ACR Convergence 2024: Systemic Lupus Erythematosus – Treatment II: Non-cellular Lupus Therapeutics

14 Nov - 19 Nov, 24

ACR 2024

Washington, D.C, USA

14 Nov - 19 Nov, 24

ACR 2024

Washington, D.C, USA

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

Speaker: Dr. Joan Merrill – Oklahoma Medical Research Foundation

Key Highlights:

Introduction:

Dr. Merrill introduced the novel drug, ABBV-599, which is novel combination therapy comprising two distinct drugs: Elsabrutinib and Upadacitinib. Elsabrutinib is a selective Bruton's Tyrosine Kinase (BTK) inhibitor, while Upadacitinib is a Janus Kinase 1 (JAK1) inhibitor.

Dr. Merrill explained the study objective which evaluated the efficacy and safety of ABBV-599 across various dosing regimens to determine its potential benefits in patients over a period of up to 48 weeks.

Study Design and Dosing Strategies:

The Phase 2 SLEek study (NCT03978520) was divided into two phases: The Double-Blind (DB) Phase and the Open-Label Extension (OLE) Phase:

Double-Blind Phase:

Duration: Weeks 0–24.

Treatment Arms:

ABBV-599 low-dose (Elsubrutinib 60 mg + Upadacitinib 15 mg).

ABBV-599 high-dose (Elsubrutinib 60 mg + Upadacitinib 30 mg).

Elsubrutinib monotherapy (ELS 60 mg).

Upadacitinib monotherapy (UPA 30 mg).

Placebo.

At the interim analysis after week 24, the ABBV-599 low-dose and ELS monotherapy groups were discontinued due to insufficient efficacy.

Open-Label Extension Phase:

Duration: Weeks 25–48.

Treatment Arms:

ABBV-599 high-dose (elsubrutinib 60 mg + upadacitinib 30 mg), N = 68

Upadacitinib monotherapy (UPA 30 mg), N = 62

Placebo group participants were re-randomized to active treatments for this phase, N = 75

The study's primary and secondary efficacy outcomes were evaluated using several endpoints, including the SRI-4 (SLE Disease Activity Index response), BICLA, Lupus Low Disease Activity State (LLDAS), glucocorticoid dosage, and the SLE flare index.

Findings from week 48 to week 104:

Efficacy Outcomes:

SRI-4: Patients in the active arms demonstrated sustained improvements through week 104, with the combination arm showing slightly higher but non-statistically significant response rates.

BICLA: Comparable trends to SRI-4 were observed, emphasising the durability of treatment effects.

Placebo Catch-Up: Although placebo patients improved after transitioning, they did not match the outcomes of continuously treated individuals.

Patients receiving Elsubrutinib/Upadacitinib HD combination therapy of Upadacitinib 30 mg maintained response rates in SRI-4 and BICLA over time through week 104.

Those who transitioned from placebo to Elsubrutinib/Upadacitinib HD combination therapy at week 48 showed improvements in SRI-4 and BICLA response rates from week 48 to week 104.

Flare Reduction and Steroid Sparing:

Patients receiving Elsubrutinib/Upadacitinib HD combination therapy, Upadacitinib (30 mg) or placebo to Elsubrutinib/Upadacitinib HD combination therapy had improved LLDAS response rates over time through 104 weeks.

Across all 3 continued groups, patients experienced a marked reduction in concomitant glucocorticoid dose, with mean daily doses of 0.3-0.6 mg by week 104.

Patients receiving Elsubrutinib/Upadacitinib HD combination therapy or Upadacitinib (30 mg) maintained a reduction in flare rate from week 48 to week 104.

Patients who transitioned from placebo to Elsubrutinib/Upadacitinib HD combination therapy at week 48 had a reduction in flare rate from week 48 to week 104 compared with week 0 to 48.

Safety Profile: Adverse events were consistent with prior data for these drug classes:

Serious Infections: Minimal increase; some herpes zoster cases but no TB or other major infections.

Malignancy and Other Risks: There was one event of NMSC (non-melanoma skin cancer) in the Elsubrutinib/Upadacitinib HD combination therapy group which resolved with excision.

No adjudicated VTE or MACE events observed.

General Tolerability: Treatment-emergent adverse events occurred at similar rates across arms, with no deaths during the long-term extension.

The incidence of TEAEs, serious TEAEs and TEAEs leading to discontinuation of study drug were similar between Elsubrutinib/Upadacitinib HD and Upadacitinib (30 mg) monotherapy groups.

Dr Merrill concluded that, in patients with moderately to severely active lupus, Upadacitinib 30 mg, either as monotherapy or in combination with elsabrutinib 60 mg, demonstrated:

Sustained reduction in disease activity.

