AbbVie Announces New Phase 2 Data for Upadacitinib Showing Clinical and Endoscopic Outcomes in Crohn's Disease at 52 Weeks

NORTH CHICAGO, Ill., Feb. 16, 2018 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global research and development-based biopharmaceutical company, today announced new results from the double-blinded extension phase of the Phase 2 CELEST study, showing that many patients treated with upadacitinib who achieved clinical response after the 16-week induction phase maintained their response to treatment after the 36-week extension phase; results seen for the higher doses (6 mg and 12 mg twice-daily) were numerically greater compared to 3 mg twice-daily at 52 weeks.¹ The CELEST study evaluated upadacitinib, an investigational oral JAK1-selective inhibitor, in adult patients with moderately to severely active Crohn's disease and inadequate response/intolerance to an immunomodulator or tumor necrosis factor alpha antagonist (TNF-a).

These data are being presented at the 13^th Congress of the European Crohn's and Colitis Organisation (ECCO) in Vienna, Austria, as part of the Clinical: Diagnosis & Outcome Poster Session (Poster #P273). Two additional sub-analyses of the 16-week CELEST induction data – one evaluating the onset of clinical remission and response, and one evaluating the potential to achieve steroid-free endoscopic/clinical remission/response – were also presented at ECCO.^2,3 Upadacitinib is an investigational medicine and is not approved by regulatory authorities. Safety and efficacy have not been established. Phase 3 trials for upadacitinib in Crohn's disease are ongoing.^4-6

"We are encouraged by these results showing upadacitinib's potential as an oral treatment for patients with moderately to severely active Crohn's disease," said Marek Honczarenko, vice president, immunology development, AbbVie. "We will continue to develop therapies that extend beyond symptoms and include endoscopic outcomes with a long-term aim to limit disease progression."

CELEST is a 52-week, Phase 2, randomized, double-blind study consisting of a 16-week dose-ranging induction and 36-week extension phase. Patients who responded to treatment in the 16-week induction phase entered the extension phase of the study, which evaluated multiple dosing regimens of upadacitinib through week 52.¹ Results from the 16-week induction phase were previously announced and presented at Digestive Disease Week® in May 2017.¹³

Results show that among patients who responded to upadacitinib induction treatment at week 16, numerically higher rates of clinical remission and endoscopic response^Δ were achieved by patients receiving 12 mg of upadacitinib twice-daily in the extension phase compared with the other treatment doses at 52 weeks.¹ Additionally, dose-related increases in rates of modified clinical remission were observed with the 3, 6 and 12 mg twice-daily doses at week 52.¹ 

In this study, the overall safety profile of upadacitinib was consistent with the safety profile of upadacitinib observed in other studies, with no new safety signals detected. No dose-dependent effect was observed for adverse events (AEs), serious AEs, and infections. Two malignancies occurred in the 12 mg twice-daily arm (Hodgkin's disease and malignant neoplasm of thymus).¹ No deaths occurred in this study.¹

Onset of Clinical Improvements with Upadacitinib during the Induction Period of CELEST
In addition to the data shown above, an oral presentation at ECCO (#OP022) of a sub-analysis of the 16-week CELEST data evaluated the onset of achieving clinical outcomes in patients with moderately to severely active Crohn's disease treated with upadacitinib. A significantly greater percentage of patients in the upadacitinib 6, 12, and 24 mg twice-daily groups achieved modified clinical remission as early as week 4 compared with placebo (p ≤0.05 for each). Over time, this clinical measure was sustained in patients receiving the upadacitinib 24 mg twice-daily induction dose for up to 16 weeks.² 

Steroid-free Clinical and Endoscopic Endpoints using Upadacitinib in the Induction Period of CELEST
An additional poster presentation at ECCO (#P601) of a separate sub-analysis of the 16-week induction CELEST data evaluated the potential for steroid-free clinical outcomes in patients with moderately to severely active Crohn's disease treated with upadacitinib. Results showed that a significantly greater percentage of patients receiving upadacitinib 24 mg twice-daily were able to discontinue taking corticosteroids and achieve clinical endpoints (modified clinical remission, clinical remission and Crohn's Disease Activity Index [CDAI] <150) at 16 weeks compared with placebo (p ≤0.05 for each). In addition, a numerically higher percentage of patients taking upadacitinib doses of 6 mg twice-daily or higher were able to discontinue corticosteroids and achieve endoscopic response at 16 weeks compared with placebo.³

