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In a phase 2 trial of iberdomide in patients with moderate-to-severe SLE, a composite response (on the Systemic Lupus Erythematosus Responder Index–4) occurred in 54% of those who received iberdomide (0.45 mg), as compared with 35% in the placebo group, but this between-group difference was not significant at lower doses. Urinary tract and respiratory tract infections and neutropenia occurred.

Background The efficacy and safety of apremilast were assessed in patients with psoriatic arthritis (PsA) in three phase III clinical trials with similar designs (PALACE 1, 2, and 3). Methods Following a 24-week, randomized (1:1:1 to apremilast 30 mg twice daily, 20 mg twice daily, or placebo), double-blind phase and a 28-week blinded active treatment phase, patients could receive apremilast in open-label extension studies for an additional 4 years. Eligible adult patients had active PsA for ≥ 6 months and three or more swollen joints and three or more tender joints despite prior treatment with disease-modifying anti-rheumatic drugs. Results A total of 1493 randomized patients received one or more doses of study medication (placebo: n  = 496; apremilast 30 mg twice daily: n  = 497; apremilast 20 mg twice daily: n  = 500). In patients continuing apremilast treatment, response was sustained without new safety issues. At week 260, 67.2% of remaining patients achieved an ACR20 response, and 44.4% and 27.4% achieved ACR50 and ACR70 responses, respectively. Among patients with baseline enthesitis and dactylitis, 62.4% achieved a Maastricht Ankylosing Spondylitis Enthesitis Score of 0 and 80.9% achieved a dactylitis count of 0, respectively. In patients who had ≥ 3% baseline psoriasis body surface area involvement, 43.6% achieved ≥ 75% reduction from the baseline Psoriasis Area and Severity Index scores. The most commonly reported adverse events (AEs) were diarrhea, nausea, headache, upper respiratory tract infection, and nasopharyngitis, with most diarrhea and nausea AEs occurring within the first 2 weeks of treatment and usually resolving within 4 weeks. Reported rates of depression during the study were low (≤ 1.8%). The majority of patients maintained their weight within 5% of baseline during the study. No new safety concerns or increases in the incidence or severity of AEs were observed over the long term. Conclusions Apremilast maintained clinical benefit and a favorable safety profile for up to 5 years among patients with PsA. Trial registration ClinicalTrials.gov NCT01172938 , NCT01212757 , NCT01212770

ObjectiveTo evaluate safety, pharmacokinetics, pharmacodynamics and efficacy of iberdomide in patients with SLE. Iberdomide is a high-affinity cereblon ligand that targets the hematopoietic transcription factors Ikaros and Aiolos for proteasomal degradation.MethodsA 12-week, multicentre, double-blind, placebo-controlled, dose-escalation study in active SLE was followed by a 2-year, open-label active treatment extension phase (ATEP) (NCT02185040). In the dose-escalation phase, adults with active SLE were randomised to oral placebo or iberdomide (0.3 mg every other day, 0.3 mg once daily, 0.6 mg and 0.3 mg alternating once daily, or 0.6 mg once daily). Primary endpoints were safety and tolerability.ResultsThe dose-escalation phase enrolled 42 patients, with 33 completing this phase and 17 patients enrolling into the ATEP. In the dose-escalation phase, the most common treatment-emergent adverse events (TEAEs; iberdomide/placebo groups) were nausea (20.6%/12.5%), diarrhoea (17.6%/12.5%) and upper respiratory tract infection (11.8%/12.5%). Most TEAEs were mild or moderate in severity and more common in the highest dose groups in both study phases. In the dose-escalation phase, Physician’s Global Assessment and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity scores improved relative to baseline and placebo in all iberdomide groups, with a trend toward continued score improvements in the ATEP. In the dose-escalation phase, iberdomide treatment resulted in dose-dependent reductions in total B cells and plasmacytoid dendritic cells in blood. Improvements in CLASI activity scores correlated with plasmacytoid dendritic cell depletion.ConclusionsThese proof-of-concept findings suggest a favourable benefit/risk ratio in SLE for iberdomide, a drug with a novel immunomodulatory mechanism of action, supporting further clinical investigation.

