Open-label Study Research Articles

Abstract CT274: BGB-A317-LBL-007-202: A phase 2, randomized, active-controlled, open-label study to evaluate the efficacy and safety of LBL-007 (anti-LAG-3) in combination with tislelizumab (TIS; anti-PD-1) plus chemotherapy (chemo) as first-line (1L) treatment in patients with unresectable locally advanced/metastatic esophageal squamous cell carcinoma (ESCC)

Abstract Background: ESCC is the predominant histological subtype of esophageal cancer, accounting for 85% of cases. Patients (pts) with locally advanced/metastatic ESCC have poor clinical outcomes, with a 5-year survival rate of 6.1% for pts with distant metastases. 1L treatment with programmed cell death protein-1 (PD-1) inhibitors + platinum-based chemo has become the new standard of care for metastatic ESCC, however, there is an unmet need for enhanced treatment efficacy and a prolonged life span. LBL-007 is a monoclonal antibody (mAb) against lymphocyte activation gene-3 (LAG-3), an immune checkpoint receptor that negatively regulates T-cell activity. TIS is an anti-PD-1 mAb that blocks the PD-1/programmed death-ligand 1 (PD-L1) immune checkpoint, resulting in T-cell activation. This study (NCT06010303) aims to evaluate the efficacy and safety of LBL-007 + TIS + chemo as a 1L treatment in pts with unresectable, locally advanced/metastatic ESCC. Methods: This phase 2 study will enroll approximately 116 pts with a pathologically confirmed diagnosis of unresectable, locally advanced/metastatic ESCC and no prior systemic therapy. Pts will be randomized 2:1 to either Arm A (LBL-007 600 mg intravenously [IV] every 3 weeks [Q3W] + TIS 200 mg IV Q3W + chemo doublet) or Arm B (TIS 200 mg IV Q3W + chemo doublet), stratified by PD-L1 expression (tumor area positivity score ≥10% or <10%). The chemo doublet will consist of either cisplatin (60-80 mg/m2 IV Q3W) + 5-fluorouracil (750-800 mg/m2 IV daily on Days 1-5 Q3W), or cisplatin + paclitaxel (175 mg/m2 IV Q3W), determined by the investigator before randomization. Treatments will be administered until disease progression, intolerable toxicity, or withdrawal for other reasons. The primary endpoint is the overall response rate, as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints include progression-free survival, duration of response, and disease control rate (all by investigator per RECIST v1.1), and the incidence and severity of adverse events per National Cancer Institute-Common Terminology Criteria for Adverse Events v5.0. A safety monitoring committee is monitoring the safety of LBL-007 + TIS + chemo vs TIS + chemo. Exploratory endpoints include comparison of overall survival, assessment of predictive, prognostic, and pharmacodynamic biomarkers, pharmacokinetic evaluation of LBL-007 and TIS, and immunogenicity. The study is currently recruiting at approximately 46 sites across Asia, including Taiwan, mainland China, South Korea, and Thailand. Citation Format: Sook Ryun Park, Ming-Huang Chen, Arunee Dechaphunkul, Ningning Ding, Xiao Lin, Jinghui Zhang, Vivian Li, Qiao Li, Yi Ba. BGB-A317-LBL-007-202: A phase 2, randomized, active-controlled, open-label study to evaluate the efficacy and safety of LBL-007 (anti-LAG-3) in combination with tislelizumab (TIS; anti-PD-1) plus chemotherapy (chemo) as first-line (1L) treatment in patients with unresectable locally advanced/metastatic esophageal squamous cell carcinoma (ESCC) [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 CT274.

