Upadacitinib Meets All Primary and Ranked Secondary Endpoints Including Superiority Versus Adalimumab in Phase 3 Study in Rheumatoid Arthritis

- In SELECT-COMPARE, upadacitinib (15 mg, once-daily) met both primary endpoints, with 71 percent of patients achieving ACR20 and 29 percent achieving clinical remission at week 12 (1)

- All ranked secondary endpoints were also met, with significantly more patients on upadacitinib achieving low disease activity (45 percent) and ACR50 (45 percent) at week 12 compared to those treated with adalimumab (29 percent for both endpoints) (1)

- Upadacitinib significantly inhibited radiographic progression at week 26 compared to placebo (1)

- The safety profile of upadacitinib was consistent with previously reported results, with no new safety signals detected (1-6)

- Upadacitinib, an oral agent engineered by AbbVie to selectively inhibit JAK1, is being studied as a once-daily therapy in rheumatoid arthritis in the SELECT program and across multiple immune-mediated diseases (7-14)

News provided by

AbbVie

Apr 09, 2018, 08:45 ET

NORTH CHICAGO, Ill., April 9, 2018 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced positive top-line results from the Phase 3 SELECT-COMPARE clinical trial showing that after 12 weeks, upadacitinib (15 mg, once-daily) met the primary endpoints of ACR20^a and clinical remission^b versus placebo.¹ All ranked secondary endpoints were also achieved versus either placebo or adalimumab (40 mg every other week).¹ The ongoing study evaluates upadacitinib, an investigational oral JAK1-selective inhibitor, in patients with moderate to severe rheumatoid arthritis who are on a stable background of methotrexate and had an inadequate response.¹Upadacitinib is not approved by regulatory authorities and its safety and efficacy have not been established.

"These results show a significant impact on both signs and symptoms and radiographic progression compared to placebo, as well as improvements in important measures such as ACR response and low disease activity compared to adalimumab," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "We are excited by these strong results which add to the body of evidence that support the potential of upadacitinib to be an important treatment option for patients with rheumatoid arthritis."

Rheumatoid arthritis, which affects an estimated 23.7 million people worldwide, is a chronic and debilitating disease.¹⁵ Despite the range of available treatments, many patients with rheumatoid arthritis still do not achieve clinical remission or low disease activity targets.^16-18

The study showed that at week 12, 71 percent of patients receiving an oral once-daily dose of upadacitinib 15 mg achieved an ACR20 response, compared with 36 percent of patients receiving placebo.¹ A significantly higher proportion of patients receiving upadacitinib achieved clinical remission (based on Disease Activity 28 [DAS28] C-Reactive Protein [CRP]) compared with placebo at week 12 (29 percent versus 6 percent, respectively).¹ Patients receiving upadacitinib achieved ACR50/70 responses of 45/25 percent compared to 15/5 percent of patients receiving placebo at week 12.¹Additionally low disease activity (LDA) based on DAS28(CRP) was seen in 45 percent of patients receiving upadacitinib compared to 29 percent receiving adalimumab and 14 percent receiving placebo at week 12, respectively.¹

SELECT-COMPARE Efficacy Results at Week 12^†
	Upadacitinib 15 mg (n=651)	Adalimumab 40 mg EOW (n=327)	Placebo (n=651)
ACR20^a	71%^***#	63%	36%
ACR50^a	45%^***###	29%	15%
ACR70^a	25%^***###	13%	5%
Clinical Remission (DAS 28-CRP)^b	29%^***###	18%	6%
Low Disease Activity (DAS28-CRP)^c	45%^***###	29%	14%

^†Primary endpoints included ACR20 and clinical remission based on DAS28(CRP) for upadacitinib versus placebo (superiority). Ranked secondary endpoints included ACR 50 versus adalimumab (both non-inferiority and superiority) and LDA versus adalimumab (non-inferiority) and versus placebo (superiority). All other comparisons were not adjusted for multiplicity. Not all ranked secondary endpoints shown.

^a ACR20/50/70 is defined as American College of Rheumatology 20 percent/50 percent/70 percent improvements in both tender and swollen joint counts, plus 3 of the following: patient assessments of pain, global disease activity and physical function, physician global assessment of disease activity and acute phase reactant (high sensitivity c-reactive protein).

^bClinical remission was based on Disease Activity Score with 28 joint counts (C-reactive protein) (DAS28 [CRP]) less than 2.6.

^cLDA was defined by a clinical response Disease Activity Score with 28 joint counts (C-reactive protein) (DAS28 [CRP]) less than or equal to 3.2.

