Sustained Disease Control Research Articles

Safety and efficacy of nipocalimab in adults with generalised myasthenia gravis (Vivacity-MG3): a phase 3, randomised, double-blind, placebo-controlled study.

Given burdensome side-effects and long latency for efficacy with conventional agents, there is a continued need for generalised myasthenia gravis treatments that are safe and provide consistently sustained, long-term disease control. Nipocalimab, a neonatal Fc receptor blocker, was associated with dose-dependent reductions in total IgG and anti-acetylcholine receptor (AChR) antibodies and clinically meaningful improvements in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale in patients with generalised myasthenia gravis in a phase 2 study. We aimed to assess the safety and efficacy of nipocalimab in a phase 3 study. Vivacity-MG3 was a phase 3, randomised, double-blind, placebo-controlled, phase 3 study conducted at 81 outpatient centres with expertise in myasthenia gravis in 17 countries in Asia-Pacific, Europe, and North America. Adults (aged ≥18 years) with generalised myasthenia gravis inadequately controlled with standard-of-care therapy (MG-ADL score ≥6) were randomly assigned (1:1) to either nipocalimab (30 mg/kg loading dose then 15 mg/kg every 2 weeks for maintenance dosing) or placebo infusions every 2 weeks, added to standard-of-care therapy in both groups, for 24 weeks. Randomisation was stratified by antibody status, day 1 MG-ADL total score, and region. The sponsor, investigators, clinical raters, and participants were masked to treatment assignment. The primary endpoint was the difference between nipocalimab and placebo based on least-squares mean change from baseline in MG-ADL total score averaged over weeks 22, 23, and 24 in the intention-to-treat population of patients who were antibody-positive (for AChR, anti-muscle-specific tyrosine kinase [MuSK], or anti-low-density lipoprotein receptor-related protein 4 [LRP4]). Adverse events were assessed in patients who received at least one dose of study drug. This study is registered at ClinicalTrials.gov, NCT04951622; the double-blind phase is completed and an open-label extension phase is ongoing. Between July 15, 2021, and Nov 17, 2023, 199 patients were enrolled, and 196 patients received study drug (98 in the nipocalimab group and 98 in the placebo group); of these, 153 (77 in the nipocalimab group and 76 in the placebo group) were antibody-positive. The least-squares mean change in MG-ADL score from baseline to weeks 22, 23, and 24 was -4·70 (SE 0·329) in the nipocalimab group versus -3·25 (0·335) in the placebo group (difference -1·45 [95% CI -2·38 to -0·52]; p=0·0024). The incidence of adverse events was similar between groups (82 [84%] of 98 in both the nipocalimab and placebo groups), including infections (42 [43%] of 98 in the nipocalimab group and placebo group) and headache (14 [14%] of 98 in the nipocalimab group and 17 [17%] of 98 in the placebo group). Serious adverse events were reported for nine (9%) of 98 patients in the nipocalimab group and 14 (14%) of 98 patients in the placebo group, three of which had a fatal outcome (nipocalimab: myasthenic crisis; placebo: cardiac arrest and myocardial infarction). Results from the completed double-blind phase of Vivacity-MG3 support the role of nipocalimab, added to standard-of-care therapies, as a safe treatment for sustained disease control over 6 months for a broad population of patients with generalised myasthenia gravis who are antibody-positive. The ongoing open-label extension phase should provide longer term sustained safety and efficacy data with nipocalimab. Janssen Research & Development, LLC, a Johnson & Johnson company.

Global Delphi consensus on treatment goals for generalised pustular psoriasis.