About the CELEST Study
CELEST is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of multiple dosing regimens of upadacitinib in adult patients with moderately to severely active Crohn's disease with a history of inadequate response to or intolerance to immunomodulators or TNF inhibitors.¹ Patients had a CDAI score between 220-450, an average daily liquid/soft stool frequency (SF) ≥2.5 or daily abdominal pain (AP) score ≥2.0, and Simplified Endoscopic Score for Crohn's Disease (SES-CD) ≥6 or ≥4 for those with isolated ileal disease. Of the 220 enrolled patients, 96 percent had failed or were intolerant to one or more TNF inhibitors.¹³ Patients were randomized to double-blind induction therapy with placebo or immediate release formulation of upadacitinib at 3, 6, 12, 24 mg twice-daily or 24 mg once-daily for 16 weeks, followed by blinded extension therapy for 36 weeks. All patients who completed the 16-week induction phase were re-randomized 1:1:1 to receive double-blind upadacitinib at 3 mg twice-daily, 12 mg twice-daily or 24 mg once-daily for 36 weeks, with a total study duration of 52 weeks. The 24 mg once-daily arm was later stopped and a 6 mg twice-daily arm was initiated. Among 180 patients re-randomized in the extension phase, 153 patients had received induction therapy with upadacitinib.¹ The co-primary endpoints were the proportion of patients who achieved clinical remission (SF ≤1.5 and AP ≤1, and both not worse than baseline) at week 16 and endoscopic remission (SES-CD ≤4 and ≥2 point reduction from baseline, no subscore >1) at week 12 or 16 within the induction phase.¹³ Endpoints (all secondary) analyzed at week 52 included clinical remission (average daily SF ≤1.5 and average daily AP score ≤1.0 and both not worse than baseline), modified clinical remission (average daily SF ≤2.8 and average daily AP score ≤1.0, and both not worse than baseline), CDAI <150, enhanced clinical response (average daily SF ≥60% reduction from induction baseline and average daily AP not worse than baseline or average daily AP ≥35% reduction from induction baseline and average daily SF not worse than baseline, or modified clinical remission), clinical response (≥30% reduction from induction baseline in average daily SF or AP and both not worse than baseline), endoscopic remission (SES-CD ≤4 and at least 2-point reduction versus baseline and no subscore >1 in any individual variable), endoscopic response (>50% reduction in SES-CD from baseline, or endoscopic remission) and mean change from baseline in high sensitivity C-reactive protein (hs-CRP) and faecal calprotectin. More information can be found on clinicaltrials.gov (NCT02365649).¹

About Upadacitinib
Discovered and developed by AbbVie, upadacitinib is an investigational oral agent engineered to selectively inhibit JAK1, which plays an important role in the pathophysiology of immune-mediated disorders.^14,15 Phase 3 trials of upadacitinib in rheumatoid arthritis, psoriatic arthritis and Crohn's disease are ongoing and it is also being investigated to treat ulcerative colitis, ankylosing spondylitis, atopic dermatitis and giant cell arteritis.^4-12

Upadacitinib is an investigational medicine and is not approved by regulatory authorities. Safety and efficacy have not been established.

About AbbVie
AbbVie is a global, research and development-based biopharmaceutical company committed to developing innovative advanced therapies for some of the world's most complex and critical conditions. The company's mission is to use its expertise, dedicated people and unique approach to innovation to markedly improve treatments across four primary therapeutic areas: immunology, oncology, virology and neuroscience. In more than 75 countries, AbbVie employees are working every day to advance health solutions for people around the world. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook or LinkedIn.

Forward-Looking Statements 
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.

Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2016 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

¹ Panes J, et al. Efficacy and Safety of Upadacitinib Maintenance Treatment for Moderate to Severe Crohn's Disease: Results From the CELEST Study. 13^th Congress of the European Crohn's and Colitis Organisation. February 2018.
² Schreiber S, et al. Rapidity of clinical and laboratory improvements following upadacitinib induction treatment: data from the CELEST study. 13^th Congress of the European Crohn's and Colitis Organisation. February 2018.
³ Panaccione R, et al. Upadacitinib improves steroid-free clinical and endoscopic endpoints in patients with Crohn's disease: data from the CELEST study. 13^th Congress of the European Crohn's and Colitis Organisation, February 2018.
⁴ A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study of the Efficacy and Safety of Upadacitinib (ABT-494) in Subjects With Moderately to Severely Active Crohn's Disease Who Have Inadequately Responded to or Are Intolerant to Conventional Therapies But Have Not Failed Biologic Therapy. ClinicalTrials.gov. 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT03345849?term=upadacitinib&cond=Crohn+Disease&phase=2&rank=2. Accessed on February 12, 2018.
⁵ A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study of the Efficacy and Safety of Upadacitinib (ABT-494) in Subjects With Moderately to Severely Active Crohn's Disease Who Have Inadequately Responded to or Are Intolerant to Biologic Therapy. ClinicalTrials.gov. 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT03345836?term=upadacitinib&cond=Crohn+Disease&phase=2&rank=1. Accessed on February 12, 2018.
⁶ A Maintenance and Long-Term Extension Study of the Efficacy and Safety of Upadacitinib (ABT-494) in Subjects With Crohn's Disease Who Completed the Studies M14-431 or M14-433. Full Text View - ClinicalTrials.gov. Clinicaltrialsgov. 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT03345823. Accessed on February 12, 2018.
⁷ A Study Comparing Upadacitinib (ABT-494) to Placebo and to Adalimumab in Participants With Psoriatic Arthritis Who Have an Inadequate Response to at Least One Non-Biologic Disease Modifying Anti-Rheumatic Drug (SELECT - PsA 1). ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT03104400. Accessed on February 2, 2018.
⁸ A Study Evaluating the Safety and Efficacy of Upadacitinib in Subjects With Active Ankylosing Spondylitis (SELECT Axis 1). Available at: https://clinicaltrials.gov/ct2/show/study/NCT03178487. Accessed on February 2, 2018.
⁹ A Study Comparing ABT-494 to Placebo in Subjects With Rheumatoid Arthritis on a Stable Dose of Conventional Synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) Who Have an Inadequate Response to csDMARDs Alone (SELECT-NEXT). ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT02675426. Accessed on February 2, 2018.
¹⁰ A Phase 2b Multicenter, Randomized, Placebo-Controlled, Double-Blind Dose-Ranging Study to Evaluate ABT-494 (Upadacitinib) in Adult Subjects With Moderate to Severe Atopic Dermatitis. ClinicalTrials.gov. Clinicaltrialsgov. Available at: https://clinicaltrials.gov/ct2/show/NCT02925117. Accessed on February 2, 2018.
¹¹ A Study to Evaluate the Safety and Efficacy of ABT-494 for Induction and Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT02819635. Accessed on February 2, 2018.
¹² AbbVie's (ABBV) CEO Richard Gonzalez on Q4 2017 Results - Earnings Call Transcript. Available at: https://seekingalpha.com/article/4140615-abbvies-abbv-ceo-richard-gonzalez-q4-2017-results-earnings-call-transcript. Accessed on February 6, 2018.
¹³ Sandborn WJ, Feagan B, Panes J, et al. Safety and Efficacy of ABT-494, an oral JAK1 inhibitor, as induction therapy in patients with Crohn's disease: Results from CELEST. Digestive Disease Week; May 6-9, 2017; Chicago, IL. Presentation 874h.
¹⁴ Voss, J, et al; Pharmacodynamics Of a Novel JAK1 Selective Inhibitor In Rat Arthritis and Anemia Models and In Healthy Human Subjects. [abstract]. Arthritis Rheum 2013;65 Suppl 10 :2374. DOI: 10.1002/art.2013.65.issue-s10
¹⁵ Pipeline – Our Science | AbbVie. AbbVie. 2017. Available at: https://www.abbvie.com/our-science/pipeline.html. Accessed February 12, 2018.

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