Phase 2 Study of Upadacitinib (RINVOQ®) Alone or as a Combination Therapy Meets Primary and Key Secondary Endpoints in Patients with Systemic Lupus Erythematosus

–  At week 24, upadacitinib 30 mg given alone or as a combination therapy (ABBV-599 high dose [elsubrutinib 60 mg and upadacitinib 30 mg]) met the primary endpoint of systemic lupus erythematosus (SLE) Responder Index (SRI-4) and steroid dose less than or equal to 10 mg prednisone equivalent once per day in patients with moderately to severely active SLE receiving standard lupus therapies¹
–  Upadacitinib maintained greater improvements in SLE disease activity at week 48 as measured by the British Isles Lupus Assessment Group-Based Composite Lupus Assessment (BICLA), SRI-4, Lupus Low Disease Activity State (LLDAS) and lupus flares compared with placebo²
–  No new safety signals were observed beyond the known safety profile for upadacitinib. Types of adverse events reported with ABBV-599 high dose were similar to those reported for patients treated with upadacitinib alone²
–  Study results are being presented as an oral presentation at the European Congress of Rheumatology, EULAR 2023

NORTH CHICAGO, Ill., May 31, 2023 /PRNewswire/ — AbbVie (NYSE: ABBV) today announced the results of the Phase 2 SLEek study evaluating upadacitinib (RINVOQ^® 30 mg) alone and in combination [ABBV-599 high dose (elsubrutinib 60 mg and upadacitinib 30 mg)] in adults with moderately to severely active systemic lupus erythematosus (SLE) who continued to receive standard lupus therapies. The study results are being presented as an oral presentation during the European Congress of Rheumatology, EULAR 2023.

In the Phase 2 SLEek study, a greater proportion of patients receiving upadacitinib 30 mg or ABBV-599 high dose achieved the primary endpoint, SLE Responder Index (SRI-4) and steroid dose less than or equal to 10 mg prednisone equivalent once per day at week 24, compared to placebo (54.8 percent; p=0.028 and 48.5 percent; p=0.081* versus 37.3 percent, respectively).¹ SRI-4 and steroid dose less than or equal to 10 mg prednisone equivalent per day assess reductions in disease activity and glucocorticoid use, respectively.³

“There are limited treatment options for people living with SLE, leaving physicians challenged on how to effectively slow disease progression and limit potential organ damage in their patients,” said Roopal Thakkar, M.D., senior vice president, development and regulatory affairs and chief medical officer, AbbVie. “As a leader in immunology, AbbVie is committed to advancing care in areas of unmet need, such as SLE. We are encouraged by these positive Phase 2 data and look forward to continuing to study upadacitinib for systemic lupus erythematosus in two Phase 3 trials as part of our ongoing clinical program.”

Key secondary endpoints were also achieved at week 48 in both active treatment groups, including lupus flares measured by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Flare Index (SFI) and time to first flare, which showed greater treatment effect in the upadacitinib 30 mg and ABBV-599 high dose groups compared to placebo.² Other measures of disease activity and treatment response were also met, including achievement of BICLA response, SRI-4, and Lupus Low Disease Activity State (LLDAS) in the upadacitinib 30 mg and ABBV-599 high dose groups compared to placebo.²

SLE—the most common type of lupus—is an autoimmune disease where the immune system attacks its own tissues, causing widespread inflammation and tissue damage in the affected organs.⁴ It can impact the joints, skin, brain, lungs, kidneys and blood vessels, causing a variety of symptoms, including fatigue, skin rashes, fevers, and pain and swelling in the joints.⁴ Disease activity in lupus—often called flares—is unpredictable.⁵ Flares can appear without warning, come and go and vary in severity—serious flares can cause organ damage and require medical attention.⁶

“Lupus is an imbalance in the immune system caused by a diverse set of inherited and environmental factors. It impacts over three million people around the world and causes an overlapping spectrum of symptoms,” said Joan Merrill, M.D., Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology Research Program. “To achieve sustainable progress with SLE, we need more treatment options for patients with this disease.”

