elsubrutinib/upadacitinib (ABBV-599) / AbbVie - LARVOL DELTA

Improvements in BILAG Musculoskeletal and Mucocutaneous Domains at Week 48 in a Phase 2 Double-Blind Placebo-Controlled Trial of ABBV-599 (Elsubrutinib + Upadacitinib Combination) and Upadacitinib Monotherapy for Treatment of Moderately to Severely Active Systemic Lupus Erythematosus (EULAR 2025) - P2, P3 | "Both the ABBV-599 HD and UPA 30 mg treatment groups showed improvements in the musculoskeletal and mucocutaneous BILAG domains at week 48 compared with placebo. Although this phase 2 study was not designed or powered to assess efficacy in individual organs, musculoskeletal and mucocutaneous activity has been observed in up to 80% of patients in SLE trials [1]. This analysis allows an early comparison of these frequent individual manifestations in a smaller trial and highlights the importance of examining improvement in each."

Clinical • Monotherapy • P2 data • Glomerulonephritis • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Musculoskeletal Diseases • Nephrology • Ophthalmology • Psychiatry • Systemic Lupus Erythematosus

Efficacy and Safety of ABBV-599 (Elsubrutinib and Upadacitinib Combination) and Upadacitinib Monotherapy for the Treatment of Systemic Lupus Erythematosus: Results Through 104 Weeks in a Long-Term Extension Study (EULAR 2025) - P2 | "In patients with moderately to severely active SLE, ABBV-599 HD or UPA 30 mg resulted in maintenance or further improvement in lowered disease activity, flare reduction, and decreased glucocorticoid use through 104 weeks of treatment. Patients who switched from PBO to ABBV-599 HD at week 48 improved in all measures through week 104. No new safety signals were identified."

Clinical • Monotherapy • Cardiovascular • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • Venous Thromboembolism

Improvements in Bilag Musculoskeletal and Mucocutaneous Domains at Week 48 in a Phase 2 Double-Blind Placebo-Controlled Trial of Abbv-599 (Elsubrutinib + Upadacitinib Combination) and Upadacitinib Monotherapy for Treatment of Moderately to Severely Active Systemic Lupus Erythematosus (CRA-AHPA 2025) - P2, P3 | "Both the ABBV-599 HD and UPA 30 mg treatment groups showed improvements in the musculoskeletal and mucocutaneous BILAG domains at week 48 compared with placebo. This analysis allows an early comparison of these frequent individual manifestations in a smaller trial and highlights the importance of examining improvement in each."

Clinical • Monotherapy • P2 data • Glomerulonephritis • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Musculoskeletal Diseases • Nephrology • Psychiatry • Systemic Lupus Erythematosus

Elsubrutinib, upadacitinib combination lowers lupus activity through 104 weeks (Healio) - P2 | N=185 | NCT04451772 | Sponsor: AbbVie | "According to the researchers, the proportions of patients who achieved SRI-4 continued increasing through week 104, rising to 85.4% (95% CI, 74.5-96.2) among patients on ABBV-599, 82.1% (95% CI, 70-94.1) in patients using upadacitinib 30 mg, and 61.3% (95% CI, 44.1-78.4) among those switched from placebo....Response rates were 78% (95% CI, 65.4-90.7) for ABBV-599, 69.2% (95% CI, 54.7-83.7) for upadacitinib 30 mg, and 54.8% (95% CI, 37.3-72.8) for the placebo switch group....There were treatment-emergent adverse events among 75.6% of patients on ABBV-599, in 66% of those using upadacitinib 30 mg, and in 85.7% of those switched from placebo, according to the researchers."

P2 data • Systemic Lupus Erythematosus

Improvements in BILAG Musculoskeletal and Mucocutaneous Domains at Week 48 in a Phase 2 Double-Blind Placebo-Controlled Trial of ABBV-599 (Elsubrutinib + Upadacitinib Combination) and Upadacitinib Monotherapy for Treatment of Moderately to Severely Active Systemic Lupus Erythematosus (ACR Convergence 2024) - P2, P3 | "Both the ABBV-599 HD and UPA 30 mg treatment groups showed improvements in the musculoskeletal and mucocutaneous BILAG domains at week 48 compared with placebo. Although this phase 2 study was not designed or powered to assess efficacy in individual organs, musculoskeletal and mucocutaneous activity has been observed in up to 80% of patients in SLE trials [1]. This analysis allows an early comparison of these frequent individual manifestations in a smaller trial and highlights the importance of examining improvement in each."

