DMARD, est. n=600); SELECT-BEYOND (NCT02706847, inadequate response to biologics, est. n=450); SELECT-COMPARE (NCT02629159, comparison with adalimumab after inadequate response to MTX alone, est. n=1500); SELECT-MONOTHERAPY (NCT02706951, monotherapy comparison to MTX monotherapy, est. n=600); SELECT-EARLY (NCT02706873, monotherapy comparison to MTX monotherapy in MTX-naive patients, est. n=975). Primary outcomes vary [5].


Jan 16: AbbVie has announced a five-study P3 randomised controlled trial programme; two studies have been described so far (SELECT-COMPARE, NCT02629159; SELECT-NEXT, NCT ID nya) and recruitment for the first has started in the US. SELECT-COMPARE (planned n=1500) will compare ABT-494 to placebo and to adalimumab in subjects with moderately to severely active rheumatoid arthritis (RA) who are on a stable background of Methotrexate (MTX) and who have an inadequate response to MTX. SELECT-NEXT (planned n=600) is designed to evaluate the safety and efficacy of two doses of ABT-494, 15 mg and 30 mg once-daily, in combination with conventional synthetic DMARDS, in adult patients with moderate to severely active RA who have had an inadequate response or intolerance to conventional synthetic DMARDs [3].


Sep 15: ABT-494 meets primary endpoint of ACR20 response at week 12 in Two PIIb Studies in Rheumatoid Arthritis. The BALANCE-I (n=276) double-blind, placebo-controlled, dose-ranging PIIb study evaluated the safety and efficacy of four doses of ABT-494 in adult patients with moderate to severely active rheumatoid arthritis who have had an inadequate response or intolerance to anti-TNF biologic therapy: ACR20 responses up to 73% and ACR50 responses up to 44% reported. The BALANCE-II (n=300) double-blind, placebo-controlled, dose-ranging PIIb study evaluated the safety and efficacy of five doses of ABT-494 in adult patients with moderate to severely active rheumatoid arthritis who have had an inadequate response to prior treatment with methotrexate: ACR20 responses up to 82% and ACR50 responses up to 50% reported. AbbVie intends to move rapidly to PIII studies of ABT-494 by the end of 2015 with a once-daily formulation. [1]

Evidence based evaluations

Moderate-to-severe psoriatic arthritis - second-line

Information

Licence extension / variation
AbbVie
AbbVie

Development and Regulatory status

None
None
Phase III Clinical Trials

Category

Janus kinase inhibitor
Prevalence varies from 20-420 per 100,000 population across the world, except in Japan where it is 1 per 100,000. In about 80% of cases the presence of psoriasis precedes the onset of psoriatic arthritis [2].
Moderate-to-severe psoriatic arthritis - second-line
Oral

Ulcerative colitis (UC)

Information

Licence extension / variation
AbbVie
AbbVie

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

Oral small molecule JAK1-selective inhibitor
UC has an incidence in the UK of approximately 10 per 100,000 people annually and a prevalence of approximately 240 per 100,000 [3].
Ulcerative colitis (UC)
Oral

Crohn's disease

Information

Licence extension / variation
AbbVie
AbbVie

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

Oral small molecule JAK1-selective inhibitor
Prevalence in the UK is about 145 per 100.000 population [1].
Crohn's disease
Oral

Moderate-to-severe atopic dermatitis

Information

Licence extension / variation
AbbVie
AbbVie

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

Oral small molecule JAK1-selective inhibitor
Atopic eczema is common and the prevalence is increasing. Eczema affects 15-20% of school children and 2-10% of adults.
Moderate-to-severe atopic dermatitis
Oral