No new safety signals were observed beyond the known safety profile for upadacitinib.² Types of adverse events reported with ABBV-599 high dose were similar to those reported for patients treated with upadacitinib alone.² The rate of treatment emergent adverse events (TEAEs) in this study were similar across groups (ABBV-599 at 86.8 percent, upadacitinib at 82.3 percent and placebo at 78.7 percent).² Serious AEs were reported in 10.3 percent of patients in the ABBV-599 high dose, 21.0 percent in upadacitinib 30 mg, and 17.3 percent in placebo groups.² Adjudicated cardiovascular events were reported in one patient in each of the three treatment groups.² There were no reports of malignancies or venous thromboembolic events.² The use of upadacitinib and elsubrutinib in SLE are not approved and their safety and efficacy have not been evaluated by regulatory authorities.

About the SLEek Phase 2 Study
In the SLEek Phase 2 study, 341 patients undergoing standard lupus therapy were randomized to receive once daily ABBV-599 high dose, ABBV-599 low dose (elsubrutinib 60 mg plus upadacitinib 15 mg), elsubrutinib 60 mg, upadacitinib 30 mg or placebo.² After a planned interim analysis when 50 percent of patients reached week 24 or withdrew from the study, the ABBV-599 low dose and elsubrutinib 60 mg arms were discontinued for lack of efficacy. 205 patients continued in the study to week 48 (ABBV-599 HD n = 68, upadacitinib 30 mg n = 62, placebo n = 75).²

As previously disclosed, AbbVie is advancing its clinical program of upadacitinib in SLE to Phase 3 based on these results. ABBV-599 will not move forward to Phase 3 due to no additional contribution of efficacy by elsubrutinib relative to upadacitinib alone. Additional results from the SLEek study are being presented at EULAR in posters 1133 and 1137.

About RINVOQ^® (upadacitinib) 
Discovered and developed by AbbVie scientists, RINVOQ is a selective and reversible JAK inhibitor that is being studied in several immune-mediated inflammatory diseases.^7-20 In human cellular assays, RINVOQ preferentially inhibits signaling by JAK1 or JAK1/3 with functional selectivity over cytokine receptors that signal via pairs of JAK2.⁷ The relevance of inhibition of specific JAK enzymes to therapeutic effectiveness and safety is not currently known.⁷

Upadacitinib (RINVOQ) is in Phase 3 development for giant cell arteritis, Takayasu arteritis and systemic lupus erythematosus.^14,18,20

EU Indications and Important Safety Information about RINVOQ^® (upadacitinib)⁷

Indications

Rheumatoid arthritis

RINVOQ is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs). RINVOQ may be used as monotherapy or in combination with methotrexate.

Psoriatic arthritis

RINVOQ is indicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have responded inadequately to, or who are intolerant to one or more DMARDs. RINVOQ may be used as monotherapy or in combination with methotrexate.

Axial spondyloarthritis

Non-radiographic axial spondyloarthritis (nr-axSpA)

RINVOQ is indicated for the treatment of active non-radiographic axial spondyloarthritis in adult patients with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI), who have responded inadequately to nonsteroidal anti- inflammatory drugs (NSAIDs).

Ankylosing spondylitis (AS, radiographic axial spondyloarthritis)

RINVOQ is indicated for the treatment of active ankylosing spondylitis in adult patients who have responded inadequately to conventional therapy.

Atopic dermatitis

RINVOQ is indicated for the treatment of moderate to severe atopic dermatitis (AD) in adults and adolescents 12 years and older who are candidates for systemic therapy.

Ulcerative colitis

RINVOQ is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent.

Crohn’s disease

RINVOQ is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease who have had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent.

Important Safety Information

Contraindications
RINVOQ is contraindicated in patients hypersensitive to the active substance or to any of the excipients, in patients with active tuberculosis (TB) or active serious infections, in patients with severe hepatic impairment, and during pregnancy.

Special warnings and precautions for use
RINVOQ should only be used if no suitable treatment alternatives are available in patients:
–  65 years of age and older;
–  patients with history of atherosclerotic cardiovascular (CV) disease or other CV risk factors (such as current or past long-time smokers);
– patients with malignancy risk factors (e.g. current malignancy or history of malignancy)

Use in patients 65 years of age and older
Considering the increased risk of MACE, malignancies, serious infections, and all-cause mortality in patients ≥65 years of age, as observed in a large randomised study of tofacitinib (another JAK inhibitor), RINVOQ should only be used in these patients if no suitable treatment alternatives are available. In patients ≥65 years of age, there is an increased risk of adverse reactions with RINVOQ 30 mg once daily. Consequently, the recommended dose for long-term use in this patient population is 15 mg once daily.