Generalised pustular psoriasis (GPP) is a chronic, systemic, neutrophilic inflammatory disease. A previous Delphi panel established areas of consensus on GPP, although patient perspectives were not included, and aspects of treatment goals remain unclear. To identify and achieve consensus on refined, specific treatment goals for GPP treatment via a Delphi panel with patient participation. Statements were generated based on a systematic literature review and revised by a Steering Committee. Statements were categorised into overarching principles, short-term treatment goals and long-term treatment goals. A global panel of 30 dermatologists and three patient representatives voted in agreement or disagreement with each statement. Consensus was defined as ≥80% approval by panellists. Consensus was reached in the first round of voting and ≥90% agreement was reached for 23/26 statements. In summary, GPP requires a timely, tailored treatment plan, co-developed by patients and physicians, that involves a multidisciplinary approach and addresses the complexity, heterogeneity and chronicity of the disease. Short-term treatment goals should include pustule clearance within 7 days and prevention of pustule recurrence, reduction of cutaneous symptom burden (≥ -4 points on the Itch and Skin Pain Numeric Rating Scale), improvement in systemic symptoms (e.g. resolution of fever within 3 days of treatment initiation and reduced fatigue), prevention of life-threatening complications, and progressive improvement of inflammatory biomarkers. In patients with comorbid psoriatic diseases, treatment decisions should prioritise GPP. Long-term treatment goals should include minimising disease activity through flare prevention and symptom control between flares, sustained disease control, management of comorbidities and improvement in quality of life (QoL). Small differences in perception between patients and physicians regarding the importance of certain treatment goals, e.g. avoiding hair and/or nail loss to improve QoL, reflect the complexity of assessing treatment goals and emphasise the need for a patient-centred approach. In the first global Delphi panel in GPP to include patient perspectives, consensus between dermatologists and patients was achieved on overarching principles of treatment, short-term and long-term treatment goals for GPP. These findings provide valuable insights for developing guidelines that consider the perspectives of both patients and physicians in the treatment of GPP.

Baricitinib dose reduction in patients with rheumatoid arthritis achieving sustained disease control: Final results from the RA-BEYOND study.

This study examines the impact of dose step-down in patients with rheumatoid arthritis (RA) who achieved sustained disease control with baricitinib 4-mg once-daily up to 96-weeks. Patients who completed a baricitinib phase 3 study could enter a long-term extension (LTE). In the LTE, patients who received baricitinib 4-mg for ≥15 months and maintained clinical disease activity index (CDAI) low disease activity (LDA) or remission (REM) were blindly randomized to continue 4-mg or taper to 2-mg. If needed, 2-mg treated patients could be rescued to 4-mg, and 4-mg treated patients could be rescued by adding or increasing conventional synthetic disease-modifying antirheumatic drugs. Efficacy and safety were assessed through 96-weeks. Non-responder imputation, considering rescued or discontinued patients as non-responders, was used for CDAI response analyses. At 96-weeks, most patients maintained LDA in both 2-mg and 4-mg arms, with a lower maintenance rate in 2-mg than 4-mg (NRI 59.9% and 70.2%, respectively). Patients maintained REM in 2-mg and 4-mg arms, 30.8% and 36.6% respectively. Rescue rates were 14.7% for baricitinib 4-mg and 22.5% for 2-mg. Of 112 patients who lost LDA in the 2-mg arm and rescued to 4-mg, 76.2% and 75.6% achieved LDA again at 12- and 24-weeks post-rescue. In a randomized, blinded, phase 3 LTE study, maintenance of RA control following induction of sustained LDA/REM with baricitinib 4-mg was greater with continued 4-mg than after taper to 2-mg. Nonetheless, 76% of patients tapered to 2-mg could maintain LDA/REM or recapture with return to 4-mg if needed.

Advancing Therapeutic Targets in IBD: Emerging Goals and Precision Medicine Approaches.

Inflammatory bowel diseases (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) are chronic, relapsing conditions characterized by dysregulated immune responses and persistent intestinal inflammation. This review aims to examine new potential therapeutic targets in IBD starting from the STRIDE-II statements. Key targets now include clinical remission, endoscopic remission, and biomarker normalization (such as C-reactive protein and fecal calprotectin). Moreover, histologic remission, transmural remission, and in the future molecular targets are emerging as important indicators of sustained disease control. The treatment goals for inflammatory bowel disease are varied: to relieve symptoms, prevent permanent intestinal damage, promote inflammation remission, and minimize complications. Consequently, the therapeutic targets have evolved to become broader and more ambitious. Integrating these advanced therapeutic targets has the potential to redefine IBD management by promoting deeper disease control and improved patient outcomes. Further research is essential to validate these strategies and optimize their clinical implementation.

Anakinra in relapsing polychondritis: a case report and review of the literature.

