Monoclonal IgG Research Articles

A phase II, randomized study of JMT101 in combination with irinotecan and SG001 versus regorafenib in patients with metastatic colorectal adenocarcinoma (mCRC).

TPS314 Background: Epidermal growth factor receptor (EGFR) inhibitorcombined withchemotherapy based on5-FU with oxaliplatin and irinotecanis the first-line treatment of wild-type RAS mCRC.JMT101 is a humanized monoclonal IgG1 antibody targeting EGFR. Previous trials showed that JMT101 monotherapy or in combination with chemotherapy had demonstrated a promising anti-tumor activity in advanced solid tumors with good safety profiles. EGFR inhibitor might have a synergetic effect with immunocheckpoint inhibitor (ICI) by activating innate and adaptive immune response. SG001 is a fully humanized and high-affinity immunoglobulin G4 monoclonal antibody that targets programmed death-1 (PD-1), which also had encouraging efficacy in advanced solid tumors. Therefore, EGFR antibody in combination with chemotherapy plus ICI is worthy exploration in patients with mCRC. Methods: This is a phase II, multicenter, open-label, two-part study. Part I is a safety run-in, followed by part II randomized treatment. Eligible patients are histologically confirmed mCRC without MSI-H/dMMR, wild-type RAS and BRAF, who progressed on at least 2 prior systemic therapy with chemotherapy based on 5-FU with oxaliplatin and irinotecan, with or without cetuximab and bevacizumab (both parts); no prior treatment with regorafenib, fruquintinib, or TAS-102 (part II). Safety run-in data will be analyzed after 3-6 patients have received JMT101 6 mg/kg plus irinotecan 180 mg/m 2 plus SG001 240 mg Q2W. Upon dose confirmation, 90 patients with mCRC will be randomized into three arms (1:1:1) to receive JMT101 plus irinotecan plus SG001, or JMT101 plus irinotecan, or regorafenib monotherapy. Primary endpoints include incidence of dose limiting toxicities (DLT) and adverse events (part I) and objective response rate (ORR) as per RECIST v1.1 by investigator (part II). Secondary endpoints include JMT101 and SG001 pharmacokinetic profile, antidrug antibodies (ADA) (both parts), disease control rate (DCR), duration of response (DOR), progression free survival (PFS), and overall survival (OS), as well as safety (part II). Prespecified goal for safety run-in part was met; randomized treatment part accrual began in February 2024. Clinical trial information: NCT06089330 .

Updated efficacy results of ASKB589 combined with CAPOX and PD-1 inhibitor as first-line treatment for metastatic gastric/gastro-esophageal junction (G/GEJ) adenocarcinoma from a phase Ib/II study.

454 Background: ASKB589 is a non-fucosylated fully human IgG1 monoclonal antibody that binds CLDN18.2 with high affinity, specificity, and improved ADCC and CDC activities. Previous findings indicated that ASKB589 exhibited a well-tolerated safety profile at doses up to 20 mg/kg and demonstrated promising antitumor effects. A dose of 6 mg/kg has been selected for further evaluation. Here, we present the updated data from dose expansion part in NCT05632939 study. Methods: This phase 1b/2 study was consisted of dose-escalation part and dose-expansion part. The expansion part aimed to assess the safety and efficacy of ASKB589 combined with CAPOX plus a PD-1 inhibitor as the initial treatment for advanced G/GEJ cancer with CLDN18.2 positive, regardless of PD-L1 expression. CLDN18.2 and PD-L1 expression were evaluated through IHC analysis using clone DS-3 and clone E1L3N at a central lab. All pts were given ASKB589 intravenously at a dosage of 6 mg/kg. Responses were assessed by RECIST 1.1 every 6 weeks. Adverse events were graded using CTCAE v5.0. Results: As of July 29, 2024, 49 evaluable pts with CLDN18.2 M/H expressions (≥2+ membrane staining intensity in ≥40% of tumor cells) regardless of PD-L1 CPS score. Forty pts (81.6%) achieved a partial or complete response, with a confirmed objective response rate (cORR) of 73.5% (95%CI: 58.9, 85.1). The median duration of response was 11.14 months (6.93, NE). Three subjects underwent surgical treatment as a result of tumor reduction following treatment. All 49 pts achieved SD or better with a disease control rate of 100%. cORR was 76.2% and 74.1% in the CPS<1 and CPS<5 groups, respectively. Of all treated pts (N=50), PFS rate at 9 months was 58.1% (95% CI: 42.2, 71.0) and OS rate at 12 months was 77.1% (95% CI: 61.2, 87.2). Mature PFS and OS data will be reported at the time of the conference. The safety profile of the triplet is generally consistent with the safety data of ASB589 plus CAPOX combination in first-line G/GEJ cancer pts presented previously, which was mainly characterized by manageable on-target-off-tumor effects, including hypoalbuminemia, nausea, and vomiting. Conclusions: The combination of ASKB589 with CAPOX and a PD-1 inhibitor as the initial treatment for pts with G/GEJ cancer was well tolerated with no unexpected safety signals. It has shown a high confirmed ORR, 100% disease control, deep and durable antitumor activity, regardless of PD-L1 expression levels. A phase 3 study of the triple regimen for the 1L G/GEJ cancer is actively enrolling pts in China. Clinical trial information: NCT05632939 . cORR based on CLDN18.2 and PD-L1 expression. n/N (%) PD-L1CPS<1 PD-L1CPS 1-5 PD-L1 CPS≥5 Total CLDN18.2 M&HcORR 16/21(76.2%) 7/10 (70.0%) 13/18 (72.2%) 36/49 (73.5%) CLDN18.2 Moderate cORR 2/3(66.7%) 0/1(0.0%) 6/9(66.7%) 8/13(61.5%) CLDN18.2 High cORR 14/18(77.8%) 7/9(77.8%) 7/9(77.8%) 28/36(77.8%)

A spleen is required for antibody mediated immune enhancement but not for RBC clearance or antigen-modulation in mice.