Abstract CT255: AdvanTIG-204: A phase 2, multicenter, randomized, 3-arm, open-label study investigating the preliminary efficacy and safety of ociperlimab (anti-TIGIT) + tislelizumab (anti-PD-1) + concurrent chemoradiotherapy (cCRT) in patients with untreated limited-stage small cell lung cancer (SCLC)

Abstract Background: Despite a high response rate to cCRT, patients with limited-stage SCLC generally experience recurrence of disease after a few months and survival remains poor. Immunotherapy has shown benefit in many tumor types, including SCLC. In preclinical and clinical studies of solid tumors, co-inhibition of T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitor motif domains (TIGIT) and PD-1 enhanced antitumor activity of anti-PD-1. AdvanTIG-204 (NCT04952597) investigated the efficacy and safety of ociperlimab + tislelizumab + cCRT in patients with untreated limited-stage SCLC. Methods: Patients with limited-stage SCLC and no prior systemic therapy were randomized 1:1:1 to Arm A (ociperlimab [900 mg IV Q3W] + tislelizumab [200 mg IV Q3W] + cCRT for 4 cycles, then ociperlimab + tislelizumab), Arm B (tislelizumab + cCRT for 4 cycles, then tislelizumab), or Arm C (cCRT for 4 cycles). Study drugs (Arms A and B) were continued for up to 12 months or until progression, unacceptable toxicity, or withdrawal. Primary endpoint: investigator-assessed PFS per RECIST v1.1. Secondary analyses included additional efficacy and safety endpoints in the ITT population, and efficacy in patient subgroups by PD-L1 and TIGIT expression (both <1% vs ≥1%), using tumor area positivity (PD-L1) and immune cell scoring (TIGIT). No hypothesis testing was predefined (p-value for descriptive purposes only). Descriptive comparisons were conducted for Arm A vs C, B vs C, and A vs B. Results: As of July 26, 2023, 126 patients (median age, 61.5 years) were randomized to Arm A (n=41), Arm B (n=42), or Arm C (n=43). Median follow-up: ~18 months (all arms). There was a trend of improvement in median PFS in Arm A (12.6 months) and Arm B (13.2 months) vs Arm C (9.5 months); HR (95% CI): Arm A vs C, 0.84 (0.46-1.52; p=0.2793); Arm B vs C, 0.80 (0.45-1.44; p=0.2414). ORR was 85.4% (3 CR) in Arm A, 88.1% (4 CR) in Arm B, and 76.7% (1 CR) in Arm C. Median DoR was 10.1 months in Arm A, 11.5 months in Arm B, and 8.2 months in Arm C. Median OS was not reached in any arm. Analyses showed that PD-L1 or TIGIT expression did not correlate with efficacy, however, small subgroup size limits interpretability. All patients experienced ≥1 treatment-related adverse event (TRAE); rates of grade ≥3 TRAEs were 73.2%, 78.6% and, 65.1% in Arms A, B, and C, respectively. The most common TRAEs included anemia (80.5% in Arm A vs 83.3% in Arm B vs 81.4% in Arm C), nausea (80.5% vs 76.2% vs 65.1%), and WBC count decreased (78.0% vs 76.2% vs 62.8%). Rates of TRAEs leading to any treatment discontinuation were 26.8%, 21.4%, and 4.7% in Arms A, B, and C, respectively. One patient in each arm experienced a TRAE leading to death. Conclusion: In patients with untreated limited-stage SCLC, tislelizumab + cCRT yielded a trend of improvement in PFS and ORR vs cCRT; addition of ociperlimab did not show detectable improvement. The overall safety profile of the treatments was tolerable, manageable, and generally consistent with the known risks of ociperlimab, tislelizumab, and cCRT. Citation Format: Youling Gong, Qingsong Pang, Rong Yu, Zhengfei Zhu, Jiangqiong Huang, Yufeng Cheng, Diansheng Zhong, Hongbo Wu, Seung Soo Yoo, Tracy Dobbs, Zinan Bao, Yunxia Zuo, Boxian Wei, Pu Sun, You Lu. AdvanTIG-204: A phase 2, multicenter, randomized, 3-arm, open-label study investigating the preliminary efficacy and safety of ociperlimab (anti-TIGIT) + tislelizumab (anti-PD-1) + concurrent chemoradiotherapy (cCRT) in patients with untreated limited-stage small cell lung cancer (SCLC) [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 CT255.