Clinical • Monotherapy • P2 data • Gastrointestinal Disorder • Glomerulonephritis • Hematological Disorders • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Musculoskeletal Diseases • Nephrology • Ophthalmology • Psychiatry • Rheumatology • Systemic Lupus Erythematosus

Efficacy and Safety of ABBV-599 (Elsubrutinib and Upadacitinib Combination) and Upadacitinib Monotherapy for the Treatment of Systemic Lupus Erythematosus: Results Through 104 Weeks in a Long-Term Extension Study (ACR Convergence 2024) - P2 | "In patients with moderately to severely active SLE, ABBV-599 HD or UPA 30 mg resulted in maintenance or further improvement in lowered disease activity, flare reduction, and decreased glucocorticoid use through 104 weeks of treatment. Patients who switched from PBO to ABBV-599 HD at week 48 improved in all measures through week 104. No new safety signals were identified."

Clinical • Monotherapy • Cardiovascular • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • Venous Thromboembolism

Lupus Research Alliance Announces Lupus Research Highlights at ACR Convergence 2024 (PRNewswire) - "The Lupus Research Alliance (LRA), the largest private funder of lupus research worldwide, today announced that a total of 33 studies, funded by the organization or supported by its clinical research affiliate Lupus Therapeutics, will be presented at ACR Convergence 2024. The annual meeting of the American College of Rheumatology takes place November 14-19, at the Walter E. Washington Convention Center in Washington, D.C."

Clinical data • Lupus • Lupus Nephritis • Systemic Lupus Erythematosus

Efficacy and Safety of Upadacitinib or Elsubrutinib Alone or in Combination for Systemic Lupus Erythematosus: A Phase 2 Randomized Controlled Trial. (PubMed, Arthritis Rheumatol) - P2 | "Upadacitinib 30mg alone or in combination with elsubrutinib (ABBV-599HD) demonstrated significant improvements in SLE disease activity, reduced flares and were well tolerated through 48 weeks."

Journal • P2 data • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

MODULAR GENE EXPRESSION CHANGES IN THE SLEEK PHASE 2 STUDY OF UPADACITINIB AND ABBV-599 IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS (EULAR 2024) - P2 | "Elsubrutinib inhibits Bruton's tyrosine kinase (BTK) associated with B-cell signaling. ABBV-599 increased neutrophil and other myeloid cell gene module scores compared to UPA, but this effect could have neutral impact related to its role in neutrophil extravasation. The BTK inhibitor in combination with UPA had little additional effect on B cells compared to UPA alone. In addition to the expected decreased expression of type I IFN gene modules, UPA treatment was associated with decreased basophil, cytotoxic T-cell, and cell cycle gene modules accounting for its efficacy in SLE patients with different baseline gene expression patterns."

Clinical • P2 data • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

A Study of the Safety of Oral Elsubrutinib Capsules and Oral Upadacitinib Tablets Given Alone or in Combination (ABBV-599) for Adult Participants With Moderately to Severely Active Systemic Lupus Erythematosus to Assess Change in Disease State (clinicaltrials.gov) - P2 | N=185 | Completed | Sponsor: AbbVie | Active, not recruiting ➔ Completed

Trial completion • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

Efficacy and Safety of ABBV-599 High Dose and Upadacitinib Monotherapy for Systemic Lupus Erythematosus: A Phase 2 Trial (APLAR 2023) - No abstract available

Clinical • Monotherapy • P2 data • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

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 (ACR Convergence 2023) - P2 | "Background/Purpose: ABBV-599 is a novel combination of elsubrutinib (ELS; a selective BTK inhibitor) and upadacitinib (UPA; a JAK inhibitor) that targets non-overlapping signaling pathways associated with systemic lupus erythematosus (SLE). ABBV-599HD (ELS 60 mg + UPA 30 mg) and UPA 30 mg demonstrated significant improvements in SLE disease activity and flares with acceptable safety through 48 weeks. J. Merrill: AbbVie, 2, Alexion, 2, Alumis, 2, Amgen, 2, AstraZeneca, 2, 5, Aurinia, 2, Bristol Myers Squibb, 2, 5, EMD Serono, 2, Genentech, 2, Gilead, 2, GlaxoSmithKline, 2, 5, Lilly, 2, Merck, 2, Pfizer, 2, Provention, 2, Remegen, 2, Sanofi, 2, UCB Pharma, 2, Zenas, 2; Y. Tanaka: AbbVie, 6, AstraZeneca, 6, BMS, 6, Boehringer-Ingelheim, 6, Chugai, 5, 6, Eisai, 5, 6, Eli Lilly, 6, Gilead, 6, GSK, 6, Mitsubishi-Tanabe, 5, Pfizer, 6, Taiho, 6, Taisho, 5, 6; D. D'Cruz: Eli Lilly, 2, GlaxoSmithKlein(GSK), 2, UCB, 2; K. Vila-Rivera: AbbVie/Abbott, 2; D. Siri:..."