Immunosuppressive medicinal products
Use in combination with other potent immunosuppressants is not recommended.

Serious infections
Serious and sometimes fatal infections have been reported in patients receiving RINVOQ. The most frequent serious infections reported included pneumonia and cellulitis. Cases of bacterial meningitis and sepsis have been reported with RINVOQ. Among opportunistic infections, TB, multidermatomal herpes zoster, oral/esophageal candidiasis, and cryptococcosis have been reported. RINVOQ should not be initiated in patients with an active, serious infection, including localized infections. RINVOQ should be interrupted if a patient develops a serious or opportunistic infection until the infection is controlled. A higher rate of serious infections was observed with RINVOQ 30 mg compared to 15 mg. As there is a higher incidence of infections in the elderly and patients with diabetes in general, caution should be used when treating these populations. In patients ≥65 years of age, RINVOQ should only be used if no suitable treatment alternatives are available.

Tuberculosis
Patients should be screened for TB before starting RINVOQ. RINVOQ should not be given to patients with active TB. Anti-TB therapy may be appropriate for select patients in consultation with a physician with expertise in the treatment of TB. Patients should be monitored for the development of signs and symptoms of TB.

Viral reactivation
Viral reactivation, including cases of herpes zoster, was reported in clinical studies. The risk of herpes zoster appears to be higher in Japanese patients treated with RINVOQ. Consider interruption of RINVOQ if the patient develops herpes zoster until the episode resolves. Screening for viral hepatitis and monitoring for reactivation should occur before and during therapy. If hepatitis B virus DNA is detected, a liver specialist should be consulted.

Vaccination
The use of live, attenuated vaccines during or immediately prior to therapy is not recommended. It is recommended that patients be brought up to date with all immunizations, including prophylactic zoster vaccinations, prior to initiating RINVOQ, in agreement with current immunization guidelines.

Malignancy
Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, including RINVOQ. In a large randomised active–controlled study of tofacitinib (another JAK inhibitor) in RA patients ≥50 years of age with ≥1 additional CV risk factor, a higher rate of malignancies, particularly lung cancer, lymphoma, and non-melanoma skin cancer (NMSC), was observed with tofacitinib compared to tumour necrosis factor (TNF) inhibitors. A higher rate of malignancies, including NMSC, was observed with RINVOQ 30 mg compared to 15 mg. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. In patients ≥65 years of age, patients who are current or past long-time smokers, or patients with other malignancy risk factors (e.g., current malignancy or history of malignancy), RINVOQ should only be used if no suitable treatment alternatives are available.

Hematological abnormalities
Treatment should not be initiated, or should be temporarily interrupted, in patients with hematological abnormalities observed during routine patient management.

Gastrointestinal Perforations
Events of diverticulitis and gastrointestinal perforations have been reported in clinical trials and from post–marketing sources. RINVOQ should be used with caution in patients who may be at risk for gastrointestinal perforation (e.g., patients with diverticular disease, a history of diverticulitis, or who are taking nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, or opioids. Patients with active Crohn’s disease are at increased risk for developing intestinal perforation. Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis or gastrointestinal perforation.

Major adverse cardiovascular events
MACE were observed in clinical studies of RINVOQ. In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in RA patients ≥50 years of age with ≥1 additional CV risk factor, a higher rate of MACE, defined as CV death, non-fatal myocardial infarction and non-fatal stroke, was observed with tofacitinib compared to TNF inhibitors. Therefore, in patients ≥65 years of age, patients who are current or past long-time smokers, and patients with history of atherosclerotic CV disease or other CV risk factors, RINVOQ should only be used if no suitable treatment alternatives are available.

Lipids
RINVOQ treatment was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol.

Hepatic transaminase elevations
Treatment with RINVOQ was associated with an increased incidence of liver enzyme elevation. If alanine transaminase (ALT) or aspartate transaminase (AST) increases are observed and drug-induced liver injury is suspected, RINVOQ should be interrupted until this diagnosis is excluded.

