Upadacitinib Monotherapy Meets All Primary and Ranked Secondary Endpoints Versus Methotrexate in a Phase 3 Study in Rheumatoid Arthritis

- In SELECT-EARLY, upadacitinib monotherapy (15/30 mg, once-daily) met both primary endpoints, with 52/56 percent of methotrexate-naïve patients achieving ACR50 at week 12 and 48/50 percent achieving clinical remission at week 24, respectively(1)

- Both doses of upadacitinib monotherapy also significantly inhibited radiographic progression at week 24 compared to methotrexate(1)

- The safety profile of upadacitinib was consistent with previously reported Phase 3 studies, with no new safety signals detected(1-8)

- SELECT-EARLY is the fifth study in the robust SELECT program, which will support regulatory submissions for upadacitinib in rheumatoid arthritis in the second half of 2018

- 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(9-16)

News provided by

AbbVie

Jun 05, 2018, 08:30 ET

NORTH CHICAGO, Ill., June 5, 2018 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced positive top-line results from SELECT-EARLY showing that both doses of upadacitinib monotherapy (15 mg and 30 mg) met the primary endpoints of ACR50^a at week 12 and clinical remission^b at week 24 versus methotrexate (MTX).¹ Additionally, all ranked secondary endpoints were met.¹ The ongoing study evaluates upadacitinib, an investigational oral JAK1-selective inhibitor, as a monotherapy treatment compared to methotrexate monotherapy in adult patients with moderate to severe rheumatoid arthritis who were methotrexate-naïve.¹ Upadacitinib is not approved by regulatory authorities and its safety and efficacy have not been established.

"SELECT-EARLY is the fifth pivotal trial that will support regulatory submissions for upadacitinib in rheumatoid arthritis later this year," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "Results from SELECT-EARLY further support our belief that upadacitinib has the potential to be an important new treatment option for patients with rheumatoid arthritis."

Rheumatoid arthritis, which affects an estimated 23.7 million people worldwide, is a chronic and debilitating disease.¹⁷ Methotrexate is commonly used as a first-line therapy in rheumatoid arthritis, but many patients do not respond to or cannot tolerate methotrexate.^18-20 Early intervention with an effective treatment is critical to control the disease and prevent permanent joint damage and impaired physical function.²¹

	SELECT-EARLY Efficacy Results^1,^†
	Week 12			Week 24
	MTX (n=314)	Upadacitinib 15 mg (n=317)	Upadacitinib 30 mg (n=314)	MTX (n=314)	Upadacitinib 15 mg (n=317)	Upadacitinib 30 mg (n=314)
ACR20^a	54%	76%	77%	59%	79%	78%
ACR50^a	28%	52%	56%	33%	60%	66%
ACR70^a	14%	32%	37%	18%	44%	50%
Clinical Remission (DAS28[CRP])^b	14%	36%	41%	18%	48%	50%
LDA (DAS28[CRP])^c	28%	53%	55%	32%	60%	65%

^†Primary endpoints included ACR50 at week 12 and clinical remission at week 24 for upadacitinib versus methotrexate (superiority). All reported endpoints achieved p-values of <0.001 versus methotrexate for both doses through week 24, except for mTSS for the 15 mg upadacitinib dose at week 24 (p<0.01). Not all ranked secondary endpoints shown.

^aACR20/50/70 is defined as at least a 20 percent/50 percent/70 percent reduction from baseline in the number of both tender and swollen joint counts and equivalent improvement in three or more of the five remaining American College of Rheumatology core set measures: patient assessments of pain, global disease activity and physical function, physician global assessment of disease activity and acute phase reactant.

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

^cLow disease activity (LDA) is defined as Disease Activity Score with 28 joint counts (C-reactive protein) (DAS28[CRP]) less than or equal to 3.2.

"It is very encouraging that approximately half of patients achieved the desired clinical target of remission in six months with upadacitinib monotherapy at either dose. Outcomes from this trial address the need for additional monotherapy options early in the disease," said Ronald van Vollenhoven, M.D. Ph.D., director of the Amsterdam Rheumatology and Immunology Center ARC and professor of rheumatology, University of Amsterdam and Free University. "Results suggest upadacitinib as a monotherapy has the potential to control rheumatoid arthritis and reduce the risk of permanent bone and joint damage for methotrexate-naïve patients."

