Results from Upadacitinib Phase 3 SELECT-MONOTHERAPY Study Published in The Lancet

• SELECT-MONOTHERAPY evaluates the safety and efficacy of upadacitinib monotherapy in adult patients with moderately to severely active rheumatoid arthritis and inadequate response to a stable dose of methotrexate¹
• Upadacitinib (15 mg and 30 mg), once daily, achieved both primary endpoints with significantly higher rates of ACR20 response and low disease activity (defined as DAS28[CRP]≤3.2) at week 14 versus continued treatment with methotrexate¹
• Patients receiving either dose of upadacitinib monotherapy also achieved significantly higher rates of clinical remission (defined as DAS28[CRP]<2.6) at week 14 than those continuing methotrexate ¹
• The safety profile of upadacitinib was consistent with previously reported Phase 3 studies¹

Maidenhead, 28 May, 2019 — AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced the publication of positive results from the pivotal Phase 3 SELECT-MONOTHERAPY clinical trial in The Lancet. The study, in 648 patients evaluates upadacitinib as a monotherapy treatment versus continuing methotrexate in patients with moderately to severely active rheumatoid arthritisand an inadequate response to methotrexate.¹ After 14 weeks of treatment, both once-daily doses of upadacitinib (15 mg n=217 and 30 mg n=215) met the study's primary endpoints with significantly higher rates of ACR20** and low disease activity (LDA)*** versus continuing stable methotrexate therapy (n=216).¹ Both doses also achieved all key secondary endpoints, including the proportion of patients achieving remission**** and improvements in physical function (defined as change in HAQ-DI from baseline).¹ Upadacitinib, an oral investigational JAK1-selective inhibitor is not approved by regulatory authorities and its safety and efficacy have not been established.

"These results show that upadacitinib as a monotherapy can provide clinically meaningful responses, including low disease activity, remission and significant improvements in physical function,” said Josef S. Smolen, M.D., Department of Medicine, Division of Rheumatology, Medical University of Vienna, Austria, and first author on the publication. "Data from this study support the potential for upadacitinib as an important treatment option for patients with rheumatoid arthritis."

Rheumatoid arthritis, which affects an estimated 400,000 people in the UK, is a chronic and debilitating disease. ² Methotrexate is commonly used as a first-line therapy in rheumatoid arthritis, but many patients do not respond to or cannot tolerate methotrexate, which puts them at risk for disease progression.^3-5 After inadequate response to methotrexate alone, methotrexate is commonly used as a background therapy with biologic DMARDs to optimise their efficacy.^4,6

“We are encouraged by the positive results published in The Lancet," said Alice Butler, UK Medical Director, AbbVie. "Data from this study, the third of six in the SELECT clinical trial programme evaluating the potential for upadacitinib in rheumatoid arthritis, helps to deepen our understanding of JAK1-selective inhibition and the potential for monotherapy in this complex disease”

Results showed that after 14 weeks, 68 percent and 71 percent of patients who switched to upadacitinib monotherapy 15 mg and 30 mg at baseline, respectively, achieved ACR20 versus 41 percent of patients who continued to receive methotrexate therapy (p≤0.0001 for both doses). ¹ Low disease activity***was achieved by 45 percent of patients receiving upadacitinib 15 mg and 53 percent receiving upadacitinib 30 mg versus 19 percent receiving methotrexate (p<0.0001 for both doses) at week 14.¹

The study also showed a significantly higher proportion of upadacitinib patients in both dose groups achieved clinical remission****, ACR50 and ACR70 at week 14 compared to patients continuing on methotrexate. ¹ 28 and 41 percent of upadacitinib-treated patients in the 15 mg and 30 mg groups, respectively, achieved clinical remission**** compared to 8 percent of those who continued methotrexate (p≤0.0001 for both doses).¹ ACR50 and ACR70 were achieved by 42 and 23 percent, 52 and 33 percent for patients in the 15 mg and 30 mg upadacitinib groups, respectively, versus 15 and 3 percent of patients continuing on methotrexate.¹

SELECT-MONOTHERAPY Efficacy Results at Week 14*1
	Methotrexate   (n=216)	Upadacitinib 15mg (n=217)	Upadacitinib 30mg (n=215)
ACR20**	41%	68%	71%
ACR50**	15%	42%	53%
ACR70**	3%	23%	33%
LDA***	19%	45%	53%
Clinical Remission****	8%	28%	41%

*All week 14 endpoints shown in the table achieved p-values of <0.001 versus methotrexate for both doses. Not all key secondary endpoints shown. Methotrexate patients shown are patients who continued on their baseline methotrexate dose in a blinded manner.

**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.

*** LDA 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.

**** Clinical remission was based on DAS28 (CRP) less than 2.6.

In the study, the safety profile of upadacitinib was consistent with previously reported Phase 3 SELECT clinical trials. ^1,7-11 Serious adverse events occurred in 5 percent/3 percent of patients in the 15 mg/30 mg upadacitinib groups, respectively, compared to 3 percent in the methotrexate group.¹ Three major adverse cardiovascular events (MACE) occurred in patients with known cardiovascular (CV) risk factors (one in the 15 mg group and two in the 30 mg group).¹ One MACE in the 15 mg arm was a fatal hemorrhagic stroke due to a ruptured aneurysm.¹ No other deaths were reported.¹ There was one adjudicated pulmonary embolism (PE) reported in the 15 mg group in a patient with multiple known risk factors.¹ Three malignancies were reported in the study, one in the methotrexate group and two in the 15 mg group.¹ One patient in the upadacitinib 15 mg group and one in the methotrexate group experienced a serious infection.¹ Herpes zoster was reported by one (1 percent) patient in the methotrexate group, three (1 percent) in the 15 mg group, and six (3 percent) in the 30 mg group.¹

About SELECT-MONOTHERAPY¹

SELECT-MONOTHERAPY is a Phase 3, multicentered, randomised, double-blind, double-dummy study designed to evaluate the safety and efficacy of upadacitinib monotherapy in adult patients with moderately to severely active rheumatoid arthritis and an inadequate response to a stable dose of methotrexate. Patients were randomised to switch from methotrexate to upadacitinib monotherapy (15 mg (n=217) or 30 mg (n=215)) once-daily or continue on their prior stable dose of methotrexate (n=216) in a blinded manner.

The two independent primary endpoints comparing upadacitinib 15 mg and 30 mg with continued methotrexate included the percentage of subjects achieving an ACR20 response and low disease activity (LDA)*** after 14 weeks of treatment. Key secondary endpoints included the proportion of patients achieving ACR50, ACR70 and clinical remission**** at week 14. The trial is ongoing and the second phase is a blinded long-term extension period, of up to five years, to evaluate the long-term safety, tolerability, and efficacy of the two once-daily doses (15 mg and 30 mg) of upadacitinib monotherapy in patients who have completed the first phase. More information on this trial can be found at www.clinicaltrials.gov (NCT02706951).

About the SELECT Study Programme^1,7-11


The robust SELECT Phase 3 rheumatoid arthritis programme evaluates more than 4,900 patients with moderately to severely active rheumatoid arthritis in six studies. The studies include assessments of efficacy, safety and tolerability across a broad range of rheumatoid arthritis patients. 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, small molecule JAK1-selective inhibitor being studied for moderately to severely active rheumatoid arthritis and other immune-mediated diseases. ^12,13 Upadacitinib is not approved and its safety and efficacy have not been evaluated by regulatory authorities.

-ENDS-

UK Media:

Natalie Bennett

AbbVie

T: 07818 428074
E: natalie.bennett@abbvie.com

References  

1. Smolen, J.S., et al. A Phase 3 Randomised, Placebo-controlled, Double-Blind Study of Upadacitinib as Monotherapy in Patients with Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: SELECT-MONOTHERAPY. The Lancet. 2019.
2. NICE. Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed (TA375). January 2016.
3. Shinde, CG, et al. Methotrexate: a gold standard for treatment of rheumatoid arthritis.J Pain Palliat Care Pharmacother. 2014 Dec;28(4):351-8. doi: 10.3109/15360288.2014.959238. Epub 2014 Oct 16.
4. Swierkot J and Szechinski J. Methotrexate in rheumatoid arthritis. Pharmacol Rep. 20116 Jul-Aug;58(4)473-92
5. Fautrel B, Nab HW, et al. Identifying patients with rheumatoid arthritis with moderate disease activity at risk of significant radiographic progression despite methotrexate treatment. RMD Open. 2015; 1(1). DOI: 10.1136/rmdopen-2014-000018
6. Singh, JA, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care & Research. 2015 Jan;68(1):1-26. doi: 10.1002/art.39480. Epub 2015 Nov 6. https://doi.org/10.1002/acr.22783.
7. Fleischmann R, et al. A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib to Placebo and to Adalimumab, in Patients with Active Rheumatoid Arthritis with Inadequate Response to Methotrexate. 2018 ACR/ARHP Annual Meeting; 890
8. Burmester GR, et al; Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018 Jun 23;391(10139):2503-2512. doi: 10.1016/S0140-6736(18)31115-2. Epub 2018 Jun 18.
9. Genovese MC, et al; Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3. Lancet. 2018 Jun 23;391(10139):2503-2512. doi: 10.1016/S0140-6736(18)31115-2. Epub 2018 Jun 18.
10. van Vollenhoven, et al. A Phase 3, Randomized, Controlled Trial Comparing Upadacitinib Monotherapy to MTX Monotherapy in MTX-Naïve Patients with Active Rheumatoid Arthritis. 2018 ACR/ARHP Annual Meeting; 891
11. A Phase 3 Study to Compare ABT-494 to Abatacept in Subjects With Rheumatoid Arthritis on Stable Dose of Conventional Synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) Who Have an Inadequate Response or Intolerance to Biologic DMARDs (SELECT-CHOICE). Clinicaltrials.gov. 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT03086343. Accessed on March 4, 2019.
12. Parmentier et al. In Vitro and In Vivo Characterization of the JAK1 Selectivity of Upadacitinib (ABT-494). BMC Rheumatology.2018 2:23; https://doi.org/10.1186/s41927-018-0031-x
13. Pipeline – Our Science | AbbVie. AbbVie. 2018. Available at: https://www.abbvie.com/our-science/pipeline.html. Accessed on February 22, 2019.

May 2019

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