ObjectiveCC-97540 (BMS-986353) is an investigational CD19 CAR T-cell therapy utilizing the lisocabtagene maraleucel CD19-directed CAR T construct with a 41BB co-stimulatory domain and an epidermal growth factor receptor safety switch and is manufactured using the optimized NEX-TTM platform (figure 1A). Here, we present preclinical and phase 1 clinical data demonstrating CD19-specific cell targeting, CC-97540 CAR T expansion, and hypogammaglobulinemia in patients with relapsed or refractory non-Hodgkin lymphoma (RR NHL), suggesting that transformational clinical responses from an immune reset may be achieved at similar doses in patients with systemic autoimmune diseases (AID) like systemic lupus erythematosus (SLE).MethodsIn vitro studies tested target cell killing using Incucyte® S3 Live-Cell Analysis System (Sartorius 4647) with endogenous and engineered cell lines expressing various levels of CD19. CC-97540 was analyzed in vivo using a NALM6 xenograft model.A multicenter phase 1 trial (NCT04231747) is investigating CC-97540 in patients with RR NHL. Following leukapheresis, patient T cells are purified and engineered followed by limited ex vivo expansion. After lymphodepleting chemotherapy (3 days fludarabine [30 mg/m2] and cyclophosphamide [300 mg/m2]), patients receive a single infusion of CC-97540 at 10×106 (dose level [DL] 1) or 25×106 (DL2) CAR T cells.ResultsCC-97540 depletes CD19-expressing target cells completely in vitro and in vivo (figure 1B,C). As of March 20, 2023, 18 patients with RR NHL have been enrolled in NCT04231747; 16 have been treated (DL1: n=10; DL2: n=6). Transgene levels demonstrated robust cellular expansion, followed by a decrease in serum IgG and IgA levels (figure 2A–C). Despite persistent hypogammaglobulinemia, absolute lymphocyte, neutrophil, and platelet counts had transient decreases with subsequent rapid recovery (figure 2D–F).ConclusionsCC-97540 is a NEX-TTM investigational CAR T product that can achieve deep CD19-specific cellular depletion in vitro and in vivo. In patients with RR NHL, hypogammaglobulinemia was induced at low CC-97540 doses, indicating that an immune reset and clinical remission may be observed at similar doses in patients with systemic AID like SLE. CC-97540 is being tested in the phase 1, multicenter, open-label study evaluating the safety and tolerability in patients with severe, refractory SLE (NCT05869955).FundingBristol Myers Squibb.Abstract P105 Figure 1Overview of the (A) construct of CC-97450 and CD19 target cell depletion (B) in vitro and (C) in vivo. (A) Vector design includes scFv that specifically binds to an epitope on the extracellular domain of CD19, CD28tm (an intracellular CD33 signaling domain), an intracellular 41BB co-stimulatory domain, and the huEGFRt safety switch. (B) Cytotoxicity: the functional capacity of CC-97540 to kill CD19-expressing cell lines was performed with K562-CD19/NLR target cells expressing CD19 co-cultured with CC-97540. (C) Endogenous CD19-expressing NALM6 xenograft NSG mice were treated intravenously with CC-97540 at 1.0 x 106 cells per mouse and compared to control (NALM6 no treatment) (n = 8 per group). Disseminated tumor growth was assessed by imaging NALM6 firefly luciferase-positive bioluminescence. 3’LTR, 3’ long terminal repeat; CD28tm, CD28 transmembrane domain; E:T, effector-to-target ratio; huEGFRt, non-functional, truncated human epidermal growth factor receptor safety switch; p/s, photons/sec; scFv, single-chain variable fragment; T2A, ribosomal skip sequenceAbstract P105 Figure 2CC-97540 pharmacokinetic and pharmacodynamic profile from patients with R/R NHL in the CC-97540-NHL-001 phase 1 clinical trial (NCT04231747). Median CC-97540 transgene levels following infusion over time are shown in red and blue lines for DL1 and DL2 with individual patient values shown in grey. The dotted line indicates the lower limit of quantification (40 copies/ug). Time courses of transgene levels were measured by droplet digital polymerase chain reaction in whole blood and plotted using Rstudio (Version 1.4.1103–4; Posit Software, PBS, Boston, MA, USA). Mean values for serum IgG, IgA, absolute neutrophil count, absolute lymphocyte count, and platelets following CC-97540 infusion are shown in red and blue lines for DL1 and DL2, respectively, with individual patient values shown in grey. Dotted lines for IgG and IgA panels represent low normal immunoglobulin levels. IgG and IgA measurements taken after intravenous immunoglobulin supplementation were excluded (GraphPad Prism 9, GraphPad Software, La Jolla, CA, USA)