Abstract CT100: Safety and efficacy of AZD8853, an anti-growth and differentiation factor 15 (GDF15) antibody, in patients (pts) with advanced/metastatic solid tumors: First-in-human study

Abstract Background: GDF15 is overexpressed in solid tumors, with immunosuppressive effects on dendritic cells (DCs), T cells and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. AZD8853 is an IgG1 monoclonal antibody that neutralizes GDF15. This Phase 1/2a, open-label study assessed AZD8853 monotherapy in previously treated advanced/metastatic non-small-cell lung cancer, microsatellite-stable colorectal cancer (MSS-CRC) and urothelial carcinoma (UC) (NCT05397171). Methods: Eligible pts were ≥18 years old with ≥1 measurable lesion per RECIST v1.1 and ECOG PS 0/1. AZD8853 was given IV Q3W until disease progression, unacceptable toxicity or consent withdrawal. The primary objective was safety including dose-limiting toxicities (DLTs). Secondary objectives included efficacy, pharmacokinetics (PK) and pharmacodynamics (PD [free serum GDF15]). Exploratory objectives included peripheral immune PD. Results: During dose escalation, 16 pts (15 MSS-CRC, 1 UC) received AZD8853 (300 mg, n=3; 1000 mg, n=6; 3000 mg, n=7). By June 6, 2023, all pts discontinued treatment and the study. Thirteen pts (81.3%) had treatment-emergent adverse events (TEAEs; Table); the most common were diarrhea (31.3%), abdominal pain (31.3%) and decreased appetite (25%). Eight pts (50%) had Grade ≥3 TEAEs and 6 (37.5%) had serious TEAEs; none treatment-related. There were no DLTs. No pts had responses by RECIST; 5 (31.3%) had stable disease and 11 (68.8%) had disease progression as best response. AZD8853 PK was linear with a half-life of 5-10 days, supporting Q3W dosing. GDF15 suppression was transient. There was no evidence of ctDNA clearance or a dose-dependent change in peripheral immune cells including CD8+ and CD4+ T cells, DCs and MDSCs. Conclusions: AZD8853 was well tolerated. No objective responses or PD effects were seen and GDF15 suppression was not sustained, therefore no further development is planned. TABLE 1. NAND Table. AZD8853 safety AZD8853 300 mg 1000 mg 3000 mg Total Safety, n (%) N=3 N=6 N=7 N=16 TEAEs 3 (100) 4 (66.7) 6 (85.7) 13 (81.3) Grade ≥3 TEAEs 1 (33.3) 3 (50.0) 4 (57.1) 8 (50.0) TRAEs 1 (33.3) 0 2 (28.6) 3 (18.8) Grade ≥3 TRAEs 0 0 0 0 Serious TEAEs 1 (33.3) 3 (50.0) 2 (28.6) 6 (37.5) TEAEs leading to discontinuation of AZD8853 0 1 (16.7)* 0 1 (6.3) TEAEs leading to death 0 1 (16.7)* 0 1 (6.3) DLTs, n (%) N=3 N=6 N=6 † N=15 DLTs 0 0 0 0 *Death due to serious AE of cardiac arrest, unrelated to AZD8853; pt had a history of coronary artery disease, coronary stenting, and pulmonary embolism.†One pt discontinued due to clinical progression prior to completing the DLT evaluation period and was not included in the DLT-evaluable set. DLTs, dose-limiting toxicities; TEAEs, treatment-emergent adverse events, TRAEs, treatment-related adverse events Citation Format: Benedito A. Carneiro, Olumide Gbolahan, Albiruni Abdul Razak, John F. Hilton, Arthur Lambert, John Hood, Michael Pluta, Veronique Bragulat, Elhan Sanai, Rakesh Kumar, Duncan Jodrell, Patricia LoRusso. Safety and efficacy of AZD8853, an anti-growth and differentiation factor 15 (GDF15) antibody, in patients (pts) with advanced/metastatic solid tumors: First-in-human study [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 CT100.