Fewer disease flares.

Substantial reduction in glucocorticoid dosage across all participants through week 104.

Both upadacitinib monotherapy and its combination with elsabrutinib were well-tolerated, with no new safety signals beyond those already associated with these therapies.

Safety, Biomarker Response, and Efficacy of E6742, a Dual Antagonist of Toll-like Receptor 7 and 8, in a First-in-patient, Randomized, Double-blind, Phase 1/2 Study in Systemic Lupus Erythematosus

Speaker: Dr. Yoshiya Tanaka – University of Occupational and Environmental Health, Japan

Key Highlights:

Introduction:

Systemic autoimmune diseases (SAD) are complex disorders characterized by dysregulated immune responses, where both innate and adaptive immunity play critical roles. B cells, through their production of autoantibodies, cytokines, and interactions with T cells, are central to the pathogenesis of these conditions. Recent genetic studies, such as the DIVAS genome-wide association study, have shed light on key signalling pathways and molecular targets, including type 1 interferon and Toll-like receptors (TLRs), which bridge innate and adaptive immune responses. This has paved the way for identifying promising therapeutic targets, such as TLR7 and TLR8, to manage and treat SAD effectively.

Mode of Action of E6742:

E6742 is a selective antagonist of Toll-like receptors 7 and 8 (TLR7/8), designed to modulate overactive immune responses in autoimmune diseases like systemic lupus erythematosus (SLE). By inhibiting TLR7/8 signaling in plasmacytoid dendritic cells and monocytes, E6742 reduces the production of pro-inflammatory cytokines (e.g., IL-6, IL-1β) and type I interferons (e.g., IFN-α), which are key drivers of inflammation. It also decreases B-cell activation and autoantibody production by downregulating cytokines like BAFF, bridging innate and adaptive immunity. This mechanism helps prevent excessive inflammation and reduces organ damage in tissues such as the skin, joints, and kidneys.

Study Design:

Study Type: Double-blind, placebo-controlled, multicentre trial.

Phases: Phase I/II study.

Participants: 24 patients with active systemic lupus erythematosus (SLE).

Randomization

Cohort 1: Randomized to receive either 100 mg BID of E6742 or placebo for 12 weeks.

Cohort 2: Randomized to receive either 200 mg BID of E6742 or placebo for 12 weeks.

Primary Endpoint: Evaluation of safety and durability of multiple doses of E6742 over 12 weeks.

Randomized Groups: 26 patients initially randomized (placebo, 100 mg BID, 200 mg BID).

1 patient withdrew due to lack of efficacy.

1 patient withdrew due to adverse events (one in placebo group, one in 200 mg group).

Baseline Characteristics:

Mean age: 38 years.

Majority: Female.

Mean disease duration: 7 years.

Most patients treated with hydroxychloroquine, (N=21, 80.8%) and immunosuppressants (N=12, 46.2%).

Mean prednisone dose: 5.6 mg/day.

Mean SLEDAI-2K (disease activity score): 7.7

Safety Profile:

The safety profile of E6742 was manageable, with adverse events (AEs) observed across all groups. The placebo group reported 637 AEs, while the 100 mg BID group had 511. Grade 2 AEs were noted in both the placebo and 100 mg BID arms, with limited data on the 200 mg BID group showing no significant differences. One serious adverse event (pneumonia) occurred in the 200 mg BID group, leading to drug discontinuation for the affected patient. Overall, the incidence of AEs was low, with no marked differences between the groups, indicating a consistent and tolerable safety profile.

Pharmacokinetics:

The pharmacokinetics of E6742 demonstrated dose-dependent plasma concentrations at both 100 mg and 200 mg BID, observed on days 1 and 15.

Maximum concentration (Cmax) was reached within 1-2 hours and reduced within 6 hours, with a half-life of approximately 6 hours.

Interferon gene signature (IGS) scores decreased rapidly within 2 weeks of treatment and returned to baseline within 4 weeks’ post-withdrawal.

Ex vivo analysis showed reduced production of IL-1β and IL-6 cytokines within 1 hour, persisting up to 6 hours, with similar trends for TNF-alpha.

Whole transcriptome analysis revealed that 156 genes were significantly regulated by E6742 at week 12.

Most of these genes were IFN or TLR7/8-related genes, and enrichment analysis confirmed that E6742 specifically regulates only the IFN-related pathway without causing non-specific responses.

Efficacy Outcomes: Clinical responses were most notable in the 200 mg group:

BICLA Response Rates: 57.1% of patients in the 200 mg group achieved BICLA response compared to 37.5% (100 mg group) and 33% (placebo) respectively

Tender Joint Count and CLASI: Improvements were observed across all treatment groups, particularly in the higher dose group.