IgG against alloantigens on transfused RBC can lead to antibody-mediated immune enhancement (AMIE). AMIE has properties not found in other forms of alloimmunization, including rapid clearance of RBCs, a requirement for Fc-gamma receptors on dendritic cells, and no dependence on IFNAR. A spleen is required for alloimmunization to transfused RBCs under normal conditions but its role in AMIE has not been assessed. Mice with surgical splenectomy or sham surgery were infused with monoclonal IgG against model antigens (HOD or KEL) followed by a transfusion of respective transgenic RBCs. Antibody binding to transfused RBCs, antigen-modulation, and RBC clearance were assessed by flow cytometry. IgM and IgG to the HOD and KEL alloantigens were quantified by flow cytometry-based crossmatch. IgG to either HOD or KEL caused brisk clearance of RBCs with almost complete antigen modulation at 24 h and a strong enhancement of both IgM and IgG in sham-operated animals. In splenectomized animals, AMIE was eliminated; antigen-modulation occurred but with decreased kinetics and magnitude; and RBC clearance was the same as in sham animals. The current study extends the role of spleen as a general requirement for all known pathways of RBC alloimmunization studied thus far. However, the dissociation of clearance and antigen-modulation from AMIE shown in the current study raises the possibility that antigen-modulation and AMIE are correlated due to a confounding common cause (i.e., IgG binding RBCs).

Rescue of in vitro models of CSF1R-related adult-onset leukodystrophy by iluzanebart: mechanisms and therapeutic implications of TREM2 agonism.

Microglia dysfunction is implicated in several neurodegenerative disorders, including a rare microgliopathy; CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP). CSF1R-ALSP is caused by heterozygous loss-of-function mutations in the colony stimulating factor 1 receptor (CSF1R) gene, which encodes a receptor required for the differentiation of myeloid cells, as well as for microglial survival and proliferation. Similar functions have also been ascribed to triggering receptor expressed on myeloid cells 2 (TREM2), which shares an analogous microglia enrichment profile and converging intracellular signaling pathway mediated by spleen associated tyrosine kinase (SYK) and phosphoinositide-3-kinase (PI3K). Iluzanebart is a human monoclonal IgG1, human TREM2 (hTREM2) agonist antibody under development for the treatment of CSF1R-ALSP. To explore the therapeutic hypothesis that loss of CSF1R signaling and related microglial hypofunction can be circumvented via activation of TREM2, we evaluated the potential of iluzanebart to compensate for CSF1R loss-of-function. Herein, we demonstrate that iluzanebart is a potent, dose-dependent, and specific activator of TREM2 signaling in human primary cells. Iluzanebart treatment rescued viability of human monocyte-derived macrophages (hMDM) and induced pluripotent stem cell-derived human microglia (iMGL) in multiple in vitro models of CSF1R-ALSP, including in induced pluripotent stem cell (iPSC) differentiated microglia carrying the heterozygous I794T mutation found in CSF1R-ALSP patients. Additionally, iluzanebart treatment in microglia modulated surface levels of CSF1R, resulting in increased receptor activation as measured by phosphorylation of CSF1R. Differentially expressed genes identified in the hippocampus of mice treated with iluzanebart were exemplary of TREM2 activation and were related to cell proliferation, regulation of inflammatory processes, and innate immune response pathways. Proliferation of microglia, changes in protein levels of specific chemokines identified by gene expression analysis, and increased CSF1R levels were also confirmed in vivo. These findings demonstrate that iluzanebart is a potent and selective TREM2 agonistic antibody, with pharmacology that supports the hypothesis that TREM2 activation can compensate for CSF1R dysfunction and its continued clinical development for individuals with CSF1R-ALSP.

Efficacy and safety of risankizumab for the treatment of patients with plaque type psoriasis.

Risankizumab (Skyrizi®, Abbvie, North Chicago, IL, USA) is a humanized immunoglobulin (Ig) G1 monoclonal antibody targeting the p19 subunit of IL-23, thereby inhibiting IL-23-dependent releasing of proinflammatory cytokines in plaque psoriasis. Risankizumab is licensed is most countries for the treatment of patients with moderate-to-severe plaque psoriasis, and in Japan for generalized pustular psoriasis, erythrodermic psoriasis and palmoplantar pustulosis. Risankizumab showed higher efficacy and favorable safety profiles in patients with moderate-to-severe plaque psoriasis, compared with adalimumab, secukinumab and ustekinumab in several randomized controlled phase 3 pivotal studies and among real-life data in large retrospective studies. Furthermore, its high efficacy even in patients with prior biologic failure, better drug survival, less need for biologic switch and longer drug-free remission durations have also been shown in real-life settings and in long-term follow up. In addition, reports of both reduced dosing and increased (bolus) dosing exist which increase our ability to use risankizumab more flexibly in an era of personalized medicine. Also, the use of risankizumab in several special population, such as elderly, Asian people, erythrodermic psoriasis, patients with high induction doses, pregnancy and human immunodeficiency virus group are discussed.

P-2029. Results from a Phase 1 First in Human Study of Pemivibart: An Extended Half-Life Monoclonal Antibody (mAb)