Abstract CT275: A phase 2, randomized, open-label study of onvansertib in combination with standard-of-care (SoC) versus SoC alone for first-line treatment of RAS-mutant metastatic colorectal cancer (mCRC)

Abstract Background: Chemotherapy in combination with bevacizumab (Bev) has been a standard first-line treatment for RAS-mutated mCRC patients for the last 2 decades. The prognosis of these patients remains poor. Onvansertib is an orally available, highly potent, and selective inhibitor of Polo-like kinase 1 (PLK1), currently in clinical development. In a Phase 1b/2 study, onvansertib in combination with FOLFIRI + Bev demonstrated safety and promising efficacy in the second-line treatment of KRAS-mutated mCRC patients (NCT03829410). A subgroup analysis showed that patients not exposed to Bev (Bev-naïve) in the first-line setting had superior clinical benefit compared to Bev-exposed patients. Based on this data, we propose to investigate the combination of onvansertib with SoC (chemo + Bev) in the first-line treatment of RAS-mutated, Bev-naïve mCRC patients. Methods: This exploratory Phase 2, open-label, randomized study is designed to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of 2 doses of onvansertib (20 mg and 30 mg) in combination with SoC (FOLFIRI + Bev or FOLFOX + Bev) versus SoC alone in patients with RAS-mutated metastatic and unresectable CRC in the first-line setting. Eligible participants must have histologically confirmed mCRC, KRAS or NRAS mutation, no previous systemic therapy in the metastatic setting, ECOG performance status of 0 or 1, measurable disease as defined per RECIST v1.1. Exclusion criteria include patients with BRAF-V600 mutations or microsatellite instability high/deficient mismatch repair, prior treatment with a VEGF inhibitor, previous oxaliplatin treatment within 12 months prior to randomization. The primary endpoint is objective response as determined according to RECIST v1.1 by an independent central review. Key secondary endpoints include progression-free survival and duration of response per independent central review. The study will enroll approximately 90 patients. Each patient will be randomized to be treated with onvansertib (20 mg or 30 mg) + SoC or SoC alone. The enrollment period for this study is approximately 12 months. Patients will be followed for overall survival for up to 1 year after the end of treatment. Trial is open and recruiting as of November 2023. This trial is registered as NCT06106308. Citation Format: Heinz-Josef Lenz, Benjamin Kuritzky, Anu Thummala, Stephan Kendall, Ravindranath Patel, Sreenivasa R. Chandana, Alisha H. Bent, Nancy Sherman, Ramanand Arun Subramanian, Fairooz Kabbinavar, Joel Randolph Hecht. A phase 2, randomized, open-label study of onvansertib in combination with standard-of-care (SoC) versus SoC alone for first-line treatment of RAS-mutant metastatic colorectal cancer (mCRC) [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 CT275.

Abstract CT076: AFNT-211: A phase1 study of autologous CD4+ and CD8+ T cells engineered to express a high avidity HLA-A*11:01-restricted, KRAS G12V-specific, transgenic TCR; CD8α/β coreceptor; and a FAS41BB switch receptor in patients with advanced/metastatic solid tumors