Venous thromboembolism
Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) were observed in clinical trials for RINVOQ. In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in RA patients ≥50 years of age with ≥1 additional CV risk factor, a dose–dependent higher rate of VTE including DVT and PE was observed with tofacitinib compared to TNF inhibitors. In patients with CV or malignancy risk factors, RINVOQ should only be used if no suitable treatment alternatives are available. In patients with known VTE risk factors other than CV or malignancy risk factors (e.g. previous VTE, patients undergoing major surgery, immobilisation, use of combined hormonal contraceptives or hormone replacement therapy, and inherited coagulation disorder), RINVOQ should be used with caution. Patients should be re-evaluated periodically to assess for changes in VTE risk. Promptly evaluate patients with signs and symptoms of VTE and discontinue RINVOQ in patients with suspected VTE.

Hypersensitivity reactions
Serious hypersensitivity reactions such as anaphylaxis and angioedema have been reported in patients receiving RINVOQ. If a clinically significant hypersensitivity reaction occurs, discontinue RINVOQ and institute appropriate therapy.

Adverse reactions
The most commonly reported adverse reactions in RA, PsA, and axSpA clinical trials (≥2% of patients in at least one of the indications) with RINVOQ 15 mg were upper respiratory tract infections, blood creatine phosphokinase (CPK) increased, ALT increased, bronchitis, nausea, neutropenia, cough, AST increased, and hypercholesterolemia. Overall, the safety profile observed in patients with psoriatic arthritis or active axial spondyloarthritis treated with RINVOQ 15 mg was consistent with the safety profile observed in patients with RA.

The most commonly reported adverse reactions in AD trials (≥2% of patients) with RINVOQ 15 mg or 30 mg were upper respiratory tract infection, acne, herpes simplex, headache, blood CPK increased, cough, folliculitis, abdominal pain, nausea, neutropenia, pyrexia, and influenza. Dose dependent increased risks of infection and herpes zoster were observed with RINVOQ. The safety profile for RINVOQ 15 mg in adolescents was similar to that in adults. The safety and efficacy of the 30 mg dose in adolescents are still being investigated.

The most commonly reported adverse reactions in the UC and CD trials (≥3% of patients) with RINVOQ 45 mg, 30 mg or 15 mg were upper respiratory tract infection, pyrexia, blood CPK increased, anemia, headache, acne, herpes zoster, neutropaenia, rash, pneumonia, hypercholesterolemia, bronchitis, aspartate transaminase increased, fatigue, folliculitis, alanine transaminase increased, herpes simplex, and influenza.

The overall safety profile observed in patients with UC was generally consistent with that observed in patients with RA.

Overall, the safety profile observed in patients with CD treated with RINVOQ was consistent with the known safety profile for RINVOQ.

The most common serious adverse reactions were serious infections.

The safety profile of upadacitinib with long–term treatment was generally similar to the safety profile during the placebo–controlled period across indications.

This is not a complete summary of all safety information.

See RINVOQ full Summary of Product Characteristics (SmPC) at www.ema.europa.eu

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

About AbbVie in Rheumatology
For more than 20 years, AbbVie has been dedicated to improving care for people living with rheumatic diseases. Anchored by a longstanding commitment to discovering and delivering transformative therapies, we pursue cutting-edge science that improves our understanding of promising new pathways and targets, ultimately helping more people living with rheumatic diseases reach their treatment goals. For more information, visit AbbVie in rheumatology.

About AbbVie  
AbbVie’s mission is to discover and deliver innovative medicines that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people’s lives across several key therapeutic areas: immunology, oncology, neuroscience, eye care, virology, women’s health and gastroenterology, in addition to products and services across our Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook, LinkedIn or Instagram.