Abstract Background Pemivibart (PEM) is a half-life extended recombinant human monoclonal IgG1 antibody that targets the SARS-CoV-2 spike protein receptor binding domain. PEM has been granted emergency use authorization (EUA) for the pre-exposure prophylaxis of COVID-19 in certain adults and adolescents with moderate-to-severe immune compromise.Table 1.Preliminary Pharmacokinetic Parameter Estimates of Pemivibart [Mean ± SD] Methods This is an ongoing Phase 1, first in human, randomized, blinded, placebo (PBO) controlled, single ascending dose study conducted in healthy participants (ppts) aged 18-65 years to evaluate PEM administered by slow IV push. Ppts were randomized 8:2 in one of 3 cohorts (n=8 PEM, n=2 placebo): PEM 1500 mg, 2500 mg, and 4500 mg. The primary objective was to assess the safety and tolerability of PEM. Secondary endpoints included serum pharmacokinetic (PK) parameters (estimated using non-compartmental analysis methodology) and immunogenicity. The trial will continue through 12 months; here we summarize the data through the 6-month timepoint.Figure 1:Mean ± Standard Deviation Serum Pemivibart Dose-Normalized Concentration-Time Profile Results Thirty ppts were randomized (24 PEM, 6 PBO); 28 ppts received the full dose as planned; two ppts received approximately 93% of the full dose of study drug due to an administration error. In the PEM arm, the median age was 32.5 years, 13.3% of ppts were 55 years or older, most ppts were white (83.3%) and not Hispanic or Latinx (93.3%). Mean body mass index was 25.78 kg/m2 across all ppts and similar between cohorts and study arms. There were no deaths, serious adverse events (SAEs), or AEs leading to permanent study drug discontinuation. Infusion-related adverse events occurred in 4 ppts (2 each in Cohort 2 and 3, respectively); these events were self-limited and resolved within 5 minutes without treatment. No unexpected safety signals were observed. PEM demonstrated linear PK with apparent dose-proportional exposure and extended serum half-life (mean 46, 44, and 50 days in Cohort 1, 2, and 3, respectively [Table 1]). No substantial anti-drug antibodies (ADAs) have been observed. Conclusion In this Phase 1 study of PEM administered by slow IV push at doses up to 4500 mg, no AEs leading to study drug discontinuation, or SAEs were reported to date in healthy adults. PEM demonstrated linear and dose-proportional PK. Complete trial data to be presented. Disclosures Anna Holmes, PhD, Invivyd, Inc.: employee|Invivyd, Inc.: Stocks/Bonds (Private Company) Yong Li, PhD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Deepali Gupta, BSc, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Ed Campanaro, MS, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Lida Mehr, B.S., Invivyd, Inc.: Advisor/Consultant Anuja Raut, M.S., Invivyd, Inc.: Advisor/Consultant Amanda Copans, Pharm.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Kristin Narayan, Ph.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Kathryn Mahoney, PharmD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company)

P-2035. Pharmacokinetics (PK) and Serum Virus Neutralizing Antibody (sVNA) Titers Following the 2nd dose of Pemivibart in the Phase 3 CANOPY Trial

Abstract Background Pemivibart (PEM) is a half-life extended recombinant human monoclonal IgG1 antibody that targets the SARS-CoV-2 spike protein receptor binding domain. PEM has been granted emergency use authorization (EUA) for the pre-exposure prophylaxis of COVID-19 in certain adults and adolescents with moderate-to-severe immune compromise, with dosing recommended every 3 months. Methods CANOPY (NCT06039449) is a Phase 3 study investigating PEM 4500 mg for the prevention of COVID-19 that enrolled adult (≥18 years) participants (ppts) with immune compromise (Cohort A, single arm, open label) and those at risk of exposure to SARS-CoV-2 (Cohort B, randomized 2:1 to PEM or placebo). Ppts received an initial dose of study drug administered via intravenous (IV) infusion on Day 1 followed by a second dose approximately 3 months later (i.e., month 3). Serum samples were collected for PK analysis at the month 3 visit prior to and after receipt of the second PEM dose and at month 6 and month 12. Here we describe calculated sVNA titers for ppts in Cohort A following a second dose of PEM and further estimates from a population PK (PPK) model constructed with available data from a Phase 1 first-in-human study and the Phase 3 CANOPY study. Results At the completion of the second (i.e., month 3) dose of PEM, the calculated sVNA geometric mean titer (GMT) to the SARS-CoV-2 Omicron JN.1 variant in Cohort A ppts was 17% higher than the corresponding value following the initial PEM dose. This is consistent with the estimated accumulation ratio based on the PPK model. Based on this model, the median calculated GMT is predicted to remain above the predefined protection titer threshold of 3514 for at least 90 days following dosing at month 3 (Figure 1). The steady-state AUC over the entire 3-month dosing interval is estimated to be approximately 30% higher than the AUC observed following the initial dose. Conclusion A second dose of PEM 4500 mg IV given at month 3 boosted calculated sVNA titers and is anticipated to provide continued protection above predefined protection titer thresholds in immune compromised participants through 90 days post-dose for JN.1. The overall risk-benefit of PEM supports use in certain adults and adolescents with moderate-to-severe immune compromise for the prevention of COVID-19 per the EUA. Disclosures Anna Holmes, PhD, Invivyd, Inc.: employee|Invivyd, Inc.: Stocks/Bonds (Private Company) Yong Li, PhD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Deepali Gupta, BSc, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Chloe Katz, PMP, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Mike Gavazzi, B.S., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Pamela Hawn, Pharm.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Kathryn Mahoney, PharmD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Myra Popejoy, Pharm.D., Invivyd, Inc.: employee|Invivyd, Inc.: Stocks/Bonds (Public Company)