Abstract Background: Activating mutations in KRAS (including KRAS G12V) are well-described oncogenic drivers in solid tumors. Patients with KRAS driver mutations have a poor prognosis, and most KRAS-mutated cancers lack effective therapies. T cell receptor (TCR)-T cell therapies targeting mutant KRAS have demonstrated proof of concept in the clinic, but duration of response remains a challenge. AFNT-211 represents a novel strategy to address the immunosuppressive tumor microenvironment and improve response rate and duration in solid tumors. Rationale: AFNT-211 autologous CD4+ and CD8+ T cells are engineered to express a high avidity HLA-A*11:01restricted, KRAS G12V-specific, transgenic TCR; the wildtype CD8α/β coreceptor; and a FAS-41BB switch receptor. The intended mechanism of action is recognition and elimination of KRAS G12V-mutated tumor cells by AFNT-211. AFNT-211 is designed to enhance anti-tumor activity via the following mechanisms of action as shown in preclinical models: (1) the CD8α/β coreceptor enables MHC-I-‍restricted TCR recognition of the KRAS G12V target by CD4+ T cells; (2) engaging CD4+ helper T cell responses drives enhanced CD8+ T cell cytotoxic activity and prevents T cell exhaustion; (3) the FAS-41BB chimeric switch receptor drives increased T cell activity, circumventing native FAS apoptotic signaling. Methods: This ongoing Phase 1, first-in-human, multicenter, open-label study of AFNT-211 (1) evaluates safety/tolerability, (2) determines the optimal biological dose (OBD) and recommended Phase 2 dose (RP2D), and (3) assesses preliminary antitumor activity. The study consists of 2 parts: dose escalation and dose expansion. Dose escalation is guided by the Bayesian optimal interval Phase 1/2 (BOIN12) design to determine the OBD. The BOIN12 design quantifies the desirability of a dose in terms of toxicity-efficacy tradeoff and adaptively allocates patients to the dose with the highest estimated desirability. The RP2D will be selected based on the BOIN12 design and the totality of benefit/risk assessment. Patients enrolling in dose expansion will be treated at the OBD/RP2D in indication-specific cohorts. This study is conducted in patients aged ≥ 18 years who are HLA-A*11:01-positive with advanced/metastatic solid tumors harboring a KRAS G12V mutation, and intolerance of/progression on at least 1 prior systemic therapy. Patients undergo leukapheresis to collect T cells for the manufacturing of AFNT-211 and receive lymphodepleting chemotherapy prior to AFNT-211 infusion. This is followed by a 28-day dose-limiting toxicity observation period (dose escalation only) and a post-treatment follow-up period for 24 months/until disease progression. The study is open for recruitment in the United States (NCT06105021). Citation Format: Shaunica Mitchell, Binaish Khan, Francis Payumo, E. Gabriela Chiorean, Zhubin Gahvari, J. Randolph Hecht, Michael Hurwitz, Rom Leidner, Heinz-Josef Lenz, Meredith Pelster, Salman Punekar, Adam Schoenfeld, Dan Zhao, Markus Vallaster, Dirk Nagorsen. AFNT-211: A phase1 study of autologous CD4+ and CD8+ T cells engineered to express a high avidity HLA-A*11:01-restricted, KRAS G12V-specific, transgenic TCR; CD8α/β coreceptor; and a FAS41BB switch receptor in patients with advanced/metastatic solid tumors [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 CT076.

Safety and Efficacy of Pegcetacoplan in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria over 48Weeks: 307 Open-Label Extension Study.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by complement-mediated hemolysis and thrombosis. Pegcetacoplan, the first targeted complement component3 (C3) PNH therapy, was safe and efficacious in treatment-naive and pre-treated patients with PNH in five clinical trials. The 307 open-label extension (OLE) study (NCT03531255) is a non-randomized, multicenter extension study of long-term safety and efficacy of pegcetacoplan in adult patients with PNH who completed a pegcetacoplan parent study. All patients received pegcetacoplan. Outcomes at the 48-week data cutoff (week48 of 307-OLE or August 27, 2021, whichever was earlier) are reported. Hemoglobin concentrations, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores, and transfusion avoidance were measured. Hemoglobin > 12g/dL and sex-specific hemoglobin normalization (i.e., male, ≥ 13.6g/dL; female, ≥ 12g/dL) were assessed as percentage of patients with data available and no transfusions 60days before data cutoff. Treatment-emergent adverse events, including hemolysis, were reported. Data from 137 patients with at least one pegcetacoplan dose at data cutoff were analyzed. Mean (standard deviation [SD]) hemoglobin increased from 8.9 (1.22) g/dL at parent study baseline to 11.6 (2.17) g/dL at 307-OLE entry and 11.6 (1.94) g/dL at data cutoff. At parent study baseline, mean (SD) FACIT-Fatigue score of 34.1 (11.08) was below the general population norm of 43.6; scores improved to 42.8 (8.79) at 307-OLE entry and 42.4 (9.84) at data cutoff. In evaluable patients, hemoglobin > 12g/dL occurred in 40.2% (43 of 107) and sex-specific hemoglobin normalization occurred in 31.8% (34 of 107) at data cutoff. Transfusion was not required for 114 of 137 patients (83.2%). Hemolysis was reported in 23 patients (16.8%). No thrombotic events or meningococcal infections occurred. Pegcetacoplan sustained long-term improvements in hemoglobin concentrations, fatigue reduction, and transfusion burden. Long-term safety findings corroborate the favorable profile established for pegcetacoplan. ClinicalTrials.gov identifier, NCT03531255.