In conclusion, E6742, a TLR7/8 inhibitor, demonstrated a favorable safety profile and was well-tolerated. It showed promising efficacy with marked interferon gene signature responses, alongside a reduction in pro-inflammatory cytokines like IL-1β and IL-6, in patients with SDA. These results provide the first clinical evidence supporting E6742 as a potential treatment for SDA, warranting further investigation in larger, long-term clinical trials.

Safety and Efficacy of Subcutaneous Ianalumab (VAY736) for up to 68 Weeks in Patients with Systemic Lupus Erythematosus: Results from Phase 2 Study

Speaker: Dr. Eduardo Mysler - Organización Médica de Investigación, Buenos Aires

Key Highlights:

Introduction:

Ianalumab is a human monoclonal antibody targeting the B cell activating factor receptor, known for its dual-action mechanism (B-cell lysis and BAFF-R signalling blockade). It works by depleting unwanted B cells through ADCC-mediated depletion while preventing the activation and production of new B cells. This dual approach helps eliminate immature, mature, memory B cells, and plasmablasts, while preserving long-lived plasma cells (memory cells). By blocking the B cell activating factor receptor, ianalumab not only removes harmful B cells but also inhibits the production of new ones, potentially offering improved therapeutic outcomes.

Study Design:

Phase 2 clinical trial, randomized, double-blind, placebo-controlled

Patient Criteria: ANA-positive patients meeting the 1997 ACR criteria with SLEDAI-2k score ≥6

Randomization: 1:1 allocation to either ianalumab (N=34) or placebo (N=33)

Trial Phases:

Phase 1: 28 weeks, primary endpoint – composite SRI-4 response

Phase 2: Up to 52 weeks

Switching: Patients initially on placebo switched to ianalumab after Phase 1

Follow-up: Post-treatment follow-up to monitor B cell recuperation at week 68

Findings:

Efficacy Outcomes:

SRI-4 Responses:

70% of ianalumab patients achieved SRI-4 compared to 10% in placebo at 28 weeks.

Placebo-to-active switchers achieved comparable results by week 52, though slightly lower than continuously treated patients.

SRI-6 and Low Disease Activity: Significant improvements in stringent endpoints, with 46% of treated patients achieving LLDAS by week 68.

Flare Reduction: Kaplan-Meier analysis demonstrated substantial reductions in moderate-to-severe flares in the ianalumab group versus placebo (6 vs. 115 total flares) upto week 68

Durability of Response: Continued treatment provided sustained improvements, highlighting the benefit of prolonged therapy.

Biomarker Insights:

B-Cell Depletion: Effective peripheral depletion observed during active treatment, with partial recovery post-therapy. Memory B-cell reserves and IgG-producing plasma cells were preserved, ensuring minimal immune suppression.

Serological Markers: Anti-dsDNA levels decreased significantly, while complement levels (C3, C4) showed moderate improvement.

Selective Immunoglobulin Modulation:

A gradual reduction in IgM levels is observed during the DB phase, continuing through the open-label (OL) treatment phase. IgM levels remain lower post-treatment but stabilize.

Minimal reductions in IgG levels during the DB phase, with stability during OL treatment and post-treatment, remaining within normal physiological ranges was seen. Safety Profile:

No new safety signals with extended treatment for up to one year

One patient Transient renal impairment (resolved within 24 hours).

One patient - CNS vasculitis occurred a year after discontinuation, considered unrelated to treatment.

No cardiovascular (MACE) events.

No deaths no opportunistic infections

Immunological Tolerance: Sustained IgG levels and absence of opportunistic infections support a favourable safety profile.

Conclusion:

The composite endpoint (SRI-4 response with sustained corticosteroid reduction) was met at Week 28.

Results were consistent for both patients on Ianulumab (double-blind) followed by open-label (OL) treatment and placebo (double-blind) followed by Ianulumab (OL).

Higher rates of treatment responders using indices like SRI-6, LLDAS (Lupus Low Disease Activity State), and DORIS (Definition of Remission in SLE).

Reductions in the severity or risk of moderate-to-severe disease flares.

Decreased serological biomarkers indicating disease activity.

Long-term Ianulumab therapy (up to 52 weeks) was well tolerated without new safety concerns.

Ianulumab's development is continuing in SLE and lupus nephritis through studies such as SIRIUS-SLE1, SIRIUS-SLE2, and SIRIUS-LN.

American College of Rheumatology Convergence 2024, November 14–19, Washington, D.C.