Relapsing polychondritis is rare and affects non-synovial fibrocartilage. Currently, there is a paucity of treatment algorithms, especially for those with refractory disease. A middle-aged man presented with polychondritis affecting the nose, ears, joints, and larynx. Two months prior, a diagnosis of non-arteritic ischemic optic neuropathy was made. Oral prednisolone was initiated, and over the following three years, he had several flares for which the following other treatments were given: moderate dose methotrexate (elevated liver enzymes), azathioprine (gastrointestinal intolerance), mycophenolate (ineffective), tocilizumab (widespread eruption), and tofacitinib (acute diverticulitis). Further investigations were unremarkable for malignancy and vasculitis. UBA1 mutation screening was negative. Given the limited therapeutic options, methotrexate at a lower dose was re-added, but he developed acute flare with laryngeal symptoms. Anakinra was initiated, prompting a successful prednisolone wean over the following weeks and disease remission. A literature review identified 11 publications comprising 25 patients. Of the 21 patients with anakinra response documented, six (28.6%) had symptomatic improvement. In one of these patients, there was co-administration of methotrexate. In summary, anakinra may remain as an option, only for those subsets of patients in whom many of the other more efficacious treatments have been tried to provide sustained disease control.

P61 Proactive therapeutic drug monitoring versus routine care with the novel biologics in psoriasis: a pragmatic, multicentric, randomized, controlled study: the HELIOS study

Abstract Introduction & Objectives Psoriasis is a chronic immune-mediated inflammatory skin disease for which treatment with biologics is highly effective. In general, these drugs are prescribed according to a ‘one-dose-fits-all’ principle, which might lead to under- or overdosing, causing suboptimal response and unnecessary high drug exposure, respectively. A tool that may support the rational use of biologics is therapeutic drug monitoring (TDM). TDM is the measurement of blood drug concentrations in order to individualize dosing regimens to achieve maximal clinical efficacy and minimize adverse events. The primary objective of this trial is to assess whether proactive TDM of IL-17 and/or IL-23 inhibitors is non-inferior compared with standard of care (SOC) with respect to sustained disease control in patients with moderate-to-severe psoriasis. Materials & Methods This is a pragmatic, multicentre, individually randomized, controlled non-inferiority trial. A total of 210 patients using secukinumab, ixekizumab or guselkumab for at least 6 months according to the standard dosing scheme, will be randomized (1:1) to TDM or SOC. In the TDM group, dosing intervals will be prolonged or shortened stepwisely. This will happen based on the blood drug concentrations of the biologic, measured every 3 months and in accordance with the decision tree. Disease activity and quality of life will be monitored every 3 months by PASI, IGA, BSA, DLQI-R and SF-36. The primary endpoint is sustained disease control, defined as an absolute PASI ≤2 or a delta PASI from baseline ≥50% for at least 80% of all 3-monthly study visits over a period of 18 months. Secondary outcomes include courses of PASI and DLQI, serious adverse events, health-related quality of life, cost-effectiveness and treatment satisfaction. The outcomes of TDM will be compared with those of SOC. Results Inclusion will start in August 2024. The first preliminary results will be presented at the European Academy of Dermatology and Venereology Congress 2026. Conclusion With this study, we aim to assess whether proactive TDM of IL-17 and IL-23 inhibiting biologics is feasible, safe and cost-effective. Proactive TDM in psoriasis patients may lead to more efficient and rational use of the highly effective—though expensive—biologics.

Adjuvant rituximab and elevated intratumoural CD8 expression are associated with sustained disease control after radiotherapy in a randomised trial of systemic therapy in early-stage follicular lymphoma