^***Denotes statistical significance at the 0.001 level for comparison versus placebo.

^#Denotes statistical significance at the 0.05 level for comparison versus adalimumab.

^###Denotes statistical significance at the 0.001 level for comparison versus adalimumab.

Study findings also showed superiority of upadacitinib over adalimumab, on ranked secondary endpoints that compared both groups.¹At week 12, 45 percent of upadacitinib patients achieved ACR50 compared with 29 percent of adalimumab patients.¹ Additionally, upadacitinib was superior to adalimumab in reduction of pain as measured by the Patient's Assessment of Pain (based on the Visual Analog Scale [VAS]), and improvements in physical function, as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI), at week 12.¹

Following 26 weeks of treatment, upadacitinib (n=593) significantly inhibited radiographic progression as measured by the change in modified total Sharp score (mTSS) from baseline, compared to placebo (n=599) (0.24 versus 0.92, p<0.001).¹ The inhibition of joint damage is important for rheumatoid arthritis patients as this can lead to permanent loss of function and subsequent disability.¹⁹

In this study, the safety profile of upadacitinib was consistent with previously reported results.^1-6 No new safety signals were detected.¹ Through Week 26, serious adverse events occurred while on the original randomized treatment assignment in 3.7 percent of patients receiving upadacitinib, 4.3 percent of patients receiving adalimumab and 2.9 percent of patients on placebo.¹ Serious infections occurred in 1.8/1.5/0.8 percent of patients on upadacitinib/adalimumab/placebo groups, respectively. There were no deaths in the upadacitinib group, two deaths in the adalimumab group (0.6 percent) and two deaths in the placebo group (0.3 percent) through week 26.¹ No adjudicated major adverse cardiovascular events (MACE) were reported in the upadacitinib group through week 26.¹ There were two patients with MACE in the adalimumab group (0.6 percent) and three in the placebo group (0.5 percent) through week 26.¹ In terms of adjudicated venous thromboembolic events (VTE) through Week 26, one patient had a deep vein thrombosis (DVT; 0.15 percent) and another had a pulmonary embolism (PE; 0.15 percent) in the upadacitinib group, three patients had a PE in the adalimumab group (0.92 percent) and one had a PE in the placebo group (0.15 percent).¹Across the SELECT rheumatoid arthritis program, including both the placebo-controlled and extension periods, the rate of DVT and PE remains consistent with the background rate for the rheumatoid arthritis patient population.^1-4,20-22

Additional results of SELECT-COMPARE, the fourth of six Phase 3 studies in the SELECT rheumatoid arthritis clinical trial program, will be presented at a future medical meeting and published in a peer-reviewed publication. AbbVie plans global regulatory submissions for upadacitinib in rheumatoid arthritis in the second half of 2018.

About SELECT-COMPARE¹SELECT-COMPARE is a Phase 3, multicenter, randomized, double-blind, study designed to evaluate the safety and efficacy of upadacitinib compared to placebo and adalimumab in adult patients with moderate to severe rheumatoid arthritis who are on a stable background of methotrexate and who have an inadequate response. Patients received background methotrexate and were randomized 2:2:1 to receive upadacitinib (15 mg once-daily), placebo or adalimumab (given as a subcutaneous injection of 40 mg every other week). The primary endpoints of the first phase included the percentage of subjects achieving ACR20 and clinical remission (based on DAS28[CRP]) after 12 weeks of treatment compared to placebo. Ranked secondary endpoints included change in the modified total Sharp score (mTSS) compared to placebo and a comparison versus adalimumab in percentage of subjects achieving ACR50, low disease activity (LDA), changes in pain as measured by the Patient's Assessment of Pain (based on VAS) and changes in physical function, as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI). The trial is ongoing and includes a 48 week randomized, double-blind treatment period followed by a long-term extension study of up to five years. More information on this trial can be found at www.clinicaltrials.gov (NCT02629159).

About the SELECT Study Program
The robust SELECT Phase 3 rheumatoid arthritis program evaluates more than 4,000 patients with moderate to severe rheumatoid arthritis in six studies. The studies include assessments of efficacy, safety and tolerability across multiple rheumatoid arthritis patient populations. Key measures of efficacy evaluated include ACR responses, Disease Activity Score (DAS28-CRP) and inhibition of radiographic progression. More information on these trials can be found at www.clinicaltrials.gov (NCT02706847, NCT03086343, NCT02629159, NCT02706873, NCT02706951, NCT02675426).