91. Clinical Efficacy Endpoints from the Phase 3 CANOPY Study Evaluating Pemivibart

Abstract Background Pemivibart (PEM) is a half-life extended recombinant human monoclonal IgG1 antibody that targets the SARS-CoV-2 spike protein receptor binding domain. PEM has been granted emergency use authorization (EUA) for the pre-exposure prophylaxis of COVID-19 in certain adults and adolescents with moderate-to-severe immune compromise. Methods CANOPY (NCT06039449) is a Phase 3 study investigating the prevention of COVID-19 in immunocompromised participants (ppts) (Cohort A; single arm, open label) and in ppts at risk of exposure to SARS-CoV-2 (Cohort B; randomized 2:1 PEM 4500 mg or placebo). Ppts received an initial dose of study drug administered via intravenous (IV) infusion on Day 1 followed by a second dose of study drug approximately 3 months later. The safety, tolerability, pharmacokinetics (PK), immunogenicity, and clinical efficacy of PEM is being evaluated. Here we describe an exploratory endpoint of reverse transcription polymerase chain reaction (RT-PCR)-confirmed symptomatic COVID-19 that developed within 90 days following the first administration of either PEM or placebo among ppts without SARS-CoV-2 infection at baseline. Nasopharyngeal and saliva samples were collected for central SARS-CoV-2 testing by RT-PCR and subsequent whole genome sequencing (WGS). Results RT-PCR-confirmed COVID-19 cases were observed in 3 of 298 ppts (1%) with significant immune compromise who received a full initial dose of PEM in Cohort A and 9 of 484 (1.9%) ppts who received either PEM or placebo in Cohort B. In Cohort B, RT-PCR confirmed COVID-19 cases were observed in 1 (0.3%) PEM-treated ppt compared to 8 (5.0%) placebo-treated ppts (Absolute Risk Reduction: -4.73% (95% CI: -8.2, -1.3), nominal p = 0.0070). Characteristics of these cases are described in Table 1. All but one COVID-19 case were self-reported as mild or moderate in severity. SARS-CoV-2 variants including JN.1, EG.5.1, and other related lineages were identified. Conclusion This exploratory analysis of COVID-19 events demonstrated a clinically meaningful reduction in COVID-19 with PEM treatment versus placebo. Disclosures Myra Popejoy, Pharm.D., Invivyd, Inc.: employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Anna Holmes, PhD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Chloe Katz, PMP, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Anne-Marie Phelan, MA, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Kazima Tosh, Ph.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Yong Li, PhD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Deepali Gupta, BSc, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Pamela Hawn, Pharm.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Kristin Narayan, Ph.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Kathryn Mahoney, PharmD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Mark Wingertzahn, Ph.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company)

P-1837. Development and Validation of a Novel Multiplex Immunoassay for the Measurement of the Antibodies against Pneumococcal Vaccine Serotypes

Abstract Background Enzyme-linked immunosorbent assay (ELISA) is a traditional WHO recommended method to measure antibody levels against pneumococcal vaccines. However, ELISA is limited in its capacity to assess all 24 pneumococcal vaccine serotypes simultaneously, which is time-consuming, labor-intensive, and it requires a large amount of serum samples. Therefore, we require a high-throughput assay to assess all vaccine serotypes simultaneously and efficiently to assess pneumococcal vaccine impact at a population level. Methods Twenty-four pneumococcal polysaccharide antigens were coupled with 24 distinct colored microspheres by employing the carboxyl method. These conjugated microspheres were exposed to the WHO reference serum in a well of a 96-well plate. The WHO reference serum contained 24 serotype-specific pneumococcal antibodies whose concentrations were known. After washing, a mouse anti-human IgG monoclonal antibody (a secondary antibody tagged with phycoerythrin) interacted with the antigen-antibody complex, and then the final reaction was read on the Bio-Plex 200 System (BioRad). We performed assay validation parameters, such as sensitivity, specificity, linearity, and reproducibility according to the WHO recommendation. Results A 4.0 log10 of dynamic range was observed in all standard curves specific for 24 serotypes. Depending on specific serotypes, a lower limit of quantitation (sensitivity) varied from 0.40 ng/mL to 10.05 ng/mL. The assays were highly specific for individual serotypes, except for 6A and 6B, and 19F and 19A (some cross-reactivity was observed, which was known and expected among these serotypes). Specificity was >90% in all serotypes, except serotypes 8 (87%) and 14 (59%). Reproducibility trials showed that the coefficient of variation for all serotypes was < 20% (desired limit), except serotype 19A (29.7%) and 23F (25.4%). Conclusion We have developed and validated the novel microsphere-based assay. As this assay enables the simultaneous measurement of 24 vaccine serotype-specific antibodies in a single well, it will reduce workload, the need for the amount of serum, and the overall cost. We expect to use this assay in pneumococcal vaccine immunogenicity studies among an elderly population in Japan and among young children in Nepal. Disclosures Konosuke Morimoto, MD, PhD, Pfizer: Grant/Research Support Koya Ariyoshi, MD, PhD, Pfizer: Grant/Research Support

Bimekizumab efficacy and safety through 3 years in patients with moderate to severe plaque psoriasis: Long-term results from the BE RADIANT phase 3b trial open-label extension period.

Overexpression of interleukin (IL)-17A and IL-17F significantly influences psoriasis pathology. Until recently, biologics targeting IL-17A alone, like secukinumab, were used to treat psoriasis. Bimekizumab is a monoclonal IgG1 antibody that targets both IL-17A and IL-17F. BE RADIANT was the first phase 3 study to investigate switching from selective inhibition of IL-17A to dual inhibition of IL-17A and IL-17F.Bimekizumab has previously shown superior achievement of complete skin clearance (PASI 100) versus secukinumab through 48 weeks. Switching from secukinumab to bimekizumab resulted in improved clinical responses. Over 2 years, no new safety signals were observed. To report 3-year efficacy and safety of bimekizumab in patients with moderate to severe plaque psoriasis receiving continuous bimekizumab, or switching from secukinumab after 1 year. The BE RADIANT phase 3b randomised controlled trial had a 48-week double-blinded period, in which patients received bimekizumab (320 mg every 4 weeks [Q4W]), or secukinumab (300 mg weekly to Week 4, then Q4W). At Week 16, bimekizumab-randomised patients underwent re-randomisation to receive Q4W or Q8W maintenance dosing. From Week 48 onwards (open-label extension), all received bimekizumab. 336 bimekizumab- and 318 baseline secukinumab-randomised patients entered the open-label extension. Among these, more bimekizumab-randomised patients achieved PASI 100 (modified non-responder imputation) at Year 1 (74.9%) versus secukinumab-randomised patients (52.8%). PASI 100 response rates were maintained over 3 years in bimekizumab-treated patients (68.8%) and increased in secukinumab-randomised patients switching to bimekizumab (68.8%).Bimekizumab was well-tolerated to 3 years. In patients receiving ≥1 bimekizumab dose, the most common treatment-emergent adverse events (TEAEs) over 3 years were nasopharyngitis, oral candidiasis, and upper respiratory tract infection (exposure adjusted incidence rates: 12.2, 10.0, and 5.5/100 patient-years, respectively). Rates of TEAEs of interest, including serious infections, inflammatory bowel disease, and suicidal ideation and behaviour, did not increase with longer exposure to bimekizumab from 1 to 3 years. Over two-thirds of bimekizumab-randomised patients and those switching from secukinumab to bimekizumab achieved and maintained complete skin clearance over 3 years of treatment. Over 3 years, bimekizumab was well-tolerated, and TEAE rates did not increase with longer exposure.