We report extended follow-up of TROG99.03, a randomised phase III trial in early-stage follicular lymphoma (ESFL) including new information on the role of adjuvant rituximab and translational studies. Patients with ESFL were randomised to involved field radiotherapy (IFRT) or IFRT plus 6-cycles cyclophosphamide/vincristine/prednisolone (IFRT+CVP). From 2006 rituximab was added to IFRT+CVP (IFRT+R-CVP). Clinical and multi-omic parameters were evaluated. Findings were validated in two independent ESFL cohorts (99 and 60 patients respectively). Between 2000 and 2012, 150 (75 per arm) patients were recruited. 48% were positron emission tomography (PET)-staged. By protocol, at median follow-up 11.3-years, progression-free survival (PFS) remained superior for IFRT+(R)CVP vs. IFRT (hazard ratio [HR]=0.60, 95% CI=0.37-0.98, p=0.043; 10-year PFS 62% vs. 43%) respectively. Although no significant difference in overall survival was observed (HR=0.44, 95% CI=0.16-1.18, p=0.11, 10-year OS 95% vs. 84%), patients receiving IFRT+(R)CVP experienced fewer composite (histological transformation and death) events (p=0.045). PFS of IFRT+R-CVP-treated patients compared with all other treatments lacking rituximab (IFRT alone plus IFRT+CVP) was superior (HR=0.36, 95% CI=0.13-0.82, p=0.013). Amongst PET-staged patients, PFS differences between IFRT+R-CVP vs. IFRT were maintained (HR=0.38, 95% CI=0.16-0.89, p=0.027) indicating benefit distinct from stage migration. FL-related mutations and BCL2-translocations were not associated with PFS. However, by multivariate analysis elevated CD8A gene expression in diagnostic biopsy tissue was independently associated with improved PFS (HR=0.45, 95% CI=0.26-0.79, p=0.037), a finding confirmed in both ESFL validation cohorts. CD8A gene expression was raised (p=0.02) and CD8+ T-cell density higher within follicles in ESFL vs. advanced-stage FL (p=0.047). Human leucocyte antigen class I specific neoantigens were detected in 43% of patients, suggesting neoantigen-specific CD8+ T-cells have a role in confining the spread of the disease. Adjuvant R-CVP and elevated intratumoural CD8 expression were independently associated with sustained disease control after radiotherapy in ESFL. Cancer Council Victora; National Health and Medical Research Council; Leukaemia Foundation; Mater Foundation.

Long-Term Maintenance of Optimal Treatment Targets for Skin and Itch Outcomes With Upadacitinib in Moderate-to-Severe Atopic Dermatitis: 140-Week Results From the Phase 3 Measure Up 1 and 2 Studies

Introduction: Despite undergoing prolonged systemic therapy, many patients with moderate-to-severe atopic dermatitis (AD) do not achieve optimal targets for skin and itch outcomes as defined by Aiming High in Eczema/AD (AHEAD) recommendations (eg, ≥90% improvement from baseline in Eczema Area and Severity Index [EASI 90] and Worst Pruritus Numerical Rating Scale [WP-NRS] score of 0/1 [no/minimal itch]). We evaluated long-term maintenance of optimal treatment targets with upadacitinib, an oral selective JAK inhibitor approved for moderate-to-severe AD in adolescents and adults. Methods: This 140-week interim analysis included adolescents and adults with moderate-to-severe AD who were randomized at baseline to upadacitinib 15 mg (UPA15) or 30 mg (UPA30) in the ongoing, phase 3, double-blind Measure Up 1 and 2 studies. Assessments included the proportion of patients (at the population level) who maintained EASI 90, WP-NRS 0/1, or simultaneous achievement of EASI 90 + WP-NRS 0/1 responses from week 16 (end of the placebo-controlled period) onwards. Data are reported as observed cases with no imputation for missing data. Results: Among patients who achieved EASI 90 at week 16 (UPA15, n=298; UPA30, n=384), EASI 90 was maintained by 79.8% (UPA15) and 83.7% (UPA30) at week 52, 76.7% (UPA15) and 83.0% (UPA30) at week 100, and 74.0% (UPA15) and 84.2% (UPA30) at week 140. Of patients achieving WP-NRS 0/1 at week 16 (UPA15, n=193; UPA30, n=281), WP-NRS 0/1 was maintained by 69.4% (UPA15) and 72.0% (UPA30) at week 52, 65.6% (UPA15) and 68.4% (UPA30) at week 100, and 62.3% (UPA15) and 66.0% (UPA30) at week 140. Of patients simultaneously achieving EASI 90 + WP-NRS 0/1 at week 16 (UPA15, n=156; UPA30, n=243), maintenance was achieved by 68.1% (UPA15) and 70.8% (UPA30) at week 52, 62.7% (UPA15) and 66.5% (UPA30) at week 100, and 58.7% (UPA15) and 64.4% (UPA30) at week 140. Among patients who did not maintain optimal outcomes, most still achieved clinically meaningful responses. Conclusion: Most patients maintained optimal skin and itch outcomes through 140 weeks of upadacitinib treatment, demonstrating its potential to provide sustained long-term disease control in atopic dermatitis.