A significantly higher proportion of upadacitinib patients in both doses achieved superior responses compared to patients on methotrexate at week 12 and 24.¹ Results at week 12 showed that of patients receiving an oral once-daily dose of upadacitinib 15/30 mg, 52/56 percent achieved ACR50, respectively, compared with 28 percent of patients receiving methotrexate.¹ At week 24, clinical remission (based on Disease Activity 28 [DAS28] C-Reactive Protein [CRP]) was achieved by 48/50 percent of patients receiving upadacitinib 15/30 mg, respectively, compared to 18 percent of patients receiving methotrexate.¹

At week 12, 76/77 percent of patients receiving 15/30 mg of upadacitinib, achieved ACR20, respectively, compared to 54 percent in the methotrexate group.¹ Additionally, ACR70 was achieved by 32/37 percent of patients receiving 15/30 mg of upadacitinib, respectively, compared to 14 percent receiving methotrexate at week 12.¹ Clinical remission was achieved by 36 percent and 41 percent of patients in the 15 mg and 30 mg groups, respectively, compared to 14 percent of patients receiving methotrexate at week 12.¹ Low disease activity (LDA)^c based on DAS28(CRP) was achieved by 53 percent and 55 percent of patients in the 15 mg and 30 mg groups, respectively, compared to 28 percent of patients receiving methotrexate at week 12.¹

At week 24, 79/60/44 percent of patients receiving the 15 mg dose of upadacitinib and 78/66/50 percent of patients receiving the 30 mg dose of upadacitinib achieved ACR20/50/70 response, compared to 59/33/18 percent of patients receiving methotrexate.¹ Low disease activity was achieved by 60 percent and 65 percent of patients in the 15 mg and 30 mg groups, respectively, compared to 32 percent of patients receiving methotrexate at week 24.¹

Following 24 weeks of treatment, both doses of upadacitinib monotherapy significantly inhibited radiographic progression as measured by the change in modified total Sharp score (mTSS) from baseline, compared to methotrexate.¹ The inhibition of joint damage is important for rheumatoid arthritis patients as this can lead to permanent loss of function and subsequent disability.²²

In this study, the safety profile of upadacitinib was consistent with previously reported results from the other SELECT trials in rheumatoid arthritis.^1-8 No new safety signals were detected.¹ Through week 24, serious adverse events occurred in 5/6 percent of patients in the 15 mg/30 mg upadacitinib groups, respectively, compared to 4 percent in the methotrexate group.¹ Serious infections occurred in 2/3 percent of patients in the 15 mg/30 mg upadacitinib groups, respectively, compared to 1 percent in the methotrexate group.¹ There were six deaths through week 24, three of which were major adverse cardiovascular events (MACE) with one in each treatment group (methotrexate, 15 mg upadacitinib and 30 mg upadacitinib, respectively).¹ There was one death in the 15 mg upadacitinib group due to metastatic malignant melanoma in a patient with a history of melanoma prior to study entry, and two deaths in the 30 mg upadacitinib group, one due to pneumonia and sepsis and another due to peritonitis.¹ There were four MACE, including the three fatal events mentioned above.¹ One additional non-fatal MACE in the 30 mg upadacitinib group was reported.¹ There were two cases of adjudicated venous thromboembolic events (VTE) in the study, one pulmonary embolism in the methotrexate group, one deep vein thrombosis in the 30 mg upadacitinib group and none in the 15 mg upadacitinib group.¹

To date, across the SELECT rheumatoid arthritis program (with more than 3,300 patient years of exposure to upadacitinib) the rates of VTEs in both the placebo-controlled and extension periods remain consistent with the background rate in the rheumatoid arthritis patient population.^1-5,23-25

Exposure-adjusted Incidence Rate of VTEs from SELECT-NEXT, SELECT-BEYOND, SELECT-MONOTHERAPY, SELECT-COMPARE and SELECT-EARLY²⁶ Number of patients with events/100 patient years exposure
Controlled Period	Any Adjudicated VTE – Controlled Period
	Placebo (PBO)/MTX	Adalimumab 40 mg EOW	Upadacitinib 15 mg	Upadacitinib 30 mg	Upadacitinib Total
	0.5	3.5	0.6	0.4	0.5
Long-term Period	Any Adjudicated VTE – Long-term Period
	PBO	Adalimumab 40 mg EOW	Upadacitinib 15 mg	Upadacitinib 30 mg	Upadacitinib Total
	N/A	1.2	0.5	0.3	0.4

Further results from SELECT-EARLY 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-EARLY¹

SELECT-EARLY is a Phase 3, multicenter, randomized, double-blind, parallel-group, active comparator controlled study designed to evaluate the safety and efficacy of upadacitinib monotherapy compared to methotrexate monotherapy in adult patients with moderate to severe rheumatoid arthritis who are methotrexate-naïve. In the first phase of the study, patients were randomized 1:1:1 to receive upadacitinib (15 mg or 30 mg, once-daily) or methotrexate. It includes a Japan sub-study in which subjects were randomized 2:1:1:1 to receive upadacitinib 7.5 mg, 15 mg, 30 mg once-daily or methotrexate. The primary endpoints of the study included the percentage of patients achieving ACR50 after 12 weeks of treatment and clinical remission (based on DAS28[CRP]) after 24 weeks of treatment compared to methotrexate. Key secondary endpoints included the proportion of patients achieving ACR20, ACR70 and low disease activity, as well as changes in the modified total Sharp score (mTSS) and 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 period for up to an additional four years. More information on this trial can be found at www.clinicaltrials.gov (NCT02706873).

About the SELECT Study Program^1-5

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.^9.10 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 and atopic dermatitis.^11-16

Upadacitinib is an investigational oral agent 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 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.

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