Objective Psoriatic arthritis (PsA) requires long‐term treatment, yet safety concerns and monitoring requirements make maintenance a challenge. This analysis of pooled Psoriatic Arthritis Long‐term Assessment of Clinical Efficacy (PALACE) 1, 2, and 3 data describes 3‐year apremilast safety and tolerability in PsA. Methods Patients with active PsA were randomized (1:1:1) to placebo, apremilast 30 mg twice daily, or apremilast 20 mg twice daily. Placebo patients were re‐randomized to apremilast 30 mg twice daily or 20 mg twice daily at week 16 (early escape) or 24. Double‐blind treatment continued to week 52; patients could continue apremilast during an open‐label, long‐term treatment phase. Results In total, 1493 patients received at least one dose of study medication and were included in the safety population (placebo: n = 495; apremilast 30 mg: n = 497; apremilast 20 mg: n = 501). Among patients receiving apremilast, 53.2% (767/1441) completed 3 years of treatment. Greater rates of adverse events (AEs) were reported with apremilast (61.1%; exposure‐adjusted incidence rate [EAIR]/100 patient‐years, 265.1) versus placebo (47.5%; EAIR/100 patient‐years, 200.7) in the placebo‐controlled period. During weeks 0 to ≤52, the most common AEs occurring in apremilast‐exposed patients were diarrhea (13.9%; EAIR/100 patient‐years, 18.6), nausea (12.3%; EAIR/100 patient‐years, 16.0), headache (9.4%; EAIR/100 patient‐years, 12.1), upper respiratory tract infection (9.1%; EAIR/100 patient‐years, 11.5), and nasopharyngitis (6.2%; EAIR/100 patient‐years, 7.7). Most AEs were mild/moderate with apremilast exposure ≤156 weeks. Rates of depression remained low (EAIR/100 patient‐years, 1.8). Major adverse cardiac events (EAIR/100 patient‐years, 0.5), malignancies (EAIR/100 patient‐years, 0.9), and serious opportunistic infections (EAIR/100 patient‐years, 0.0) were infrequent over the 3‐year exposure period. Discontinuation rates due to AEs were low (<7.5%) across all apremilast‐exposure periods. Incidences of clinically meaningful abnormalities in postbaseline laboratory values was low; most values returned to baseline levels with continued treatment and without intervention. Conclusion Apremilast demonstrated a favorable safety profile and was well tolerated up to 156 weeks.

The change in transaminase levels over a single week during therapy with methotrexate (MTX) has not been investigated or reported to date. In clinical practice, it is common to observe abnormal transaminase levels upon routine blood work for toxicity monitoring. Many have suggested that such lab abnormalities can sometimes be attributed to sampling blood for toxicity monitoring proximately following MTX dosing. The aim of our study was to evaluate changes in transaminase levels (AST/ALT) over 1 week after MTX administration in rheumatoid arthritis (RA) patients. In this small proof of concept study, we evaluated 13 patients with RA taking stable doses of methotrexate and background medications (e.g., NSAIDs and prednisone), but no other disease-modifying anti-rheumatic drugs (DMARDs). All patients were on a stable dose of folic acid. Patients received their usual doses of MTX administered at a specified time, and then sequential blood samples were obtained over the course of 7 days. Peripheral blood was obtained at each time point to measure serum transaminases. We did not observe any significant change in sequential transaminases over 1 week in relationship to MTX administration. It is possible that MTX therapy alone does not lead to significant weekly transaminase variations, contrary to our clinical expectations. The addition of other medications (i.e., NSAIDs) to stable MTX regimen may result in transaminase abnormalities.

ObjectiveEvaluate apremilast efficacy across various psoriatic arthritis (PsA) manifestations beginning at week 2 in biological-naïve patients with PsA.MethodsPatients were randomised (1:1) to apremilast 30 mg twice daily or placebo. At week 16, patients whose swollen and tender joint counts had not improved by ≥10% were eligible for early escape. At week 24, all patients received apremilast through week 52.ResultsAmong 219 randomised patients (apremilast: n=110; placebo: n=109), a significantly greater American College of Rheumatology 20 response at week 16 (primary outcome) was observed with apremilast versus placebo (38.2% (42/110) vs 20.2% (22/109); P=0.004); response rates at week 2 (first assessment) were 16.4% (18/110) versus 6.4% (7/109) (P=0.025). Improvements in other efficacy outcomes, including 28-joint count Disease Activity Score (DAS-28) using C reactive protein (CRP), swollen joint count, Health Assessment Questionnaire-Disability Index (HAQ-DI), enthesitis and morning stiffness severity, were observed with apremilast at week 2. At week 16, apremilast significantly reduced PsA disease activity versus placebo, with changes in DAS-28 (CRP) (P<0.0001), HAQ-DI (P=0.023) and Gladman Enthesitis Index (P=0.001). Improvements were maintained with continued treatment through week 52. Over 52 weeks, apremilast’s safety profile was consistent with prior phase 3 studies in psoriasis and PsA. During weeks 0–24, the incidence of protocol-defined diarrhoea was 11.0% (apremilast) and 8.3% (placebo); serious adverse event rates were 2.8% (apremilast) and 4.6% (placebo).ConclusionsIn biological-naïve patients with PsA, onset of effect with apremilast was observed at week 2 and continued through week 52. The safety profile was consistent with previous reports.Trial registration number NCT01925768; Results.

ObjectivesIberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Pharmacodynamics and pharmacokinetics of oral iberdomide were evaluated in a phase 2b study of patients with active systemic lupus erythematosus (SLE).MethodsAdults with autoantibody-positive SLE were randomised to placebo (n=83) or once daily iberdomide 0.15 mg (n=42), 0.3 mg (n=82) or 0.45 mg (n=81). Pharmacodynamic changes in whole blood leucocytes were measured by flow cytometry, regulatory T cells (Tregs) by epigenetic assay, plasma cytokines by ultrasensitive cytokine assay and gene expression by Modular Immune Profiling.ResultsIberdomide exhibited linear pharmacokinetics and dose-dependently modulated leucocytes and cytokines. Compared with placebo at week 24, iberdomide 0.45 mg significantly (p<0.001) reduced B cells, including those expressing CD268 (TNFRSF13C) (−58.3%), and plasmacytoid dendritic cells (−73.9%), and increased Tregs (+104.9%) and interleukin 2 (IL-2) (+144.1%). Clinical efficacy was previously reported in patients with high IKZF3 expression and high type I interferon (IFN) signature at baseline and confirmed here in those with an especially high IFN signature. Iberdomide decreased the type I IFN gene signature only in patients with high expression at baseline (−81.5%; p<0.001) but decreased other gene signatures in all patients.ConclusionIberdomide significantly reduced activity of type I IFN and B cell pathways, and increased IL-2 and Tregs, suggesting a selective rebalancing of immune abnormalities in SLE. Clinical efficacy corresponded to reduction of the type I IFN gene signature.Trial registration number NCT03161483.

Systemic lupus erythematosus (SLE) is a disease of high unmet therapeutic need. The challenge of accurately measuring clinically meaningful responses to treatment has hindered progress towards positive outcomes in SLE trials, impeding the approval of potential new therapies. Current primary end points used in SLE trials are based on legacy disease activity measures that were neither specifically designed for the clinical trial context, nor developed according to contemporary recommendations for clinical outcome assessments (COAs), such as that substantial patient input should be incorporated into their design. The Treatment Response Measure for SLE (TRM-SLE) Taskforce is a global collaboration of SLE clinician–academics, patients and patient representatives, industry partners and regulatory experts, established to realize the goal of developing a new COA for SLE clinical trials. The aim of this project is a novel COA designed specifically to measure treatment effects that are clinically meaningful to patients and clinicians, and intended for implementation in a trial end point that supports regulatory approval of novel therapeutic agents in SLE. This Consensus Statement reports the first outcomes of the TRM-SLE project, including a structured process for TRM-SLE development.In this Consensus Statement, the Treatment Response Measure for Systemic Lupus Erythematosus Consortium presents the initial outcomes of a project to develop a clinical outcome assessment that can contribute to the regulatory approval process for therapeutic agents via its incorporation in end points of clinical trials in systemic lupus erythematosus.

ObjectiveThe Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical trial programme findings demonstrated that apremilast, an oral phosphodiesterase 4 inhibitor, is effective for treating psoriatic arthritis (PsA). Enthesitis and dactylitis are difficult-to-treat features of PsA leading to disability and affecting quality of life. PALACE 1, 2 and 3 data were pooled to assess the efficacy of apremilast on enthesitis and dactylitis outcomes in patients with these conditions at baseline.MethodsPatients with enthesitis (n=945) or dactylitis (n=633) at baseline were analysed after receiving double-blind treatment with placebo, apremilast 30 mg two times per day or apremilast 20 mg two times per day up to 52 weeks and continuing up to 5 years. Data were analysed through 156 weeks. Enthesitis was evaluated by Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) and dactylitis via dactylitis count.ResultsAt week 24, patients receiving apremilast 30 mg two times per day demonstrated a significantly greater mean change in enthesitis (−1.3 vs −0.9; p<0.05) and dactylitis (−1.8 vs −1.3; p<0.01) vs placebo. Patients in the 30 mg dose group showed significantly greater mean (−23.6% vs −7.0%; p<0.05) and median (−50.0% vs −21.1%; p<0.05) per cent changes in MASES; mean and median per cent changes in dactylitis count were numerically, but not significantly, different for either apremilast dose in patients with dactylitis. In the patient population remaining on apremilast, observed mean and median improvements in both conditions were sustained through 156 weeks.ConclusionApremilast is effective for the treatment of active PsA, including improvements in enthesitis and dactylitis up to 3 years.Trial registration numbers NCT01172938, NCT01212757 and NCT01212770.