Sustained Clinical Benefit and Intracranial Activity of Tarlatamab in Previously Treated Small Cell Lung Cancer: DeLLphi-300 Trial Update.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3, has shown durable anticancer activity and manageable safety in previously treated small cell lung cancer (SCLC) in DeLLphi-300 phase I and DeLLphi-301 phase II trials. Here, we report extended follow-up of DeLLphi-300 (median follow-up, 12.1 months [range, 0.2-34.3]) in fully enrolled cohorts treated with tarlatamab ≥10 mg dose administered once every two weeks, once every three weeks, or once on day 1 and once on day 8 of a 21-day cycle (N = 152). Overall, the objective response rate (ORR) was 25.0%; the median duration of response (mDOR) was 11.2 months (95% CI, 6.6 to 22.3), and the median overall survival (mOS) was 17.5 months (95% CI, 11.4 to not estimable [NE]). Among 17 patients receiving 10 mg tarlatamab once every two weeks, the ORR was 35.3%, the mDOR was 14.9 months (95% CI, 3.0 to NE), the mOS was 20.3 months (95% CI, 5.1 to NE), and 29.4% had sustained disease control with time on treatment ≥52 weeks. No new safety signals were identified. In modified Response Assessment in Neuro-Oncology Brain Metastases analyses, CNS tumor shrinkage of ≥30% was observed in 62.5% of patients (10 of 16) who had a baseline CNS lesion of ≥10 mm, including in a subset of patients with tumor shrinkage long after previous brain radiotherapy. In DeLLphi-300 extended follow-up, tarlatamab demonstrated unprecedented survival and potential findings of intracranial activity in previously treated SCLC.

Leukemic occult infiltrative optic neuropathy presenting as optic neuritis: a case report

Isolated ocular relapses of leukemia are rare and typically present as infiltrative lesions of the optic nerve. This report presents a case of an isolated ocular relapse of leukemia in a female patient, characterized by occult infiltrative optic neuropathy. Despite the absence of leukemic cell infiltration on MRI, a 33-year-old female patient presented with optic neuritis, which resolved after intrathecal administration of chemotherapeutic agents. However, due to her non-compliance with the treatment regimen, leukemia progressed to infiltrative optic neuropathy. She refused radiation therapy, and while intrathecal injections provided temporary stabilization, they were insufficient for sustained disease control. This case uniquely documents the extended progression of an isolated ocular relapse of leukemia, evolving from an occult infiltrative lesion initially presenting as optic neuritis to a more pronounced infiltrative lesion. It suggests that leukemic optic nerve infiltration can occur in patients with leukemia even in the absence of MRI-detectable abnormalities. Radiation therapy emerges as a critical modality in the management of infiltrative lesions of the optic nerve.

Proactive therapeutic drug monitoring of biologic drugs in patients with inflammatory bowel disease, inflammatory arthritis, and psoriasis: systematic review and meta-analysis

ObjectiveTo address the efficacy and safety of proactive therapeutic drug monitoring of biologic drugs for patients with inflammatory bowel disease, inflammatory arthritis, and psoriasis.DesignSystematic review and meta-analysis.Data sourcesMedline, Embase, Central,...

High-Dose Brolucizumab for Refractory Neovascular Age-Related Macular Degeneration Resistant to Standard-Dose Brolucizumab.

The aim of this study was to evaluate the efficacy and safety of escalating the dosage of intravitreal brolucizumab in patients with refractory neovascular age-related macular degeneration (AMD). This retrospective study included 17 eyes of 17 patients with refractory AMD treated with high-dose brolucizumab (12mg/0.1ml) for over 12months. Patients initially received at least one anti-vascular endothelial growth factor (anti-VEGF) agent and were switched to standard-dose brolucizumab (6mg/0.05ml). Those who showed a suboptimal response to standard-dose treatment had their dosage of brolucizumab escalated. Visual acuity was maintained from 68.3 ± 3.4 letters to 70.7 ± 3.2 letters after 12months of high-dose treatment (P = 0.128). Central subfield thickness was 343.7 ± 17.0μm before high-dose treatment and 316.7 ± 18.5μm at 12months (P = 0.083). The proportions of patients with subretinal fluid and serous pigment epithelial detachment significantly decreased from 82.4% to 41.2% and from 52.9% to 17.6%, respectively, after high-dose treatment (P = 0.039 and P = 0.031, respectively). The treatment interval extended from 7.2 ± 2.4weeks to 10.2 ± 2.2weeks after switching to standard-dose brolucizumab (P < 0.001) and was maintained at 13.5 ± 2.8weeks after increasing the dose (P = 0.154). No severe ocular adverse events were observed. High-dose brolucizumab was effective in patients who did not respond to standard-dose brolucizumab after switching from previous anti-VEGF agents. Increasing the dosage could offer sustained disease control and reduce the treatment burden for patients with refractory AMD.