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 and uses of future or conditional verbs, 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 expressed or implied 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 2022 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission, as updated by its subsequent Quarterly Reports on Form 10-Q. AbbVie undertakes no obligation, and specifically declines, to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

References

1. Data on File. Final Lock (Week 48) Key Results ABBV-599 Study M19-130 (Phase 2) Intended Indication: Systemic Lupus Erythematosus (SLE). Accessed on April 10, 2023.
2. Merrill, J.T., et al. Efficacy and Safety of ABBV-599 High Dose (Elsubrutinib 60 mg and Upadacitinib 30 mg) and Upadacitinib Monotherapy for the Treatment of Systemic Lupus Erythematosus: A Phase 2, Double-blind, Placebo-controlled Trial. EULAR 2023 Congress; OP0139.
3. Arora, S., Isenberg, D.A. and Castrejon, I. (2020), Measures of Adult Systemic Lupus Erythematosus: Disease Activity and Damage. Arthritis Care Res, 72: 27-46. https://doi.org/10.1002/acr.24221.
4. Centers for Disease Control and Prevention. Systemic Lupus Erythematosus (SLE). Available at: https://www.cdc.gov/lupus/facts/detailed.html. Accessed April 2023.
5. Catalina MD, Owen KA, Labonte AC, et al. The pathogenesis of systemic lupus erythematosus: Harnessing big data to understand the molecular basis of lupus. J Autoimmun. 2020 Jun;110:102359. doi: 10.1016/j.jaut.2019.102359. Epub 2019 Dec 2. PMID: 31806421.
6. Centers for Disease Control and Prevention. Managing Lupus. Available at: https://www.cdc.gov/lupus/basics/managing.htm. Accessed April 2023.
7. RINVOQ [Summary of Product Characteristics]. AbbVie Deutschland GmbH & Co KG. Available at: www.ema.europa.eu
8. Danese S, Vermeire S, Zhou W, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. The Lancet. 2022;399(10341):2113-2128. doi:10.1016/S0140-6736(22)00581-5. 
9. Mease PJ, Lertratanakul A, Anderson JK, et al. Upadacitinib for psoriatic arthritis refractory to biologics: SELECT-PsA 2. Annals of the Rheumatic Diseases. 2021;80(3):312-320. doi:10.1136/annrheumdis-2020-218870.  
10. Guttman-Yassky E, Teixeira HD, Simpson EL, et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. The Lancet. 2021;397(10290):2151-2168. doi:10.1016/S0140-6736(21)00588-2.  
11. Van der Heijde D, Song IH, Pangan AL, et al. Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial. Lancet. 2019;394(10214):2108-2117. doi:10.1016/S0140-6736(19)32534-6. 
12. A Study of the Efficacy and Safety of Upadacitinib (ABT-494) in Participants with Moderately to Severely Active Ulcerative Colitis. clinicaltrials.gov; 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT03653026. Accessed August 26, 2022.
13. A Study to Evaluate the Safety and Efficacy of Upadacitinib (ABT-494) for Induction and Maintenance Therapy in Participants with Moderately to Severely Active Ulcerative Colitis (UC). clinicaltrials.gov; 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT02819635. Accessed August 26, 2022.
14. A Study to Evaluate the Efficacy and Safety of Upadacitinib in Subjects with Takayasu Arteritis (TAK) (SELECT-TAK). clinicaltrials.gov; 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04161898. Accessed August 26, 2022.
15. A Study to Evaluate Efficacy and Safety of Upadacitinib in Adult Participants with Axial Spondyloarthritis. clinicaltrials.gov; 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04169373. Accessed August 26, 2022.  
16. Burmester GR, Kremer JM, Van den Bosch F, 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;391(10139):2503-2512. doi:10.1016/S0140-6736(18)31115-2.  
17. Cohen SB, van Vollenhoven RF, Winthrop KL, et al. Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme. Ann Rheum Dis. Published online October 28, 2020:annrheumdis-2020-218510. doi:10.1136/annrheumdis-2020-218510.  
18. A Study to Evaluate the Safety and Efficacy of Upadacitinib in Participants with Giant Cell Arteritis. clinicaltrials.gov; 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT03725202. Accessed August 26, 2022.  
19. A Maintenance and Long-Term Extension Study of the Efficacy and Safety of Upadacitinib (ABT-494) in Participants with Crohn’s Disease Who Completed the Studies M14-431 or M14-433. clinicaltrials.gov; 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT03345823. Accessed August 26, 2022.
20. Program to Assess Adverse Events and Change in Disease Activity of Oral Upadacitinib in Adult Participants With Moderate to Severe Systemic Lupus Erythematosus (SELECT-SLE). Clinicaltrials.gov; 2023. Available at: https://www.clinicaltrials.gov/ct2/show/NCT05843643.  Accessed May 15, 2023.

SOURCE AbbVie