De novo proliferative glomerulonephritis with monoclonal IgG deposits in an adolescent kidney transplant recipient.

Proliferative Glomerulonephritis with Monoclonal IgG Deposits (PGNMID) is a glomerular disease characterized by membranoproliferative and mesangioproliferative lesions, with granular capillary wall monoclonal IgG positivity and immunoglobulin light chain restriction. Most commonly a disease of older adults, we present the case of an 18-year-old patient who developed de novo PGNMID in a kidney allograft three years after kidney transplantation. There was minimal proteinuria and no serum paraproteinemia was detected, so the patient was managed conservatively. To our knowledge, this is the youngest reported case of de novo PGNMID occurring in a kidney allograft and highlights the importance of considering PGNMID as a possible etiology of de novo glomerular disease in adolescent and young adult patients.

P0609 Real-world short and long-term effectiveness of risankizumab in refractory Crohn’s disease: RISANCROHN study from the ENEIDA Registry

Abstract Background Phase III trials have demonstrated the efficacy of risankizumab (RZB), this being the first humanized monoclonal IgG1 antibody which targets the interleukin 23 p19 subunit, in Crohn’s disease (CD). However, real-world data with this drug is limited. The aim of our study was to assess the real-world effectiveness of RZB in patients with CD. Methods Adult CD patients that had received treatment with RZB in the ENEIDA registry —a large prospectively maintained Spanish database promoted by the Spanish Working Group of Crohn’s and Colitis (GETECCU)— were included. Clinical and demographical data including number of previous biologics and advanced therapies were included. The primary endpoints were steroid-free clinical remission (SFCR) after induction period (Harvey-Bradshaw score <5) and long-term SFCR at the end of follow-up. Influence of previous use of ustekinumab (UST) and number of previous advanced therapies in short- and long-term efficacy was also evaluated. Statistical analysis was performed using the Chi-square/Student-t test and multivariate analysis with logistic regression. Results 857 CD patients (60% male) were included: median age 50 (18-84) years, median disease duration 14 years, 27% smokers. 50% were L1, 8% L2, 38% L3, and 4% exclusively L4. B1 phenotype was present in 42%, 37% B2, 21% B3. Perianal disease was present in 28%, 46% had previously CD-related surgery and 39% extraintestinal manifestations. Only 3% were biological naïve, 50% had been exposed to 1-2 advanced therapies, and 47% to 3 or more. Following induction 56% of the patients achieved SFCR. Remission was more frequent in patients who had not previously been treated with UST (64% vs. 53% in those previously exposed to UST, p<0.01). In the multivariate analysis, a higher number of prior advanced therapies was associated with lower remission rates (p<0.01). Long-term efficacy was evaluated in 652 patients (median follow-up 7 months). At the end of the follow-up 61.2% of patients maintained SFCR. Long-term remission rate in patients non-exposed to UST was 72%, and 55% exposed to UST (p<0.01). In the multivariate analysis, younger age was associated with higher long-term remission rates (p<0.01). 11% needed dose optimization/reinduction during follow-up. 68 patients (7.9%) presented adverse events but only 18 (2%) needed to give up the treatment. Conclusion This study represents the largest cohort of real-world data on RZB in CD, including highly refractory patients with multiple prior drug failures. RZB induced SFCR in 56% of patients after induction and 61% in the long term. Higher remission rates were observed in patients who had never been exposed to UST. Younger age and fewer previous advanced therapies were associated with better outcomes.

OP41 Duvakitug (TEV-48574), an anti-TL1a monoclonal antibody, demonstrates efficacy and favourable safety as an induction treatment in adults with moderately to severely active ulcerative colitis: Results from a phase 2b, randomised, double-blind, placebo-controlled, dose-ranging, basket trial (RELIEVE UCCD)

Abstract Background Duvakitug is a human IgG1 monoclonal antibody that inhibits TL1A binding to DR3, a key driver of inflammation and fibrosis. In comparison, it has less binding selectivity for DcR3, which regulates excess TL1A, maintaining homeostasis. Duvakitug has demonstrated reduced inflammation and fibrosis in colitis animal models.1 The efficacy and safety of duvakitug in adults with moderately to severely active ulcerative colitis (UC) and Crohn’s disease was assessed in a phase 2b basket trial (NCT05499130).2 Methods RELIEVE UCCD was a randomised, placebo (PBO)-controlled, double-blind induction study. The UC cohort comprised of adults with moderately to severely active disease with inadequate response, loss of response or intolerance to previous conventional and/or advanced therapies (ATs). Eligible patients were randomised to receive subcutaneously a 2250 mg loading dose of duvakitug or PBO, followed by either duvakitug 450 mg, 900 mg or PBO (1:1:1; stratified by prior AT) every 2 weeks.2 The primary endpoint was clinical remission (per modified Mayo score) at week 14. Safety was assessed by adverse event (AE) reporting and laboratory monitoring. Results In total, 137 patients were randomised, treated and included in the UC cohort analysis (450 mg: n=47; 900 mg: n=46; PBO: n=44). Demographics and baseline characteristics were generally similar across arms (Table 1). Both duvakitug doses successfully achieved the week 14 primary endpoint of clinical remission (36% [450 mg], 48% [900 mg] versus 20% [PBO]; PBO-adjusted rates: 16% [450 mg], 27% [900 mg]). The results were statistically significant based on the prespecified Bayesian analysis, with a >0.90 posterior probability that each duvakitug dose is superior to PBO. Duvakitug treatment effect was observed in both AT-experienced and -naïve patients (Table 2). AE incidence was lower for duvakitug (49% [450 mg], 43% [900 mg]) versus PBO (52%), as was incidence of AEs leading to discontinuation (0% [450 mg], 2% [900 mg] versus 5% [PBO]). Conclusion Duvakitug demonstrated statistically significant and clinically meaningful treatment responses compared to PBO in patients with UC; it was well tolerated with no emergent safety signals observed. These induction study results support further development of duvakitug as a potential treatment option for patients with moderately to severely active UC. Funding Duvakitug is being developed in partnership by Teva and Sanofi.

OP40 Duvakitug (TEV-48574), an anti-TL1a monoclonal antibody, demonstrates efficacy and favourable safety as an induction treatment in adults with moderately to severely active Crohn’s disease: results from a phase 2b, randomised, double-blind, placebo-controlled dose-ranging, basket trial (RELIEVE UCCD)

Abstract Background Duvakitug is a human IgG1 monoclonal antibody that inhibits TL1A binding to DR3, a key driver of inflammation and fibrosis. In comparison, it has less binding selectivity for DcR3, which regulates excess TL1A, maintaining homeostasis. Duvakitug has demonstrated reduced inflammation and fibrosis in colitis animal models.1 Few data are available for the potential of anti-TL1A therapies in Crohn’s disease (CD). A phase 2b induction basket trial (NCT05499130)2 assessed the efficacy, safety and tolerability of duvakitug in adults with moderately to severely active ulcerative colitis and CD. Methods RELIEVE UCCD was a randomised, placebo (PBO)-controlled, double-blind induction study. The CD cohort comprised of adults with moderately to severely active disease with documented inadequate response, loss of response or intolerance to conventional and/or advanced therapies (ATs). Patients were randomised to receive subcutaneously a 2250 mg loading dose of duvakitug or PBO, followed by either duvakitug 450 mg, 900 mg or PBO (1:1:1; stratified by prior AT) every 2 weeks.2 Primary endpoint was endoscopic response (≥50% reduction from baseline in Simple Endoscopic Score for CD [SES-CD]) at week 14. Safety and tolerability were assessed by adverse event (AE) reporting and laboratory monitoring. Results In total, 138 patients with CD were randomised, treated and included in the analysis (n=46 per arm). Demographics and baseline characteristics were similar across arms (Table 1). Both duvakitug doses achieved the primary endpoint (26% [450 mg], 48% [900 mg] versus 13% [PBO]; PBO-adjusted rates: 13% [450 mg], 35% [900 mg]) with statistically significant endoscopic responses based on the prespecified Bayesian analysis, with a >0.90 posterior probability that each duvakitug dose is superior to PBO. Duvakitug treatment effect was observed in both AT-experienced and -naïve patients (Table 2). AE incidence was similar for duvakitug 900 mg (43%) and PBO (48%), and lower than duvakitug 450 mg (67%). Incidences of AEs leading to discontinuation were 2% each for duvakitug 900 mg and PBO, and 9% for duvakitug 450 mg. Conclusion These are the first data reported for a double-blind, randomised, PBO-controlled induction study of an anti-TL1A antibody in patients with CD. Duvakitug demonstrated statistically significant and clinically meaningful endoscopic response versus PBO with no emergent safety signals observed. These results support further development of duvakitug as a treatment option for patients with moderately to severely active CD. Funding Duvakitug is being developed in partnership between Teva and Sanofi.

P0587 Effectiveness and safety of Risankizumab in Crohn’s disease patients from a large Italian cohort: preliminary results from the RESOLVE IgIBD study

Abstract Background Risankizumab has been recently approved for the treatment of moderate-to-severe Crohn's disease (CD). It is a humanized IgG1 monoclonal antibody that binds to the p19 subunit of IL-23, selectively inhibiting IL-23. Due to the limited available real-world data on its effectiveness, this study aims to assess the short-term effectiveness and safety of risankizumab induction in a large, real-life Italian cohort of CD patients. Methods From September 2023, following AIFA reimbursement, until now, all consecutive CD patients treated with risankizumab in 14 Italian centers were retrospectively enrolled. Only patients who completed the induction phase of risankizumab, with at least a 12-weeks follow-up were included in the final analysis. Clinical characteristics, disease activity scores, steroid usage, and adverse effects were collected. The primary endpoint was steroid-free clinical remission (SFCR) (Harvey Bradshaw Index [HBI] <5) at 12 weeks. Secondary endpoints included clinical response (≥3 point decrease in HBI and/or HBI <5), biochemical remission (CRP≤ 5 mg/L), remission of extra-intestinal manifestations (EIMs), occurrence of disease complications, and adverse events. Results To date, 147 patients have been enrolled, with 67 completing the 12-week follow-up. Of these, 34 (50.7%) patients had received ≥3 biologics, and 38 (56.7%) had previous intestinal resections. Fifty-four patients underwent colonoscopy within the last 6 months before starting risankizumab, exhibiting a mean SES-CD of 10.9±6.0 and a mean Rutgeerts score of 3.1±1.4. The rates of SFCR and clinical response at week 12 were 58.2% (39/67) and 76.1% (51/67) respectively, while 53.7% (22/41) and 65.9% (27/41) in ustekinumab exposed patients. Fecal calprotectin levels decreased from 963.6±1346.0 to 311.8±403.0 at week 12. Thirty-eight patients (56.7%) achieved normal CRP levels at week 12. Clinical remission of rheumatological and dermatological EIMs was observed at week 12 in 16.7% (3/18) and 75.0% (6/8) of patients, respectively. Two patients developed disease complications, including one case of worsening of the disease and one of new fistula development. This latter patient discontinued treatment before week 12. Additionally, two patients (3.0%) experienced minor adverse events after risankizumab administration. No patients underwent surgery during the 12-weeks follow-up. Conclusion In a large cohort of refractory CD patients with multiple prior drug failures, including frequent failures with ustekinumab, nearly 60% achieved SFCR following risankizumab induction. Risankizumab demonstrated good effectiveness in managing dermatological EIMs, but less effectiveness in rheumatological EIMs. The safety profile of risankizumab was consistent with existing literature.

DOP014 Efficacy and safety up to 3 years of risankizumab maintenance treatment in patients with moderately to severely active ulcerative colitis: interim results from phase 3 COMMAND open-label extension study

Abstract Background Risankizumab (RZB), a high-affinity humanised IgG1 monoclonal antibody targeting interleukin-23 p19, has shown sustained efficacy and an acceptable safety profile for patients (pts) with ulcerative colitis (UC).1 This interim analysis reports efficacy data at week (wk) 0 and wk 96, as well as safety data of the COMMAND (NCT03398135) open-label extension (OLE). Methods The COMMAND OLE enrolled pts who completed 52-wks maintenance dosing in the COMMAND substudies or entered directly from the induction study.1 All pts received RZB180 subcutaneous (SC) starting at OLE wk 0, except pts who had prior rescue therapy (single RZB 1200 mg intravenous [IV] dose then RZB360 Q8w) who continued RZB360 in the OLE. The OLE was not designed to compare RZB180 and RZB360 groups. The data cut-off date for this interim analysis was as of June 30, 2024. Efficacy endpoints assessed were clinical remission (CR) per AMS, clinical response per AMS, endoscopic improvement, endoscopic remission, and corticosteroid-free CR per Partial AMS up to wk 96. Data are reported as observed prior to RZB rescue therapy during OLE. The safety analysis also includes pts who directly entered the OLE from induction; presented as events/100 pt years (E/100 PY). Results Of the pts who entered the OLE (RZB180, N = 701; RZB360, N = 302), approximately 40% of pts had the opportunity to reach OLE wk 96 as of the cut-off date. At OLE wk 0 and 96, a similar proportion of patients in the RZB180 group achieved clinical and endoscopic outcomes (Figure 1A). In the RZB360 group, the percent of pts achieving clinical and endoscopic endpoints increased from OLE wk 0 through OLE wk 96 (Figure 1B). Similar rates of serious AEs, severe AEs, and AEs leading to discontinuation of study drug were reported in the RZB180 group and the RZB360 group with no new safety risks identified (Table 1). Conclusion In this interim analysis of the OLE, a sustained benefit was observed with long-term RZB treatment up to 96 wks. The long-term safety profile for RZB remains consistent and supports the long-term use.

DOP099 Prolonged Pharmacodynamic Effects of Risankizumab Following Withdrawal in Patients with Moderately to Severely Active Ulcerative Colitis

Abstract Background Risankizumab (RZB) is a high-affinity humanized IgG1 monoclonal antibody that selectively binds to the p19 subunit of human IL-23 cytokine, thereby inhibiting its interaction with the IL-23 receptor.1 RZB was intentionally designed with modifications to the antibody that could contribute to prolonged half-life, low immunogenicity, and increased stability and bioavailability.1 The objective of this post-hoc analysis was to characterise the pharmacokinetic (PK) and pharmacodynamic (PD) effects of RZB following withdrawal in patients with moderately to severely active ulcerative colitis (UC). Methods In the UC maintenance trial (COMMAND, NCT03398135), 272 patients who responded to 12 weeks of intravenous (IV) RZB 1200 mg induction therapy were re-randomised to receive subcutaneous (SC) RZB maintenance dosing (180 mg or 360 mg) or placebo (PBO; RZB withdrawal).2 This analysis evaluated clinical endpoints, PK, and biomarkers of the SC PBO/withdrawal. Change from baseline in partial modified Mayo score, serum RZB concentrations and levels of high-sensitivity C-reactive protein (hs-CRP) and fecal calprotectin (FCP) were assessed at each predetermined study visits throughout the maintenance trial. Results A total of 90 patients were re-randomised to receive PBO (withdrew from RZB induction) in COMMAND. Predicted PK profiles of exposure over time in the PBO/withdrawal group showed that, following the third and final RZB induction dose, residual RZB concentrations lasted for at least 16 weeks before complete washout.3 The PBO/withdrawal group did not have meaningful increases from baseline in partial modified Mayo score until after about week 24 of maintenance (36 weeks since the last dose of RZB) (Figure). Levels of hs-CRP and FCP in the PBO/withdrawal patients remained low throughout maintenance and did not meaningfully increase until week 52. Conclusion Patients with moderately to severely active UC who received IV RZB 1200 mg induction therapy and were re-randomised to PBO exhibited continued response to RZB as demonstrated by disease activity and biomarkers for at least 6 months, exceeding the time of PK washout. hs-CRP and FCP did not increase until week 52 of maintenance and remained below baseline values. This durability of response may have important clinical implications and warrants continued investigation.

P0637 Ebrasodebart (Ent001) First in Human trial in healthy volunteers: pharmacokinetic results and predicted therapeutic concentrations to preserve mucosal healing in patients with Ulcerative Colitis