Phase 1 Safety and Pharmacokinetics Study of TAVO101, an Anti-Human Thymic Stromal Lymphopoietin Antibody for the Treatment of Allergic Inflammatory Conditions.

TAVO101 is a humanized anti-human thymic stromal lymphopoietin (TSLP) monoclonal antibody under clinical development for the treatment of atopic dermatitis (AD) and other allergic inflammatory conditions. The crystallizable fragment region of the antibody was engineered for half-life extension and attenuated effector functions. This Phase 1, double-blinded, randomized, placebo-controlled study assessed the safety, tolerability, pharmacokinetics, and immunogenicity of TAVO101 in healthy adult subjects in seven ascending dose cohorts. Subjects received a single intravenous administration of TAVO101 or placebo with a 195-day follow-up. TAVO101 was safe and well tolerated. The incidences and severities of treatment-emergent adverse events were mostly mild and comparable between the active and placebo groups, with no trends of dose relationship. There were no severe adverse events, deaths, or treatment-related withdrawals. TAVO101 exhibited a linear pharmacokinetic profile, low clearance, and a median elimination half-life of 67 days in healthy subjects. All TAVO101-treated subjects tested negative for anti-drug antibodies. To support development in AD, TAVO101 was studied in an oxazolone-induced AD model in hTSLP transgenic mice and demonstrated efficacy. This long-acting anti-TSLP antibody has the potential for stronger and sustained allergic inflammatory disease control. The results from this study warranted further clinical development of TAVO101 in patients.

The effect of novel aromatic heterocycle substituted aminamidine derivatives on Necator americanus.

The efficacy of current drugs against hookworms at a single dose is highly variable across regions, age groups and infection intensity. Extensive and repeated use of these drugs also leads to potential drug resistance. Therefore, novel drugs are required for sustained disease control. Novel aromatic heterocycle substituted aminamidine derivatives (AADs) were synthesized based on tribendimine (TBD), and their in vivo potency against Necator americanus was tested. The efficacy of the AADs was tested in male hamsters. Oral and IV pharmacokinetic parameters were determined in male Sprague-Dawley rats. The proteomic profiles of N. americanus samples treated with AADs were compared using tandem mass tag-based quantitative proteomic analyses. Most AADs exhibited better anthelmintic activity than TBD at a single oral dose. Compound 3c exhibited improved solubility (>50×), and the curative dose was as low as 25 mg/kg. Similar to TBD, 3c was rapidly metabolized after oral administration and transformed into p-(1-dimethylamino ethylimino)aniline (dADT), an active metabolite against intestinal nematodes. dADT from 3c had better pharmacokinetic profiles than that from TBD and achieved an oral bioavailability of 99.5%. Compound 3c possessed rapid anthelmintic activity, clearing all worms within 24 h after an oral dose of 50 mg/kg. Quantitative proteomic analysis indicated that it might be related to ATP metabolism and cuticle protein synthesis. Compound 3c is a novel and promising compound against N. americanus in vivo.

Forecasted infliximab concentrations during induction predict time to remission and sustained disease control of inflammatory bowel disease

BackgroundInfliximab (IFX) exposure is established as a predictive factor of pharmacokinetic (PK) origin in inflammatory bowel disease (IBD), and expert consensus is to achieve adequate exposure during induction to achieve and sustain remission. MethodsWe retrospectively evaluated the performance of a Bayesian PK tool in IBD patients starting IFX. Trough IFX serum levels collected immediately before the third (at week 6) and fourth (at week 14) infusions were evaluated from 307 IBD patients (median age=17 years, 50 % females, 83 % with Crohn's disease). Forecasted IFX concentration at the fourth infusion were estimated using serum IFX, antibodies to IFX, albumin and weight determined immediately before the third infusion using population PK calculator with Bayesian prior. The outcome variable was a clinical & biochemical remission status achieved (CRP levels below 3 mg/L in presence of clinical remission). Statistics consisted of Kaplan Meier analysis with calculation of Hazard ratio (HR), and logistic regression. ResultsIFX concentration above 15 µg/mL immediately before the third infusion associated with shorter time to clinical & biochemical remission than concentration below 15 µg/mL without reaching significance (163±14 days vs 200±16 days, respectively; p=0.052). However, using PK parameters at the third infusion, forecasted IFX concentrations above 10 µg/mL immediately before the fourth infusion were significantly associated with a higher rate (HR=1.6 95 %CI: 1.1 to 2.1 p<0.01) and shorter time to remission (148±18 days vs 200±13 days p<0.01). In the presence of IFX concentration above 15 µg/mL at the third infusion, there was a significant 2.5-fold higher likelihood of sustained clinical & biochemical remission status during maintenance as compared to IFX concentrations below 15 µg/mL (p<0.01). Forecasted IFX level above 10 µg/mL at fourth infusion associated with significantly 3.9-fold higher likelihood of clinical & biochemical remission as compared to forecasted IFX concentrations below 10 µg/mL (p<0.01). ConclusionsThese data further support that optimized IFX concentrations during induction are associated with enhanced disease control in IBD.

Exploring Current Molecular Targets in the Treatment of Neovascular Age-Related Macular Degeneration toward the Perspective of Long-Term Agents.

Long-lasting anti-vascular endothelial growth factor (anti-VEGF) agents have become an option to reduce treatment frequency, with ongoing research exploring optimal responses and safety profiles. This review delves into molecular targets, pharmacological aspects, and strategies for achieving effective and enduring disease control in neovascular age-related macular degeneration (AMD). The molecular pathways involved in macular neovascularization, including angiogenesis and arteriogenesis, are explored. VEGF, PlGF, Ang-1, and Ang-2 play crucial roles in regulating angiogenesis, influencing vessel growth, maturation, and stability. The complex interplay of these factors, along with growth factors like TGFβ and bFGF, contributes to the pathogenesis of neovascular membranes. Current anti-VEGF therapies, including bevacizumab, ranibizumab, aflibercept, brolucizumab, and faricimab, are discussed with a focus on their pharmacokinetics and clinical applications. Strategies to achieve sustained disease control in AMD involve smaller molecules, increased drug dosages, and novel formulations. This narrative review provides a comprehensive overview of the molecular targets and pharmacological aspects of neovascular AMD treatment.

Progressive and Sustained Disease Control in Patients with Atopic Dermatitis (AD) Aged 12–17 Years Treated with Tralokinumab for 52 Weeks

Introduction: The ECZTRA 6 trial showed that tralokinumab 300mg provided progressive and sustained efficacy in adolescent patients with moderate-to-severe AD, and was well tolerated with a reassuring long-term safety profile over 52 weeks. Objective: To evaluate EASI response and PROs in adolescents from ECZTRA 6 treated with tralokinumab 300mg for the full 52-week treatment period. Methods: Patients were randomized to tralokinumab 300mg Q2W (n=97) or placebo (n=94) for 16 weeks. At Week 16, patients initiated on tralokinumab and achieving primary endpoints (IGA 0/1 and/or EASI-75) without rescue were re-randomized to tralokinumab 300mg Q2/4W monotherapy for 36 additional weeks; other patients were switched to open-label tralokinumab 300mg Q2W plus optional topical corticosteroids. Post-hoc analyses were conducted by pooling Week 16–52 data for all patients initially randomized to tralokinumab 300mg Q2W. Results: Greater proportions of tralokinumab- vs placebo-treated patients achieved primary endpoints at Week 16; progressive improvement was seen through Week 52. In addition, pruritus NRS score was improved for a greater proportion of tralokinumab- vs placebo-treated patients from baseline to Week 16, with further improvement up to Week 52. Progressive improvements over time were also observed for proportions of patients with reductions of pruritus NRS ≥4, POEM ≥4, and CDLQI ≥6, from baseline. The safety profile was consistent with prolonged treatment following Week 16. Conclusions: At Week 16, tralokinumab 300mg Q2W improved EASI and PROs in adolescents with AD, with progressive and sustained improvement seen up to Week 52.

Sustained Disease Control in DME Patients upon Treatment Cessation with Brolucizumab.