Clinical • Monotherapy • P2 data • Cardiovascular • Immunology • Inflammatory Arthritis • Lupus • Oncology • Systemic Lupus Erythematosus • Vascular Neurology

Treatment with Upadacitinib in Patients with Systemic Lupus Erythematosus Results in the Inhibition of B-Cell–related Biomarkers: Analysis of the M19-130 (SLEek) Phase 2 Study (ACR Convergence 2023) - P2 | "A phase 2 study (NCT03978520) in SLE of upadacitinib (UPA, Janus kinase inhibitor) administered alone or in combination (ABBV-599) with elsubrutinib (a Bruton's tyrosine kinase inhibitor)...At screening, patients were stratified by immunosuppressant use (Yes/No), corticosteroid dose ( > 10-mg prednisone or not), IFN score (High/Low), and SLE Disease Activity Index 2000 score... These results suggest an association between clinical benefit seen with UPA and an impact on pathogenic B cells involved in SLE, with biomarker effects of both UPA and ABBV-599 apparently driven by UPA. These findings are consistent with our previous analysis in this population that showed treatment with UPA or ABBV-599 significantly reduced the IFN gene scores compared with PBO at weeks 4 and 24. (2) Szelinski F, et al."

Biomarker • Clinical • P2 data • Immunology • Inflammatory Arthritis • Lupus • Rheumatoid Arthritis • Rheumatology • Systemic Lupus Erythematosus • CCL21 • CCL3 • CD22 • CD79B • CXCL10 • CXCL9

Treatment of Systemic Lupus Erythematosus Patients With Upadacitinib Results in the Coordinated Inhibition of Type 1 IFN-related Biomarkers: Biomarker Analysis of the M19-130 (SLEek) Phase 2 Study (EULAR 2023) - "In a phase 2 study of SLE patients, upadacitinib (UPA, Janus kinase inhibitor) given alone or in combination with elsubrutinib (ABBV-599, Bruton’s tyrosine kinase inhibitor) resulted in significant improvement in disease activity as measured by British Isles Lupus Assessment Group-Based Combined Lupus Assessment (BICLA) and SLE Responder Index-4 (SRI-4) at weeks 24 and 48...At screening, patients were stratified by their SLE Disease Activity Index 2000 (SLEDAI-2K) score, corticosteroid dose (> 10-mg prednisone or not), immunosuppressant and IFN score...Conclusion These results suggest that the clinical benefit demonstrated by UPA in patients with SLE includes the modulation of Type I IFN with impact on several core pathogenic pathways involved in SLE. The main biomarker effects of UPA and ABBV-599 were driven by UPA."

Biomarker • Clinical • P2 data • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • CXCL10 • IFNG • IGF2BP1

Pharmacokinetics and Exposure-Response Relationships of Upadacitinib or Elsubrutinib Alone or in Combination (ABBV-599) in Systemic Lupus Erythematous (EULAR 2023) - "Conclusion Population pharmacokinetic and exposure-response analyses demonstrated that plasma exposures associated with UPA 30 mg QD were efficacious in subjects with SLE, while maintaining an acceptable safety profile. Addition of ELS, as part of ABBV-599, was not estimated to provide any additional efficacy benefit over UPA alone."

PK/PD data • Hematological Disorders • Herpes Zoster • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Neutropenia • Systemic Lupus Erythematosus • Varicella Zoster

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) - P2 | "+ P <.1; * P <.05; ** P <.01, *** P <.001 vs PBO. ABBV-599HD, elsubrutinib 60 mg QD and UPA 30 mg QD; CLASI-50, ≥ 50% reduction in CLASI activity score; Joint-Count 50, ≥ 50% improvement in tender or swollen lupus joints; LLDAS, Lupus Low Disease Activity State; NE, not estimated; PBO, placebo; SFI, SELENA SLEDAI Flare Index; UPA, upadacitinib."