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.^7,8 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.^9-14,23

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

About HUMIRA® in the European Union²⁴HUMIRA, in combination with methotrexate, is indicated for the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to disease-modifying anti-rheumatic drugs, including methotrexate, has been inadequate.

Important EU Safety Information²⁴HUMIRA is contraindicated in patients with active tuberculosis or other severe infections such as sepsis, and opportunistic infections and in patients with moderate to severe heart failure (NYHA class III/IV). It is also contraindicated in patients hypersensitive to the active substance or to any of the excipients; serious allergic reactions including anaphylaxis have been reported. The use of HUMIRA increases the risk of developing serious infections which may, in rare cases, be life-threatening. Rare cases of lymphoma and leukemia have been reported in patients treated with HUMIRA. On rare occasions, a severe type of cancer called hepatosplenic T-cell lymphoma has been observed and often results in death. A risk for the development of malignancies in patients treated with TNF-antagonists cannot be excluded. Rare cases of pancytopenia, aplastic anaemia, demyelinating disease, lupus, lupus-related conditions and Stevens-Johnson syndrome have been reported in patients treated with HUMIRA. The most frequently reported adverse events across all indications included respiratory infections, injection site reactions, headache and musculoskeletal pain.

Globally, prescribing information varies; refer to the individual country product label for complete information.

(See SmPC for full safety details)

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 are, or may be considered, 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," of AbbVie's 2017 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 AbbVie. Data on File, ABVRRTI66053.
²AbbVie. Data on File, ABVRRTI65458.
³AbbVie. Data on File, ABVRRTI64730.
⁴ AbbVie. Data on File, ABVRRTI64466.
⁵ Kremer JM, Emery P, Camp HS, et al. A Phase 2b study of ABT-494, a selective JAK1 inhibitor, in patients with rheumatoid arthritis and an inadequate response to anti-TNF therapy. Arthritis Rheumatol 2016; (doi:10.1002/art.39801): July 7 [Epub ahead of print].
⁶Genovese MC, Smolen JS, Weinblatt ME, et al. A randomized Phase 2b study of ABT-494, a selective JAK1 inhibitor in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Rheumatol 2016;(doi: 10.1002/art.39808):July 7 [Epub ahead of print].
⁷ 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
⁸Pipeline – Our Science | AbbVie. AbbVie. 2017. Available at: https://www.abbvie.com/our-science/pipeline.html. Accessed on April 5, 2018.
⁹A Study Comparing ABT494 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. 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT02675426. Accessed on April 5, 2018.
¹⁰A 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. 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT03104400. Accessed on April 5, 2018.
¹¹ A 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. Clinicaltrialsgov. 2018. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03345836. Accessed April 5, 2018.
¹² A Study Evaluating the Safety and Efficacy of Upadacitinib in Subjects With Active Ankylosing Spondylitis (SELECT Axis 1). 2018. Available at: https://clinicaltrials.gov/ct2/show/study/NCT03178487. Accessed on April 5, 2018.
¹³A 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. 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT02819635. Accessed on April 5, 2018.
¹⁴ A Study to Evaluate ABT-494 in Adult Subjects With Moderate to Severe Atopic Dermatitis. ClinicalTrials.gov. 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT02925117. Accessed on April 5, 2018.
¹⁵ World Health Organization. The Global Burden of Disease, 2004 Update. Available at: http://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_full.pdf. Accessed on March 5, 2018.
¹⁶ Nagy G, van Vollenhoven RF. Sustained biologic-free and drug-free remission in rheumatoid arthritis, where are we now? Arthritis Res Ther 2015; 17:181.
¹⁷ Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017. pii: annrheumdis-2016-210715. [Epub ahead of print]
¹⁸ Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol 2016;68(1):1-26.
¹⁹Favalli EG., et al. Structural integrity versus radiographic progression in rheumatoid arthritis. Rheumatoid & Musculosketal Diseases. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632139/. Accessed on April 5, 2018.
²⁰ Kim SC. Risk of Venous Thromboembolism in Patients with Rheumatoid Arthritis. Arthritis Care & Research. Vol. 65, No. 10, October 2013, pp 1600–1607.
²¹ AbbVie. Data on File, ABVRRTI64959.
²² AbbVie. Data on File, ABVRRTI66056.
²³AbbVie'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 April 5, 2018.
²⁴HUMIRA [Summary of Product Characteristics]. AbbVie Ltd.; Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000481/WC500050870.pdf. Last updated March 21, 2018. Accessed April 5, 2018.