Background: Treatment cessation due to a dry retina has not been systematically addressed in diabetic macular edema (DME). In three out of four patients receiving 6 mg of brolucizumab in the KITE study, treatment was terminated after the study ended. Methods: The KITE study was a double-masked, multicenter, active-controlled, randomized trial (NCT03481660) in DME patients. Per protocol, patients received five loading injections of Brolucizumab at 6-week intervals, with the option to adjust to 8 weeks in case of disease activity or to extend in the second year to a maximum of 16 weeks in the absence of retinal fluid. Results: After two years, one patient required eight weekly injections, while three patients reached a maximal treatment interval of 16 weeks. The severity of diabetic retinopathy improved in all patients with no dye leakage according to fluorescein angiography (FA) and no retinal fluid according to OCT in three patients. Treatment was paused in these three patients for >36 months, while the fourth patient required continuous treatment at 5-week intervals after switching to other licensed anti-VEGF agents. Conclusions: The adoption of treatment according to individual needs, including considering treatment cessation, may contribute to improved treatment adherence in many patients and be more frequently possible than expected.

Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial

Intravitreal aflibercept 8 mg could improve treatment outcomes and provide sustained disease control in patients with neovascular age-related macular degeneration (nAMD), with extended dosing compared with aflibercept 2 mg. PULSAR is a phase 3, randomised, three-group, double-masked, non-inferiority, 96-week trial conducted across 223 sites worldwide. Adults with nAMD were randomised 1:1:1 to aflibercept 8 mg every 12 weeks (8q12), aflibercept 8 mg every 16 weeks (8q16), or aflibercept 2 mg every 8 weeks (2q8), following three initial monthly doses in all groups. From week 16, patients in the aflibercept 8 mg groups had their dosing interval shortened if pre-specified dose regimen modification criteria denoting disease activity were met. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48. All patients with at least one dose of study treatment were included in the efficacy and safety analyses. This trial is registered with ClinicalTrials.gov (NCT04423718) and is ongoing. Of 1011 patients randomised to aflibercept 8q12 (n=336), 8q16 (n=338), or 2q8 (n=337) between Aug 11, 2020, and July 30, 2021, 1009 patients received study treatment (aflibercept 8q12 n=335; aflibercept 8q16 n=338; and aflibercept 2q8 n=336). Aflibercept 8q12 and 8q16 showed non-inferior BCVA gains versus aflibercept 2q8 (mean BCVA change from baseline +6·7 [SD 12·6] and +6·2 [11·7] vs +7·6 [12·2] letters). The least squares mean differences between aflibercept 8q12 versus 2q8 and 8q16 versus 2q8, respectively, were -0·97 (95% CI -2·87 to 0·92) and -1·14 (-2·97 to 0·69) letters (non-inferiority margin at 4 letters). The incidence of ocular adverse events in the study eye was similar across groups (aflibercept 8q12 n=129 [39%]; aflibercept 8q16 n=127 [38%]; and aflibercept 2q8 n=130 [39%]). Aflibercept 8 mg showed efficacy and safety with extended dosing intervals, which has the potential to improve the management of patients with nAMD. Bayer AG and Regeneron Pharmaceuticals.

A human lymphoma organoid model for evaluating and targeting the follicular lymphoma tumor immune microenvironment

Heterogeneity in the tumor microenvironment (TME) of follicular lymphomas (FLs) can affect clinical outcomes. Current immunotherapeutic strategies, including antibody- and cell-based therapies, variably overcome pro-tumorigenic mechanisms for sustained disease control. Modeling the intact FL TME, with its native, syngeneic tumor-infiltrating leukocytes, is a major challenge. Here, we describe an organoid culture method for cultivating patient-derived lymphoma organoids (PDLOs), which include cells from the native FL TME. We define the robustness of this method by successfully culturing cryopreserved FL specimens from diverse patients and demonstrate the stability of TME cellular composition, tumor somatic mutations, gene expression profiles, and B/T cell receptor dynamics over 3weeks. PDLOs treated with CD3:CD19 and CD3:CD20 therapeutic bispecific antibodies showed B cell killing and Tcell activation. This stable system offers a robust platform for advancing precision medicine efforts in FL through patient-specific modeling, high-throughput screening, TME signature identification, and treatment response evaluation.