Clinical • Monotherapy • P2 data • Cardiovascular • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Novel Coronavirus Disease • Oncology • Systemic Lupus Erythematosus • Vascular Neurology

A Study of the Safety of Oral Elsubrutinib Capsules and Oral Upadacitinib Tablets Given Alone or in Combination (ABBV-599) for Adult Participants With Moderately to Severely Active Systemic Lupus Erythematosus to Assess Change in Disease State (clinicaltrials.gov) - P2 | N=260 | Active, not recruiting | Sponsor: AbbVie | Enrolling by invitation ➔ Active, not recruiting | Trial completion date: Sep 2023 ➔ Dec 2023

Enrollment closed • Trial completion date • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

A Study to Investigate the Safety and Efficacy of Elsubrutinib and Upadacitinib Given Alone or in Combination in Participants With Moderately to Severely Active Systemic Lupus Erythematosus (SLE) (clinicaltrials.gov) - P2 | N=341 | Completed | Sponsor: AbbVie | Active, not recruiting ➔ Completed

Trial completion • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

A Study to Investigate the Safety and Efficacy of Elsubrutinib and Upadacitinib Given Alone or in Combination in Participants With Moderately to Severely Active Systemic Lupus Erythematosus (SLE) (clinicaltrials.gov) - P2 | N=325 | Active, not recruiting | Sponsor: AbbVie | Trial primary completion date: Aug 2022 ➔ Jan 2022

Trial primary completion date • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

A Study in Rheumatoid Arthritis Patients Who Have Completed a Preceding Study With ABBV-105 Given Alone or in Combination With Upadacitinib (clinicaltrials.gov) - P2; N=97; Terminated; Sponsor: AbbVie; Completed ➔ Terminated; Study M16-763 was terminated early as the benefit of each treatment arm from the feeder study (Study M16-063) did not provide appreciable evidence of differentiated clinical effect to warrant further long-term continuation.

Clinical • Combination therapy • Trial termination • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CRP

A Study to Investigate the Safety and Efficacy of Elsubrutinib and Upadacitinib Given Alone or in Combination in Participants With Moderately to Severely Active Systemic Lupus Erythematosus (SLE) (clinicaltrials.gov) - P2; N=341; Active, not recruiting; Sponsor: AbbVie; Recruiting ➔ Active, not recruiting; Trial primary completion date: Dec 2021 ➔ Aug 2022

Clinical • Enrollment closed • Trial primary completion date • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

A Study of the Safety of Oral Elsubrutinib Capsules and Oral Upadacitinib Tablets Given Alone or in Combination (ABBV-599) for Adult Participants With Moderately to Severely Active Systemic Lupus Erythematosus to Assess Change in Disease State (clinicaltrials.gov) - P2; N=260; Enrolling by invitation; Sponsor: AbbVie; Recruiting ➔ Enrolling by invitation

Clinical • Enrollment status • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

A Study of the Safety of Oral Elsubrutinib Capsules and Oral Upadacitinib Tablets Given Alone or in Combination (ABBV-599) for Adult Participants With Moderately to Severely Active Systemic Lupus Erythematosus to Assess Change in Disease State (clinicaltrials.gov) - P2; N=260; Recruiting; Sponsor: AbbVie; Enrolling by invitation ➔ Recruiting; Trial completion date: May 2023 ➔ Sep 2023; Trial primary completion date: May 2023 ➔ Sep 2023

Enrollment status • Trial completion date • Trial primary completion date • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

A Study to Investigate the Safety and Efficacy of Elsubrutinib and Upadacitinib Given Alone or in Combination in Participants With Moderately to Severely Active Systemic Lupus Erythematosus (SLE) (clinicaltrials.gov) - P2; N=310; Recruiting; Sponsor: AbbVie; Trial primary completion date: Sep 2021 ➔ Dec 2021

Clinical • Trial primary completion date • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

A Study of the Safety of Oral Elsubrutinib Capsules and Oral Upadacitinib Tablets Given Alone or in Combination (ABBV-599) for Adult Participants With Moderately to Severely Active Systemic Lupus Erythematosus to Assess Change in Disease State (clinicaltrials.gov) - P2; N=300; Enrolling by invitation; Sponsor: AbbVie; Recruiting ➔ Enrolling by invitation

Clinical • Enrollment status • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus