Human Immunoglobulin G1 Monoclonal Antibody Research Articles

#425 Felzartamab (anti-CD38) in patients with IgA Nephropathy—interim results from the IGNAZ study

Abstract Background and Aims Most patients with IgA nephropathy (IgAN) will progress to kidney failure within 10-15 years of diagnosis. Sustained proteinuria is the best predictor of adverse long-term kidney outcomes and is a surrogate marker for efficacy. CD38+ plasma cells are likely the main source of pathogenic Gd-IgA1, and the related autoantibodies in IgAN. Felzartamab (felza; HIB202) is a recombinant purified human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to CD38 on plasma cells and is being studied across immune-mediated kidney diseases such as IgAN, Primary Membranous Nephropathy, Lupus Nephritis, and Antibody Mediated Rejection. The primary aims of the IGNAZ study were to assess: 1) efficacy of felza compared to placebo on urine protein:creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR) change from baseline, and 2) the relationship between exposure, safety, and efficacy in each of 3 dose groups vs. placebo. Interim results with 15 months of follow-up from this 24-month trial are presented. Method In Part 1, 48 IgAN subjects were randomized in a 1:1:1:1 ratio across a placebo and 3 active arms in this multicenter, double-blind placebo-controlled, phase IIa trial. The M1, M2, and M3 active arms received 2 doses in 15 days, 5 doses in 2 months, and 9 doses in 5 months, respectively. In Part 2, 6 Japanese subjects received the M3 regimen, open-label, and have been followed for 9 months. Key inclusion criteria included ages 18-80 years, biopsy confirmed diagnosis of IgAN within the past 8 years, proteinuria at screening ≥1.0 g/d, eGFR ≥30 ml/min/1.73 m2 (by CKD-EPI), and background stable and maximally tolerated renin angiotensin system inhibitors. Results 48 randomized subjects were enrolled at 28 sites in the US and in 14 different countries in Europe and in Asia, of which 46 completed the treatment phase. Mean (SD) baseline characteristics (Parts 1 and 2 combined): age 41.6 (12.3) yrs, UPCR 1.67 (1.0) g/g, eGFR 74.6 (30.3) ml/min/1.73 m2. 67% of subjects were male. Intention-to-treat with felza demonstrated rapid, clinically meaningful reductions in UPCR with the maximal treatment effect being observed in the M3 9-dose regimen. In Part 1, percentage change from baseline in UPCR was −14% for placebo and −25% for M3 9-dose arm at month 3, and +9% for placebo and −35% for M3 at month 6 (Fig. A). Reductions in proteinuria observed at month 6 persisted until Month 15, 10 months after the last dose: +6% and −38% mean UPCR change from baseline for placebo and the M3 9-dose arm, respectively (Fig. B). Relatively stable eGFR values were observed for the felza arms compared to loss of eGFR in the placebo arm. Rapid, durable reductions in IgA and Gd-IgA1 levels were seen across the dosing arms, with reductions lasting 10 months after the last dose (Fig. C). IgG recovery occurred faster off-treatment than IgA. Results in the Part 2 subjects were similar to the Part 1 M3 cohort through 9 months. There were no apparent dose-dependent adverse events and no exposure-safety relationship. Treatment-emergent adverse events (TEAEs) were generally of mild or moderate intensity or toxicity grade. The most common TEAE assessed as related by study investigator was infusion related reactions (IRR), most of which occurred on the first infusion. There was one treatment-related serious AE due to an IRR. Five subjects discontinued treatment due to IRRs or drug hypersensitivity; for four of the five subjects, the infusion rate was higher than protocol-specified or had an error in pre-medication. TEAE infections were comparable between placebo and felza arms: Placebo (33.3%), M1 (33.3%), M2 (36.4%), M3 (38.5%), Part 2 (50.0%); all were Grades 1 or 2, and non-serious. Conclusion This proof-of-concept study highlights the potential for disease modification in IgAN with the anti-CD38 mAb felza and supports continued research as a potential treatment for high-risk IgAN patients. Felza treatment resulted in clinically meaningful, prolonged UPCR reductions and eGFR stabilization sustained ≥10 months after dosing was completed. Felza was generally well tolerated with rapid recovery of IgG with durable reductions in IgA and pathogenic Gd-IgA1 levels.

A Phase 1a Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7303509, an Anti-TGFβ3 Antibody, in Healthy Volunteers.

Transforming growth factor beta (TGFβ) cytokines (TGFβ1, TGFβ2, and TGFβ3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFβ inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFβ3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs). This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50mg, 150mg, 240mg) or subcutaneously (SC; 240mg, 675mg, 1200mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations. The study enrolled 49 HVs, with a median age of 39 (range 18-73)years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (Cmax) and area under the concentration-timecurve from time 0 to infinity (AUC0-inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50mg IV) tested positive for ADAs at a single time point (day15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFβ3 inhibition. RO7303509 was well tolerated at single SC doses up to 1200mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFβ3-specific inhibition may be suitable for development as a chronic antifibrotic therapy. ISRCTN13175485.

Abstract CT083: A first-in-human phase 1/2a study of a novel anti-PAUF monoclonal antibody PBP1510 in patients with advanced/metastatic pancreatic cancer

Abstract Background Pancreatic Adenocarcinoma Up-regulated Factor (PAUF) is a protein overexpressed in pancreatic cancer but not in non-cancerous tissues and plays an important role in carcinogenesis and metastasis. PBP1510 is a first-in-class, anti-PAUF humanized immunoglobulin G1 monoclonal antibody developed for treatment of pancreatic cancer. PBP1510 demonstrated promising pancreatic cancer growth inhibition efficacies in in vivo patient-derived xenograft studies and is being evaluated in humans for the first time in the ongoing PAUF-I study. Methods PAUF-I (NCT05141149) is an open-label, multi-center, Phase 1/2a study in advanced/metastatic pancreatic cancer patients. Eligible patients must have a tumor that has progressed on standard chemotherapy, with at least 1 measurable lesion per RECIST v1.1 criteria, an ECOG performance status score of 0 or 1, a life expectancy of ≥ 3 months, and adequate baseline organ function to enroll. PBP1510 is administered as a 90-minute intravenous infusion in 28-day cycles and tumor assessments are performed every 8 weeks from the first dose. Phase 1 uses a 3 + 3 dose-escalation design to assess the safety, tolerability, pharmacokinetics (PK), and immunogenicity of ascending doses of PBP1510 as a single agent or in combination with gemcitabine (Table 1). The observation period for dose-limiting toxicities (DLT) is 28 days. ORR and pre- and post-treatment PAUF levels in tumor tissue will be explored in the analyses. A recommended phase 2 dose (RP2D) will be selected based on PK, safety, and efficacy data from Phase 1. Phase 2a is the dose expansion phase which aims to evaluate the safety, tolerability, PK, immunogenicity, and efficacy of PBP1510 administered at RP2D in combination with gemcitabine. As of January 2024, 6 patients have been enrolled. The 1M cohort (1 mg/kg) was completed without any report of DLT. Dose escalation is in progress and DLT evaluation is ongoing for the 2nd and 3rd patients in the 2M cohort. TABLE 1: NAND Dose escalation and cohorts (Phase 1) Monotherapy Combination Cohort PBP1510 Dose (mg/kg) Gemcitabine Dose (mg/m2) Cohort PBP1510 Dose (mg/kg) Gemcitabine Dose (mg/m2) 1M 1 - 1C 1 1000 2M 3 - 2C 3 1000 3M 6 - 3C 6 1000 4M 10 - 4C 10 1000 5M 15 - 5C 15 1000 Citation Format: Jaime Feliu Batlle, Daniel A. King, Jamie Kim, Sumita Pradhan, Yun-Yong Park, Kedar Diwakar Mandakhalikar, Wei Qi Loh. A first-in-human phase 1/2a study of a novel anti-PAUF monoclonal antibody PBP1510 in patients with advanced/metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT083.

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Pharmacokinetics, Immunogenicity, Safety, and Tolerability After Subcutaneous Administration of Tozorakimab in Healthy Chinese Participants.

Tozorakimab is a high-affinity human immunoglobulin G1 monoclonal antibody that neutralizes interleukin (IL)-33, an IL-1 family cytokine. This phase 1, single-center, randomized, double-blind, placebo-controlled, single ascending dose study (NCT05070312) evaluated tozorakimab in a healthy Chinese population. Outcomes included the characterization of the pharmacokinetic (PK) profile and immunogenicity of tozorakimab. Safety outcomes included treatment-emergent adverse events (TEAEs) and clinical laboratory, electrocardiogram, and vital sign parameters. Healthy, non-smoking, male, and female Chinese participants aged 18-45 years with a body mass index 19-24kg/m2 were enrolled. In total, 36 participants across 2 cohorts of 18 participants were randomized 2:1 to receive a single subcutaneous dose of tozorakimab (300mg [2mL] or 600mg [4mL]) or matching placebo (2 or 4mL). Tozorakimab showed dose-dependent serum PK concentrations with an approximate monophasic distribution in serum over time and a maximum observed peak concentration of 20.1 and 33.7μg/mL in the 300- and 600-mg cohorts, respectively. No treatment-emergent anti-drug antibodies for tozorakimab were observed in any of the participants. There were no clinically relevant trends in the occurrence of TEAEs across the treatment groups. There were no clinically relevant trends over time in clinical laboratory (hematology, clinical chemistry, and urinalysis), electrocardiogram, or vital sign parameters in any treatment group. Overall, tozorakimab demonstrated dose-dependent systemic exposure in healthy Chinese participants and was well tolerated, with no safety concerns identified in this study.

Dual CTLA-4 and PD-1 checkpoint blockade using CS1002 and CS1003 (nofazinlimab) in patients with advanced solid tumors: A first-in-human, dose-escalation, and dose-expansion study.

This study investigated the safety and efficacy of an anti-CTLA-4 monoclonal antibody (CS1002) as monotherapy and in combination with an anti-PD-1 monoclonal antibody (CS1003) in patients with advanced/metastatic solid tumors. The phase 1 study involved phase 1a monotherapy dose-escalation (part 1) and phase 1b combination therapy dose escalation (part 2) and expansion (part 3). Various dosing schedules of CS1002 (0.3, 1, or 3mg/kg every 3 weeks, or 3mg/kg every 9 weeks) were evaluated with 200mg CS1003 every 3 weeks in part 3. Parts 1, 2, and 3 included a total of 13, 18, and 61 patients, respectively. No dose-limiting toxicities or maximum tolerated doses were observed. Treatment-related adverse events (TRAEs) were reported in 30.8%, 83.3%, and 75.0% of patients in parts 1, 2, and 3, respectively. Grade ≥3 TRAEs were experienced by 15.4%, 50.0%, and 18.3% of patients in each part. Of 61 patients evaluable for efficacy, 23 (37.7%) achieved objective responses in multiple tumor types. Higher objective response rates were observed with conventional and high-dose CS1002 regimens (1mg/kg every 3 weeks or 3mg/kg every 9 weeks) compared to low-dose CS1002 (0.3mg/kg every 3 weeks) in microsatellite instability-high/mismatch repair-deficient tumors, melanoma, and hepatocellular carcinoma (50.0% vs. 58.8%, 14.3% vs. 42.9%, and 0% vs. 16.7%). CS1002, as monotherapy, and in combination with CS1003, had a manageable safety profile across a broad dosing range. Promising antitumor activities were observed in patients with immune oncology (IO)-naive and IO-refractory tumors across CS1002 dose levels when combined with CS1003, supporting further evaluation of this treatment combination for solid tumors. CS1002 is a human immunoglobulin (Ig) G1 monoclonal antibody that blocks the interaction of CTLA-4 with its ligands and increases T-cell activation/proliferation. CS1003, now named nofazinlimab, is a humanized, recombinant IgG4 monoclonal antibody that blocks the interaction between human PD-1 and its ligands. In this original article, we determined the safety profile of CS1002 as monotherapy and in combination with CS1003. Furthermore, we explored the antitumor activity of the combination in anti-programmed cell death protein (ligand)-1 (PD-[L]1)-naive microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) pan tumors, and anti-PD-(L)1-refractory melanoma and hepatocellular carcinoma (HCC). CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising antitumor activities across CS1002 dose levels when combined with CS1003. This supports further assessment of CS1002 in combination with CS1003 for the treatment of solid tumors.

Efficacy and Safety of Risankizumab in Patients with Psoriatic Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Currently, the cause of psoriatic arthritis (PsA) is unknown, and the effectiveness of current drug treatments is unsatisfactory. In March 2019, the US Food and Drug Administration (FDA) approved risankizumab, a humanized immunoglobulinG1 (IgG1) monoclonal antibody targeting the p19 subunit of interleukin (IL)-23, for the treatment of PsA in adults. This study aimed to conduct a meta-analysis of double-blind, randomized, placebo-controlled trials to evaluate the effectiveness and safety of risankizumab in moderate-to-severe PsA. We conducted a thorough search of relevant databases from the establishment of the databases to October 1, 2023. We conducted a meta-analysis using Stata 12.0 and utilized I2 and Egger tests to assess heterogeneity and publication bias among the studies. Bias assessment was performed using the risk bias map and bias risk summary diagram generated by Revman5.4 software. The review protocols were registered on PROSPERO (CRD42023451894) and adhered to the preferred reporting item of system evaluation (PRISMA) guideline. Six randomized controlled trials (RCTs) involving 5038 patients with PsA treated with either risankizumab or placebo were included in the analysis. At 24weeks, the risankizumab group demonstrated a significantly higher American College of Rheumatology-20 (ACR20) response rate compared to the placebo group (RR1.760, 95%CI 1.568-1.977, P < 0.001). Additionally, the risankizumab group showed a significantly higher Minimal Disease Activity (MDA) response rate compared to the placebo group (RR1.827, 95%CI 1.048-3.184, P < 0.05). The risankizumab group also exhibited improvement in Short Form 36 Questionnaire (SF-36) score (SMD 0.51, 95%CI 0.33-0.69, P < 0.001), with significantly lower Health Assessment Questionnaire Disability Index (HAQ-DI) score (SMD - 0.27, 95%CI - 0.37 to - 0.17, P < 0.001) and higher Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score (SMD 0.27, 95%CI 0.20-0.35, P < 0.001) compared to the placebo group. Moreover, the risankizumab group had a significantly lower Psoriasis Area and Severity Index (PASI) score (SMD - 6.12, 95%CI - 10.02 to 2.23, P < 0.001). A study by Mease et al. indicated that patients receiving risankizumab generally demonstrated numerical improvements in the Leeds Enthesitis Index (LEI), although the small sample size limits the evidence. Further research is necessary to provide evidence-based guidelines. There were no significant differences in the incidence of serious adverse events (SAE) and serious treatment-emergent adverse events (STEAE) between the risankizumab and placebo groups (RR0.76, 95%CI 0.45-1.28, P = 0.31; RR0.99, 95%CI 0.49-1.99, P = 0.97, respectively), and the overall incidence of adverse events (AE) was not comparable (RR1.10, 95%CI 0.63-1.94, P = 0.73). Risankizumab showed superior efficacy across multiple outcome measures compared to placebo, with no significant increase in adverse events. Our findings endorse risankizumab as an excellent treatment option for PsA, offering valuable insights for clinicians and patients when choosing appropriate therapeutic interventions. Retrospectively registered (CRD42023451894, 16 August 2023).

Efficacy and Safety of the Anti-mucosal Addressin Cell Adhesion Molecule-1 Antibody Ontamalimab in Patients with Moderate-to-Severe Ulcerative Colitis or Crohn’s Disease

Abstract Background and Aims Ontamalimab is a fully human immunoglobulin G2 monoclonal antibody against mucosal addressin cell adhesion molecule-1, developed as treatment for inflammatory bowel disease. Methods Six phase 3, multicentre, randomised, double-blind, placebo-controlled clinical trials compared efficacy and safety of ontamalimab [25 mg and 75 mg once every 4 weeks] with placebo in patients with moderate-to-severe ulcerative colitis or Crohn’s disease [two induction studies and one re-randomised maintenance study per condition]. This clinical trial programme was discontinued in 2020 for reasons unrelated to drug safety/efficacy; Crohn’s disease studies are described in the Supplementary data. Results The induction [12-week] and maintenance [52-week] studies included 659 and 366 randomised patients, respectively. More patients who received ontamalimab induction than placebo achieved the primary endpoint of clinical remission at Week 12 [25 mg, 18.5% vs 15.8%, p = 0.617, 27.0% vs 12.5%, p = 0.027; 75 mg, 29.8% vs 15.8%, p = 0.018, 29.5% vs 12.5% p = 0.014]; significantly more patients who received ontamalimab maintenance therapy than placebo achieved Week 52 clinical remission [25 mg, 53.5% vs 8.2%, p &amp;lt;0.001; 75 mg, 40.2% vs 12.8%, p &amp;lt;0.001]. Endoscopic improvement was generally significantly different vs placebo [induction: 25 mg, 27.8% vs 21.1%, p = 0.253, 35.1% vs 12.5%, p = 0.001; 75 mg, 41.1% vs 21.1%, p = 0.002, 33.9% vs 12.5%, p = 0.003; maintenance: 25 mg, 56.3% vs 9.6%, p &amp;lt;0.001; 75 mg, 48.8% vs 15.1%, p &amp;lt;0.001]. Adverse event rates were similar between ontamalimab and placebo groups. Conclusions Ontamalimab 75 mg was effective, with no safety concerns, as induction and maintenance therapy for patients with moderate-to-severe ulcerative colitis. [NCT03259334; NCT03259308; NCT03290781; NCT03559517; NCT03566823; NCT03627091]

Abstract B114: A Phase 1/1b study of KAZ954 alone and in combination with spartalizumab (PDR001) and taminadenant (NIR178) in patients with advanced gastrointestinal malignancies

Abstract Background:KAZ954 (KAZ), a humanized immunoglobulin G1 monoclonal antibody, is a potent, selective inhibitor of anti-ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2). Preclinical data show that KAZ blocks the hydrolysis of adenosine triphosphate, enhances immune activation in the tumor microenvironment, and augments the efficacy of PDR001 (PDR, anti-PD-1), and NIR178 (NIR, adenosine A2aR inhibitor). Methods: This is an open-label, multicenter, dose-escalation (ESC)/expansion study (NCT04237649). We present the dose-ESC results of KAZ single-agent (SA) and with PDR or NIR in patients (pts) with advanced gastrointestinal (GI) malignancies. Dose ESC was guided by Bayesian logistic regression models and comprised 3 arms: (1) SA KAZ administered intravenously (IV) at 30, 50, 100, and 150 mg biweekly (Q2W) flat dosing; KAZ 100 mg priming dose followed by 300, 600, and 1200 mg experimental dose; (2) KAZ 100 mg priming dose followed by 300, 600, and 1200 mg experimental dose with PDR 400 mg IV every 4 weeks; and (3) KAZ 100 mg priming dose followed by 300 and 600 mg experimental dose with NIR 160 and 240 mg twice daily orally. Primary objectives were to evaluate safety and tolerability and determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE). Secondary objectives were to assess antitumor activity and pharmacokinetics (PK). Tumor biopsies and blood samples were taken for biomarker analysis. Results: As of March 20, 2023, 77 pts were enrolled in ESC KAZ (n=43), KAZ+PDR (n=18), and KAZ+NIR (n=16) arms. Tumor types enrolled were microsatellite-stable colorectal cancer (37, 48%), pancreatic ductal adenocarcinoma (27, 35%), cholangiocarcinoma (10, 13%), and esophageal cancer (3, 4%). At data cutoff, 43 (100%), 15 (83.3%), and 11 (68.8%) pts discontinued treatment, and treatment-related adverse events (TRAEs) were reported in 37 (86%), 12 (66.7%), and 13 (81.3%) pts in KAZ, KAZ+PDR, and KAZ+NIR arms, respectively. KAZ had an acceptable and manageable safety profile. Given the occurrence of cytokine release syndrome (CRS) observed with cycle 1 day 1 (C1D1), prophylactic premedication with acetaminophen, antihistamine, and corticosteroid, together with a priming dose on C1D1, was established as the recommended regimen to administer KAZ. Grade ≥3 TRAEs were reported in 9 pts(20.9%) in KAZ, most commonly CRS and decreased lymphocyte count (n=2 each); 7 pts(38.9%) in KAZ+PDR, most commonly lymphopenia and increased aspartate aminotransferase (n=2 each); and 2 pts(12.5%) in KAZ+NIR (asthenia and lymphopenia [n=1 each]). No MTDs were reached in any treatment arm explored. Although no objective responses were observed, 12(27.9%), 2(11.1%), and 2(12.5%) pts showed stable disease in the KAZ, KAZ+PDR, and KAZ+NIR arms, respectively. Conclusions: KAZ was considered to be safe and well tolerated at all doses, and PK/PD analysis suggest effective ENTPD2 inhibition from a dose range of 150 to 1200 mg Q2W. Although a biologically active dose range was established, further dose-exploration studies are required to establish an RDE. Citation Format: Devalingam Mahalingam, Chia-Chi Lin, Philippe L. Bedard, Massimo Di Nicola, Zev Wainberg, Patricia LoRusso, Shubham Pant, Brigette B.Y. Ma, Wei-Peng Yong, Mia C. Weiss, Alessio Amatu, Kentaro Yamazaki, Lisa Nardi, Jong Bong Lee, Mike Roy, Anhthu Dang, Shu Yang, Bernard Pereira, Javier A. Otero, Teresa Macarulla. A Phase 1/1b study of KAZ954 alone and in combination with spartalizumab (PDR001) and taminadenant (NIR178) in patients with advanced gastrointestinal malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B114.

A Phase III Clinical Trial Program Investigating the Efficacy and Safety of Ianalumab in Patients with Primary Immune Thrombocytopenia (VAYHIT1 and VAYHIT2) and Warm Autoimmune Hemolytic Anemia (VAYHIA)

Background: Immune thrombocytopenia (ITP) and warm autoimmune hemolytic anemia (wAIHA) are characterized by autoantibody destruction of platelets and red blood cells, respectively. Autoreactive B cells play a role in the pathophysiology of ITP and wAIHA. Serum levels of B-cell activating factor (BAFF) are elevated in these disorders and correlate with increased disease activity. Ianalumab is a novel, fully human immunoglobulin G1 monoclonal antibody that targets BAFF receptor (BAFF-R) and has a unique dual mechanism of action: direct antibody-dependent cellular cytotoxicity-mediated B-cell depletion and inhibition of B-cell differentiation, proliferation and survival via blockade of BAFF-R-mediated signaling. Corticosteroids (CS) are the standard first-line treatment for ITP; however, few patients achieve a long-term response. Additionally, extended and recurrent use of CS is associated with substantial toxicity. Thrombopoietin receptor agonists (TPO-RAs), such as eltrombopag, are commonly used second-line ITP treatments and often achieve a response; however, responses are rarely maintained once treatment ends, so chronic administration is typically required. For wAIHA, few treatments have been approved, and patients rarely achieve durable responses on CS or off-label rituximab. Thus, there are significant unmet needs for patients with ITP or wAIHA. Aim: We report the designs of the randomized, double-blind, multicenter, 3-arm Phase III VAYHIT1 (NCT05653349), VAYHIT2 (NCT05653219) and VAYHIA (NCT05648968) trials. The trials aim to assess whether ianalumab, working with a distinct and complementary mechanism to standard-of-care treatments, can induce durable responses in patients with ITP or wAIHA. Trial designs: VAYHIT1 and VAYHIT2 will assess the efficacy and safety of ianalumab vs placebo in addition to first-line CS and short-term eltrombopag, respectively, in adults with primary ITP. In both trials, patients will be randomized 1:1:1 to intravenous (IV) low-dose ianalumab, high-dose ianalumab or placebo every 4 weeks (wks). The primary endpoint in both trials is the time from randomization to treatment failure, defined as platelet count &amp;lt;30 G/L later than 8 wks from randomization, need for rescue treatment later than 8 wks from randomization, start of a new ITP therapy, or death. In VAYHIT2, ineligibility to taper or inability to discontinue eltrombopag after the completion of treatment with ianalumab or placebo will also be assessed as treatment failure. Secondary endpoints include response rate, complete response rate and safety ( Table). VAYHIA will assess the efficacy and safety of ianalumab vs placebo in adults with wAIHA who have failed ≥1 treatment. Patients will be randomized 1:1:1 to IV low-dose ianalumab, high-dose ianalumab or placebo every 4 wks. Selected supportive care is allowed. The primary endpoint is durable hemoglobin (Hb) response, defined as Hb ≥10 g/dL and an Hb increase of ≥2 g/dL from baseline for ≥8 consecutive wks between Wk 9 and Wk 25 in the absence of rescue or prohibited treatment. The key secondary endpoint is duration of durable Hb response ( Table). An optional open-label crossover period will allow patients who receive placebo and do not achieve a durable Hb response to receive high-dose ianalumab. Patients from all 3 trials will be monitored for efficacy until treatment failure (or up to 39 months after the last patient was randomized, whichever comes first) and safety for up to 2 years. Conclusions: These trials have been designed based on the hypothesis that, when administered early in disease progression, medical therapy targeting complementary physiological pathways may restore self-tolerance in patients with ITP and wAIHA. Ianalumab in combination with standard of care is expected to safely induce a high response rate that will be maintained beyond treatment completion. Ianalumab may address the unmet needs for patients with ITP and wAIHA. Current status: At the time of writing, VAYHIT1, VAYHIT2 and VAYHIA are recruiting. The open-label, single-arm, Phase II VAYHIT3 trial is also assessing ianalumab in patients with primary ITP previously treated with at least 1 CS and 1 TPO-RA (NCT05885555).

VAYHIT3: An Open-Label, Single-Arm, Phase II Trial to Evaluate the Efficacy and Safety of Ianalumab in Patients with Primary Immune Thrombocytopenia (ITP) Previously Treated with at Least 1 Corticosteroid and 1 Thrombopoietin Receptor Agonist (TPO-RA)

Background: In patients with ITP, autoreactive B cells mediate the production of autoantibodies that target platelets and megakaryocytes, resulting in an increased rate of platelet destruction and decreased platelet production. B-cell activating factor (BAFF) regulates the differentiation, proliferation and survival of B cells via interactions with the BAFF receptor (BAFF-R). Patients with ITP have elevated serum BAFF levels, which positively correlate with increased disease activity. Ianalumab is a novel, fully human immunoglobulin G1 monoclonal antibody that targets BAFF-R and has a unique dual mechanism of action: direct B-cell depletion mediated by antibody-dependent cellular cytotoxicity and inhibition of B-cell differentiation, proliferation and survival via blockade of BAFF-R-mediated signaling. Following first-line corticosteroids, TPO-RAs are a standard second-line treatment for ITP; however, patients often require chronic TPO-RA treatment and endure potential side effects with increased costs. For patients who previously received corticosteroids and a TPO-RA, the choice of subsequent therapy (eg a different TPO-RA, rituximab, fostamatinib, mycophenolate mofetil, splenectomy) is not well defined. Thus, in patients with ITP requiring additional lines of therapy, there is an unmet need for new, well-tolerated therapies with disease-modifying potential that can safely induce high response rates after a short therapeutic course and maintain durable responses after treatment discontinuation. Trial design: VAYHIT3 (NCT05885555) is a multicenter, open-label, single-arm, Phase II trial enrolling approximately 40 adult patients with primary ITP who have previously received at least 1 corticosteroid and 1 TPO-RA. Additional prior therapies are allowed. Eligible patients must have lost response, had an insufficient response, had no response or been intolerant to their last ITP therapy. Along with a platelet count of &amp;lt;30 G/L, patients must be assessed by the investigator as needing treatment. Exclusion criteria include a neutrophil count of &amp;lt;1000/mm 3 and prior splenectomy. All patients will receive intravenous ianalumab every 4 weeks (Figure). Patients may receive concomitant therapy with a corticosteroid or TPO-RA if clinically indicated, which may be tapered. The primary efficacy analysis will occur after all patients have been followed up until Week 25 Day 1 or discontinued the study earlier. All patients with a platelet count of ≥30 G/L in the absence of a rescue therapy in the last 4 weeks or new ITP therapy at Week 25 Day 1 visit will continue efficacy monitoring until they have a platelet count of &amp;lt;30 G/L, start a new ITP therapy or require a rescue therapy. Safety will be monitored in all patients for up to 2 years after the last dose of ianalumab. Endpoints: The primary endpoint is confirmed response, defined as a platelet count of ≥50 G/L for 2 or more consecutive assessments at least 7 days apart between Week 1 Day 1 and Week 25 Day 1 visits and in the absence of both a rescue therapy for ≥4 weeks prior to the assessment of platelet count and the receipt of a new ITP therapy. Secondary endpoints include time to confirmed response, time to loss of response, quality and stability of response, proportions of patients experiencing bleeding events and requiring rescue therapies, changes in B cell and immunoglobulin levels, and pharmacokinetics, immunogenicity and safety of ianalumab. Exploratory biomarker assessments are also included to expand upon the understanding of ianalumab pharmacodynamics and exposure-response in patients with ITP. Conclusions: VAYHIT3 will evaluate the ability of a short therapeutic course of ianalumab to induce durable responses in patients who have received 2 or more prior lines of therapy, including at least 1 corticosteroid and 1 TPO-RA, for whom significant unmet needs exist. Current status: VAYHIT3 is recruiting. Ianalumab is also being investigated in 2 ongoing, randomized, double-blind, Phase III ITP trials: VAYHIT1 (NCT05653349) is assessing ianalumab versus placebo in addition to first-line corticosteroids, and VAYHIT2 (NCT05653219) is assessing ianalumab versus placebo in addition to eltrombopag in patients who failed first-line corticosteroid treatment.

Maintenance of Response to Risankizumab in Patients With Psoriatic Arthritis: A 3-year Analysis of the KEEPsAKE 1 and 2 Trials

Introduction: Risankizumab, a humanized immunoglobulin G1 monoclonal antibody, specifically inhibits the p19 subunit of human interleukin 23 and is approved for treatment of active psoriatic arthritis (PsA) in adults. This post hoc analysis evaluated the long-term maintenance of clinical response through ~3 years of risankizumab treatment using data from 2 ongoing phase 3 trials, KEEPsAKE 1 and KEEPsAKE 2.&#x0D; Methods: Eligible patients had active PsA with inadequate response or intolerance to ≥1 conventional synthetic disease modifying antirheumatic drugs (KEEPsAKE 1 [NCT03675308]; KEEPsAKE 2 [NCT03671148]) and/or inadequate response or intolerance to 1–2 biologic therapies (KEEPsAKE 2 only). Patients received double-blinded risankizumab 150 mg or placebo at weeks 0, 4, and 16 and open-label risankizumab 150 mg every 12 weeks thereafter. This analysis includes patients who received continuous risankizumab through both treatment periods. Assessments included improvement of ≥20%/50%/70% in PsA symptoms using American College of Rheumatology criteria (ACR20/50/70), achievement of minimal disease activity (MDA), reduction of ≥90% in Psoriasis Area and Severity Index (PASI 90; in patients with ≥3% body surface area affected by psoriasis at baseline), and clinically meaningful reduction in pain (≥10 mm on a visual analog scale [VAS]). Maintenance of response analyses were based on patients who were responders at weeks 24 or 52 for each endpoint. Nonresponder imputation incorporating multiple imputation (NRI-MI) for missing data due to COVID-19 or geopolitical conflict was used. As-observed data were also reported.&#x0D; Results: Among patients receiving continuous risankizumab, ACR20 was achieved at week 24 in 267/454 (KEEPsAKE 1, 58.8%) and 111/208 (KEEPsAKE 2, 53.4%) patients (as observed). Maintenance of response in week 24 ACR20 responders (NRI-MI) was achieved for ACR20 by most patients at week 52 (KEEPsAKE 1, 89.1%; KEEPsAKE 2, 77.0 %) and week 148 (KEEPsAKE 1, 74.7%; KEEPsAKE 2; 68.5%). Similar patterns of maintenance of response were observed for ACR50 and ACR70. Week 24 responders also maintained MDA at weeks 52 (KEEPsAKE 1, 82.2%; KEEPsAKE 2, 66.7%) and 148 (KEEPsAKE 1, 77.1%; KEEPsAKE 2, 71.9%). The PASI 90 response was maintained at weeks 52 (KEEPsAKE 1, 86.6%; KEEPsAKE 2, 88.4%) and 148 (KEEPsAKE 1, 76.3%; KEEPsAKE 2, 81.2%). Week 24 responders maintained clinically meaningful reductions in pain VAS at weeks 52 (KEEPsAKE 1, 83.9%; KEEPsAKE 2, 74.4%) and 148 (KEEPsAKE 1, 75.0%; KEEPsAKE 2, 72.0%). Comparable maintenance of response was recorded at week 148 for each endpoint among week 52 responders (NRI-MI).&#x0D; Conclusion: Risankizumab demonstrated durable long-term efficacy in patients with active PsA. A high proportion of patients receiving continuous risankizumab treatment in KEEPsAKE 1 and KEEPsAKE 2 achieved responses in ACR20/50/70, MDA, PASI 90, or pain VAS at weeks 24 or 52 and maintained responses through week 148.

Maintenance of Clinical Response With Continued Risankizumab Treatment for Moderate-to-Severe Psoriasis Through 304 Weeks: Interim Analysis of the LIMMitless Open-Label Extension Study

Introduction: Interleukin (IL)-23 is a key regulator of plaque psoriasis pathogenesis. Risankizumab, a humanized immunoglobulin G1 monoclonal antibody that specifically inhibits IL-23 by binding to its p19 subunit, is approved for the treatment of moderate-to-severe plaque psoriasis in adults; however, additional data on long-term maintenance of efficacy with risankizumab treatment are needed. Here we report on the maintenance of clinical response through 304 weeks of continuous risankizumab treatment.&#x0D; Methods: In this interim analysis, we evaluated patients with moderate-to-severe plaque psoriasis who were randomized to receive risankizumab 150 mg at weeks 0, 4, and 16 and every 12 weeks thereafter during 2 double‑blind, phase 3, 52-week base studies (UltIMMa 1 [NCT02684370] and UltIMMa 2 [NCT02684357]) and enrolled in LIMMitless, an ongoing, phase 3, multicenter, single‑arm, open-label extension (OLE) study (NCT03047395) evaluating the long-term safety and efficacy of continuous risankizumab 150 mg treatment every 12 weeks for plaque psoriasis. Safety was assessed through ≤ 324 weeks by monitoring of treatment‑emergent adverse events through the data cutoff date (May 22, 2023). Efficacy was assessed by the proportion of patients who maintained ≥ 90% or 100% improvement from baseline in Psoriasis Area and Severity Index (PASI 90/100) during LIMMitless and mean improvement in PASI from baseline of the UltIMMa-1/2 study through 252 additional weeks in the LIMMitless study (total of 304 weeks). Missing efficacy data were imputed using modified nonresponder imputation (mNRI), last observation carried forward (LOCF), or observed cases (OC) methodology.&#x0D; Results: A total of 525 patients were randomized to receive risankizumab 150 mg treatment for 52 weeks in the UltlMMa‑1/2 studies and continued open-label risankizumab 150 mg treatment in the LIMMitless OLE study. Risankizumab was well tolerated through ≤ 324 weeks; no new safety concerns were reported in patients with moderate-to-severe plaque psoriasis. At OLE entry, most patients (451, 85.9%) achieved PASI 90; of those, 422 (93.6%) maintained PASI 90 through week 304 by mNRI (LOCF, 92.7%; OC, 93.8%). Of 320 patients (61.0%) who achieved PASI 100 at OLE entry, 209 (65.3%) maintained PASI 100 through week 304 by mNRI (LOCF, 80.6%; OC, 79.9%). Mean PASI improvement from baseline was generally consistent from OLE entry (95.6% for both LOCF and OC) through week 304 (LOCF, 95.9%; OC, 96.5%).&#x0D; Conclusion: In this 304-week interim analysis of continuous risankizumab treatment, the safety profile was consistent with previous interim analyses from the LIMMitless study. With continuous risankizumab treatment, most patients maintained PASI 90 or PASI 100 responses from OLE entry through 252 additional weeks in the LIMMitless study.

Bintrafusp Alfa Versus Pembrolizumab in Patients With Treatment-Naive, Programmed Death-Ligand 1–High Advanced NSCLC: A Randomized, Open-Label, Phase 3 Trial

IntroductionBintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β “trap”) fused to a human immunoglobulin G1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), has exhibited clinical activity in a phase 1 expansion cohort of patients with PD-L1–high advanced NSCLC. MethodsThis adaptive phase 3 trial (NCT03631706) compared the efficacy and safety of bintrafusp alfa versus pembrolizumab as first-line treatment in patients with PD-L1–high advanced NSCLC. Primary end points were progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1 per independent review committee and overall survival. ResultsPatients (N = 304) were randomized one-to-one to receive either bintrafusp alfa or pembrolizumab (n = 152 each). The median follow-up was 14.3 months (95% confidence interval [CI]: 13.1–16.0 mo) for bintrafusp alfa and 14.5 months (95% CI: 13.1–15.9 mo) for pembrolizumab. Progression-free survival by independent review committee was not significantly different between bintrafusp alfa and pembrolizumab arms (median = 7.0 mo [95% CI: 4.2 mo–not reached (NR)] versus 11.1 mo [95% CI: 8.1 mo–NR]; hazard ratio = 1.232 [95% CI: 0.885–1.714]). The median overall survival was 21.1 months (95% CI: 21.1 mo–NR) for bintrafusp alfa and 22.1 months (95% CI: 20.4 mo–NR) for pembrolizumab (hazard ratio = 1.201 [95% CI: 0.796–1.811]). Treatment-related adverse events were higher with bintrafusp alfa versus pembrolizumab; grade 3-4 treatment-related adverse events occurred in 42.4% versus 13.2% of patients, respectively. The study was discontinued at an interim analysis as it was unlikely to meet the primary end point. ConclusionsFirst-line treatment with bintrafusp alfa did not exhibit superior efficacy compared with pembrolizumab in patients with PD-L1–high, advanced NSCLC.

Preliminary results of a phase 1/2, first-in-human, open-label, dose escalation study of ZL-1211 (anti-Claudin 18.2 mAb) in patients with unresectable or metastatic solid tumors.

2537 Background: ZL-1121 is a humanized immunoglobulin G1 monoclonal antibody targeting Claudin18.2. Site mutations (S239D and I332E) were introduced in the Fc portion of ZL-1211 to enhance antibody dependent cellular cytotoxicity. Herein, we present the preliminary results from the ongoing dose escalation part of the study. Methods: This is a first-in-human, phase 1/2, multicenter, dose escalation/cohort expansion study of ZL-1211 administered intravenously to adult patients with Claudin 18.2-positive advanced solid tumors. A Bayesian optimal interval design with 3+3 run-in was adopted to assess 5 dose levels of ZL-1211 monotherapy (1 to 40 mg/kg biweekly) for phase 1 dose escalation, followed by phase 2 cohort expansion. The primary objectives were to determine the maximum tolerated dose and/or the recommended phase 2 dose, assess the safety/tolerability, and evaluate the preliminary antitumor activities of ZL-1211. Tumor assessments were performed every 8 weeks per RECIST v1.1. Blood samples were collected for pharmacokinetic (PK) analyses. Results: As of Dec 12, 2022, 19 patients (11 pancreatic cancer, 6 gastric cancer, 1 esophageal cancer, and 1 bile duct cancer) had been enrolled in the dose escalation phase to receive ZL-1211 at 1 mg/kg (n = 3), 5 mg/kg (n = 7), 10 mg/kg (n = 4), and 20 mg/kg (n = 5). The median age was 60 years and the majority of the patients (78.9%) received ≥2 lines of prior systemic therapy. No dose limiting toxicities (DLT) had been observed as of the cut-off date. The most common treatment-related adverse events (TRAEs) were gastrointestinal disorders, including nausea (11/19, 57.9%), vomiting (6/19, 31.6%), and abdominal pain (3/19, 15.8%). Other common TRAEs (≥15%) were hypoalbuminaemia (3/19, 15.8%) and infusion-related reactions (3/19, 15.8%). Grade 3 TRAEs occurred in 3 patients, 1 with nausea and vomiting, 1 with platelet count decreased, and 1 with anaemia, leukopenia, platelet count decreased, and weight decreased. No Grade ≥ 4 TRAEs were reported. Two patients experienced serious TRAEs: 1 reporting 2 cases each of grade 3 vomiting and nausea and 1 reporting a grade 3 platelet count decreased and a grade 2 abdominal pain, all of which had recovered. TRAEs led to treatment interruption in 5 patients (26.3%) and treatment withdrawal in 1 patient (5.3%). No TRAEs leading to death were reported. Six of 9 tumor-evaluable patients achieved stable disease as the best overall response. Three patients had tumor regression: 17.1% in a pancreatic cancer patient of the 5 mg/kg cohort; 14.5% in a pancreatic cancer patient and 24.9% in a gastric cancer patient in the 10 mg/kg cohort. Preliminary PK analyses revealed linear PK of ZL-1211 over the dose range tested. Conclusions: ZL-1211 displayed an acceptable safety/tolerability profile to date and demonstrated preliminary antitumor effects. Clinical trial information: NCT05065710 .

HARBOR: ABBV-916 In Subjects With Early Alzheimer’s Disease Combined Multiple-Ascending Dose/Proof-Of-Concept Study Design (P7-6.008)

<h3>Objective:</h3> This study evaluates safety, tolerability, pharmacokinetics, immunogenicity, and amyloid reduction associated with ABBV-916, a recombinant humanized immunoglobulin G1 monoclonal antibody, in subjects with early AD. <h3>Background:</h3> Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. <h3>Design/Methods:</h3> Approximately 163 subjects will be enrolled in this Phase 1b/2 multicenter, randomized, placebo-controlled, double-blind, dose-finding study (NCT05291234), which consists of 2 stages: multiple-ascending dose (MAD; Phase 1b; Stage A) and proof-of-concept (POC; Phase 2; Stage B). Each stage has a 60-day screening period, 24-week double-blind period (ABBV-916 or placebo administered intravenously once every 4 weeks) and a 16-week safety follow-up period, with the option of a 2-year open-label extension. Subjects must meet the following inclusion criteria: be between 50 and 90 years of age, diagnosis of Stage 3 or 4 AD, as defined by the 2018 NIA-AA Research Framework, a Mini-Mental State Examination score between 20 and 28, a positive Precivity AD-Aβ blood test, and an amyloid PET scan consistent with amyloid pathology. <h3>Results:</h3> Safety evaluations include adverse events reports, clinical laboratory tests, MRI, vital signs, electrocardiograms, and the Columbia-Suicide Severity Rating Scale. Cerebrospinal fluid collection is required for subjects in Stage A and optional for subjects in Stage B. Change from baseline in brain amyloid plaque deposition is measured by amyloid PET scan in Stage B. <h3>Conclusions:</h3> This study tests the hypothesis that ABBV-916 will lead to rapid and robust removal of amyloid plaques from the brain of subjects with AD. <b>Disclosure:</b> Dr. Watson has nothing to disclose. Shau Yu Lynch has received personal compensation for serving as an employee of AbbVie. Shau Yu Lynch has received personal compensation for serving as an employee of Eisai. Shau Yu Lynch has stock in AbbVie. Hana Florian has received personal compensation for serving as an employee of AbbVie. Hana Florian has stock in AbbVie. Dr. Wang has received personal compensation for serving as an employee of AbbVie Inc.. Dr. Wang has stock in AbbVie Inc.. Mr. Bachhav has received personal compensation for serving as an employee of AbbVie Inc, USA. Mr. Bachhav has stock in AbbVie Inc. USA. Dr. Boiser has received personal compensation for serving as an employee of AbbVie. Dr. Boiser has stock in AbbVie. Dr. Bannon has received personal compensation for serving as an employee of AbbVie. Dr. Bannon has stock in AbbVie. Dr. Stage has received personal compensation for serving as an employee of AbbVie. Dr. Stage has stock in AbbVie.. Dr. Graff has received personal compensation for serving as an employee of AbbVie. Dr. Graff has stock in AbbVie.

Abstract CT116: First-in-human study of AZD8853, an anti-growth and differentiation factor 15 (GDF15) antibody, in patients (pts) with advanced/metastatic solid tumors

Abstract Background: The cytokine GDF15 is overexpressed in solid malignant tumors such as colorectal, lung and urothelial cancer, where it modulates T cells, dendritic cells (DCs) and myeloid-derived cells, driving the tumor microenvironment toward an immunosuppressive, tumor-promoting state. AZD8853 is a humanized immunoglobulin G1 monoclonal antibody that binds to, and neutralizes, GDF15. Anti-GDF15 treatment increased T cell proliferation and DC activation, leading to an antitumor immune response in preclinical studies of anti-PD-L1 resistant models. In vitro and in vivo preclinical data support the potential antitumor activity of AZD8853 in pts with selected advanced/metastatic cancers. Methods: This Phase I/IIa, first-in-human, open-label study (NCT05397171) assesses the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of AZD8853 in pts with histologically or cytologically confirmed locally advanced, unresectable or metastatic mismatch repair-proficient colorectal cancer (pMMR-CRC), non-small-cell lung cancer (NSCLC) and urothelial carcinoma (UC). Up to 165 pts will be enrolled in 3 parts: Part A, dose escalation; Part B, pharmacodynamics expansion; and Part C, efficacy expansion. All pts receive AZD8853 IV. Eligible pts are ≥18 years old with ≥1 measurable target lesion per RECIST v1.1, ECOG PS of 0/1, life expectancy ≥12 weeks and adequate organ and bone marrow function. Pts with NSCLC must have had ≥1 prior line of systemic treatment in the advanced/metastatic setting, and no sensitizing EGFR or ALK aberrations. Pts with pMMR-CRC must have had ≥2 prior treatments in the advanced/metastatic setting. Pts with UC must have had ≥1 prior treatment in the advanced/metastatic setting including platinum-containing therapy and/or a PD-(L)1-inhibitor. Pts with Grade ≥2 unresolved toxicities from prior therapy, symptomatic CNS metastases or leptomeningeal disease, or prespecified active/ongoing infections are excluded. The primary objective is safety, including dose-limiting toxicities, adverse events (AEs), serious AEs and AEs leading to AZD8853 discontinuation. The secondary objectives include assessment of efficacy (objective response rate, disease control rate, duration of response, percentage change from baseline in target lesion size, change from baseline in circulating tumor DNA, and progression-free and overall survival), PK and immunogenicity. Changes in GDF15 serum levels are measured in Parts A and B. Tumoral CD8+ T cell infiltration is measured in a subset of pts from Part B using PET/CT imaging and IHC of paired biopsies. The study is currently recruiting at centers in the USA and Canada with additional sites planned in the UK, France and Spain. Citation Format: Benedito A. Carneiro, Maria Diab, Brian A. Van Tine, Anthony F. Shields, Albiruni Abdul Razak, John F. Hilton, Rafael Santana-Davila, Elhan Sanai, Jorge Zeron-Medina, Veronique Bragulat, Kath Lowery, Arthur Lambert, John Hood, Rakesh Kumar, Duncan Jodrell, Patricia LoRusso. First-in-human study of AZD8853, an anti-growth and differentiation factor 15 (GDF15) antibody, in patients (pts) with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT116.