Abstract Background Ebrasodebart (Ent001) is a human IgG4 monoclonal antibody that antagonizes the binding of IGFBP3 to the novel cell death receptor TMEM219, expressed on Intestinal Stem Cells (ISCs) and well conserved across human and animal species. Ebrasodebart is thus expected to inhibit TMEM219-mediated activation of Caspase-8 and the exaggerated apoptosis of ISCs observed in patients with Ulcerative Colitis (UC). Ebrasodebart is currently in clinical development as a novel first-in class investigational treatment in patients with UC. A FIH single ascending dose (SAD) study in healthy volunteers (HVs) was conducted to define the safety, tolerability and pharmacokinetics (PK) of ebrasodebart at the concentrations anticipated to be required to elicit pharmacological and therapeutic activity in patients. Methods Thirty (30) HVs were enrolled in the monocentric, randomized, double-blind, placebo-controlled SAD study, 29 subjects completed the study. In vitro and in vivo concentration-response preclinical experiments defined the pharmacologically active concentrations, measuring the inhibition of IGFBP3-induced Caspase-8 activation in human intestinal epithelial cell lines and organoids, and the exposure-response in DSS-induced chronic colitic mice, while modeling and simulation (M&S) predicted effective concentrations. Results After single intravenous (IV) doses of ebrasodebart in HVs, maximum exposure (Cmax) and systemic exposure (AUCinf) increased in an approximately dose proportional manner with a low intersubject variability at all dose levels (CV% < 20% for Cmax and AUCinf). Geometric mean t1/2 was between 17 to 19 days at the predicted therapeutic doses. Ebrasodebart achieved a Cmax of 296 µg/mL and AUC0-inf of 37646 µg/mL*h well below the No Observed Adverse Effect Level (NOAEL) from the 26-week chronic toxicity study in monkeys, but significantly higher than the minimal pharmacologically active concentration in vitro. The concentrations achieved in the FIH trial were also higher than those that significantly reduced the Disease Activity Index and both histological and endoscopic scores in mice, exceeding M&S predictions for pharmacological effectiveness in patients. Conclusion These data indicate that ebrasodebart concentrations with predictable PK and expected therapeutic efficacy can be safely reached in humans, and remained significantly below the NOAEL in monkeys, suggesting a potential for a wide therapeutic window in patients. A multicentric Phase 1b, randomized, double-blind, placebo-controlled trial is ongoing to evaluate safety, tolerability, PK, immunogenicity and preliminary efficacy of multiple ascending doses of ebrasodebart in patients with moderately to severely active UC.

P0717 Real-world data of Mirikizumab in the induction and maintenance therapy for ulcerative colitis

Abstract Background Mirikizumab, a humanized IgG4 monoclonal antibody binding subunit p19 of interleukin 23, has been approved for the therapy of ulcerative colitis since May 2023. Phase 3 studies showed significant efficacy in both inducing and sustaining clinical remission in patients with moderate to severe active ulcerative colitis. Methods All patients with active ulcerative colitis who began induction therapy with Mirikizumab at our outpatient clinic between July 2023 and June 2024 were analyzed retrospectively with a follow-up period until October 2024. Patients with prednisolone therapy exceeding 20 mg, loperamide intake or deviation of standard clinical application period were excluded. The primary endpoints were defined as achieving clinical remission following the completion of intravenous induction (at weeks 12, 16 or 24) and the maintenance of clinical remission at any time between week 8 and week 49 following the initiation of subcutaneous application. Secondary endpoints included rates of clinical remission and relapse in patients previously treated with Ustekinumab, a monoclonal antibody targeting the p40 subunit of interleukin-12 and -23. Results A total of 40 patients started Mirikizumab induction therapy, with 23 meeting the inclusion criteria. Seventeen patients were observed in the maintenance period. After completion of induction, 20 out of 23 patients (87.0%) achieved clinical remission. Among these, 12 (60.0%) had previously been treated with Ustekinumab. During the maintenance period, 6 out of 17 patients (35.3%) experienced a relapse, of whom 5 (83.3%) had prior therapy with Ustekinumab. Within the Ustekinumab subgroup, 5 out of 10 patients (50.0%) suffered relapse after initially achieving clinical remission. Conclusion Mirikizumab is an effective therapy in patients with active ulcerative colitis, including those who had a prior loss of response to Ustekinumab therapy. Patients with prior Ustekinumab therapy exhibited a higher rate of relapse during the maintenance phase.

P1112 Pharmacokinetic comparability and safety between original and citrate-free mirikizumab formulations for subcutaneous injections: Results from three clinical trials in healthy participants

Abstract Background Mirikizumab (miri), a humanized IgG4 monoclonal antibody which selectively binds to the p19 subunit of human IL-23, is administered via subcutaneous (SC) injection. Since injection site pain (ISP) may be negatively affected by formulation buffer excipients such as citrate1, a citrate-free (CF) formulation of miri has been developed. We assessed the bioequivalence, ISP, and overall safety of the CF formulation of miri. Methods Three phase 1, two-arm, randomised, single-dose, subject-blind, parallel design studies were conducted in healthy subjects: one pilot relative bioavailability (RBA) study A (NCT04548219), and two bioequivalence (BE) studies B (NCT05515601) and C (NCT05644353). Subjects were randomised 1:1 to CF or original miri in all studies. The primary endpoint in all studies was to assess the comparability between CF and original formulations via Cmax, area under the concentration versus time curve (AUC) (0-∞), and AUC(0-tlast). Study A assessed the RBA of a single 200 mg SC dose, Study B assessed the BE of a single 200 mg SC dose, and Study C assessed the BE of a single 300 mg SC dose. The 200 mg and 300 mg doses are proposed for ulcerative colitis and Crohn’s disease, respectively. The secondary endpoint was safety assessment by spontaneous treatment-emergent adverse events and serious adverse events. In addition, in Study A, ISP was also quantified prospectively using the 100-mm validated visual analogue scale (VAS) assessment form2. Injection site reactions (ISRs) were prospectively assessed in Study A. Results The number of subjects who received miri were 60 in Study A, 396 in Study B, and 450 in Study C. Baseline characteristics were similar across studies and treatment groups. There was no statistically significant difference in exposure between the formulations in Study A. Figure 1 shows that the CF formulation demonstrated BE in Studies B and C, with the 90% confidence intervals (CIs) of the ratios of geometric least squares means (LSM) within the pre-specified equivalence limits. Figure 2 shows a statistically significant difference of 13.43 in the VAS Pain Score LSM at 1-minute post-dose for Study A, which is also considered clinically relevant3. Overall, CF and original miri demonstrated an acceptable safety profile consistent with previous work in healthy participants. Conclusion The CF formulation of mirikizumab is bioequivalent to the original formulation and is associated with a lower VAS pain score which may positively affect treatment experience.