Efficacy and Safety of Risankizumab for the Treatment of Hidradenitis Suppurativa: A Phase 2, Randomized, Placebo-Controlled Trial.

Hidradenitis suppurativa (HS) is a chronic, immune-mediated skin condition characterized by inflammatory lesions that can cause pain, impaired physical activity, and reduced quality of life. This study evaluated the efficacy and safety of risankizumab, a humanized immunoglobulin G1 monoclonal antibody that specifically inhibits interleukin 23 by binding to its p19 subunit, for the treatment of HS. This phase II multicenter, randomized, placebo-controlled, double-blind study investigated the efficacy and safety of risankizumab in patients with moderate-to-severe HS. Patients were randomized 1:1:1 to receive subcutaneous risankizumab 180mg; risankizumab 360mg; or placebo at weeks0, 1, 2, 4, and 12. Patients initially randomized to placebo received blinded risankizumab 360mg at weeks16, 17, and 18; patients initially randomized to risankizumab received blinded matching placebo at the same time points. From weeks20-60, all patients received open-label risankizumab 360mg every 8weeks. The primary endpoint was the achievement of HS Clinical Response (HiSCR) at week16. Safety was assessed by monitoring of treatment-emergent adverse events (TEAEs). A total of 243 patients were randomized (risankizumab 180mg, n = 80; risankizumab 360mg, n = 81; placebo, n = 82). HiSCR was achieved by 46.8% of patients with risankizumab 180mg, 43.4% with risankizumab 360mg, and 41.5% with placebo at week16. The primary endpoint was not met, and the study was terminated early. Incidence of TEAEs, severe TEAEs, TEAEs considered possibly related to study drug, and TEAEs leading to discontinuation of study drug were generally low and comparable across treatment groups. Risankizumab does not appear to be an efficacious treatment for moderate-to-severe HS. Future studies to understand the complex molecular mechanisms underlying HS pathogenesis and develop improved therapies are warranted. ClinicalTrials.gov identifier: NCT03926169.

Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Patients With Non-Small Cell Lung Cancer Resistant or Refractory to Immune Checkpoint Inhibitors.

Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor beta receptor II (a TGF-β "trap") fused to a human immunoglobulin G1 monoclonal antibody blocking programmed cell death 1 ligand 1 (PD-L1). We report the efficacy and safety in patients with non-small cell lung cancer (NSCLC) that progressed following anti-PD-(L)1 therapy. In this expansion cohort of NCT02517398-a global, open-label, phase I trial-adults with advanced NSCLC that progressed following chemotherapy and was primary refractory or had acquired resistance to anti-PD-(L)1 treatment received intravenous bintrafusp alfa 1200 mg every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal. The primary endpoint was best overall response (by Response Evaluation Criteria in Solid Tumors version 1.1 adjudicated by independent review committee); secondary endpoints included safety. Eighty-three eligible patients (62 [74.7%] treated with ≥3 prior therapies) received bintrafusp alfa. Four patients (3 primary refractory, 1 acquired resistant) had confirmed partial responses (objective response rate, 4.8%; 95% CI, 1.3%-11.9%), and 9 had stable disease. Tumor cell PD-L1 expression was not associated with response. Nineteen patients (22.9%) experienced grade ≥3 treatment-related adverse events, most commonly asthenia (3 [3.6%]) and fatigue, eczema, and pruritus (2 each [2.4%]). One patient had grade 4 amylase increased. One patient died during treatment for pneumonia before initiation of bintrafusp alfa. Although the primary endpoint was not met, bintrafusp alfa showed some clinical activity and a manageable safety profile in patients with heavily pretreated NSCLC, including prior anti-PD-(L)1 therapy. Tumor responses occurred irrespective of whether disease was primary refractory or had acquired resistance to prior anti-PD-(L)1 therapy.

Prophylactic Administration of the Monoclonal Antibody Adintrevimab Protects against SARS-CoV-2 in Hamster and Non-Human Primate Models of COVID-19.

Adintrevimab is a human immunoglobulin G1 monoclonal antibody engineered to have broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and other SARS-like coronaviruses with pandemic potential. In both Syrian golden hamster and rhesus macaque models, prophylactic administration of a single dose of adintrevimab provided protection against SARS-CoV-2/WA1/2020 infection in a dose-dependent manner, as measured by significant reductions in lung viral load and virus-induced lung pathology, and by inhibition of viral replication in the upper and lower respiratory tract.

Abstract 9318: The Safety, Pharmacokinetics, Pharmacodynamics and Immunogenicity of Ebronucimab in Healthy Volunteers: Result From a Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Dose-Escalation Study

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have demonstrated to be effective therapeutic agents for lowing low-density lipoprotein cholesterol (LDL-C). Ebronucimab (AK102) is a novel fully human immunoglobulin G1 (IgG1) monoclonal antibody against PCSK9. The objective of this study is to investigate the safety and tolerability of ebronucimab in healthy subjects. Methods: A total of 32 healthy adult subjects were planned to be enrolled and treated in a dose escalation manner. In each cohort, 8 subjects were randomized in a 3:1 ratio to receive a single dose of ebronucimab (75, 150, 300 or 500 mg) or matching placebo via subcutaneous injection (Figure 1). Blood was drawn at pre-selected timepoints to evaluate the pharmacokinetic parameters, free PCSK9 concentration and anti-drug antibody (ADA). Safety assessment was carried out up to day 85 ± 3 or early termination visit. Results: Safety Among the 32 subjects recruited, 87.5% (21/24) subjects administrated ebronucimab and 75% (6/8) subjects treated with placebo reported treatment emergent adverse events (TEAEs). The majority of adverse events were mild and moderate in severity. No relationship was identified between the dose of ebronucimab and the incidence of TEAEs. No TEAEs leading to study discontinuation and death were reported. Pharmacokinetics (PK)/Pharmacodynamics (PD) Following a single subcutaneous injection of 75 mg to 500 mg ebronucimab in healthy subjects, the median of T max ranged from 2.0 to 6.0 days and t 1/2 was within 4.11 to 5.01 days across cohorts. C max, AUC 0-t , and AUC 0-∞ increased approximately in a dose-proportional manner, see Table 1 and Figure 2. Serum free PCSK9 was almost completely inhibited after ebronucimab injection. The lowest level of free PCSK9 was observed around 2 days post administration and maintained at a low level 14-22 days post injection, see Figure 3. Immunogenicity A total of 3 subjects were tested ADA positive at least once during the study (75 mg, 1 subject; 500 mg, 2 subjects). The incidence of ADAs in subjects treated with ebronucimab was 12.5 % (3/24). Conclusions: Ebronucimab was well tolerated in healthy subjects and no special safety signal was identified during the study.