A phase I study of pevonedistat, azacitidine, and venetoclax in patients with relapsed/refractory acute myeloid leukemia.

Azacitidine/venetoclax is an active regimen in patients with newly diagnosed AML. However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL-1 is suggested to be a potential resistance mechanism. Pevonedistat inhibits MCL-1 through activation of NOXA, and pevonedistat/azacitidine has previously shown activity in AML. To assess the tolerability and efficacy of adding pevonedistat to azacitidine/venetoclax in relapsed/refractory AML, we conducted a phase I multicenter openlabel study in 16 adults with relapsed/refractory AML. Patients were treated with azacitidine, venetoclax along with pevonedistat intravenously on days 1, 3 and 5 of each 28-day cycle at 10, 15 or 20 mg/m2 in successive cohorts in the dose escalation phase. The impact of treatment on protein neddylation as well as expression of pro-apoptotic BCL2 family members was assessed. The recommended phase II dose of pevonedistat was 20 mg/m2. Grade 3 or higher adverse events included neutropenia (31%), thrombocytopenia (13%), febrile neutropenia (19%), anemia (19%), hypertension (19%) and sepsis (19%). The overall response rate was 46.7% for the whole cohort including complete remission (CR) in 5 of 7 (71.4%) patients who were naïve to the hypomethylating agent/venetoclax. No measurable residual disease (MRD) was detected in 80.0% of the patients who achieved CR. The median time to best response was 50 (range: 23 - 77) days. Four patients were bridged to allogeneic stem cell transplantation. The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. (NCT04172844).

Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis

BackgroundIvacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF. MethodsIn this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements. ResultsSeven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (−40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed. ConclusionsIn this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age.

Effect of a topical silicone gel and a polyurethane dressing on the evolution of scars

ObjectiveTo assess the effectiveness and safety of a topical silicone gel (BE + Gel reductor y reparador de cicatrices) and a polyurethane dressing (BE + Apósito reductor y reparador de cicatrices) on the evolution of scars of patients who were previously recruited in the emergency care unit while seeking wound care. MethodA single center, stratified observational, open label study was performed in the emergency care unit of Donostia Universitary Hospital (recruitment) and in the Biodonostia Health Research Institute (intervention). Scars located in unexposed body areas with the dressing, and scars located in exposed areas with either the gel or the dressing. Investigators assessed interventions at day 1 and on weeks 4, 8 and 12. Vancouver Scar Scale (VSS) and a photographical assessment were used to determine the scars evolution, and the subjective perception of the scar was evaluated by means of a questionnaire administered to the patients. ResultsPatients whose scars were treated with the silicone gel had an average initial VSS score of 5.4 ± 2.08. This value was reduced to 0.86 ± 1.17 after 90 days of treatment. Patients treated with the polyurethane dressing had an average initial VSS score of 5.8 ± 2.29. After 90 days of treatment, this average score was reduced to 0.33 ± 0.66. Positive evolution of scars was also supported by photographs and by a patient questionnaire. ConclusionsBoth treatments appear to be safe and effective, objectively, and subjectively, in the context of scar evolution.

A deep-learning model for intracranial aneurysm detection on CT angiography images in China: a stepwise, multicentre, early-stage clinical validation study

Artificial intelligence (AI) models in real-world implementation are scarce. Our study aimed to develop a CT angiography (CTA)-based AI model for intracranial aneurysm detection, assess how it helps clinicians improve diagnostic performance, and validate its application in real-world clinical implementation. We developed a deep-learning model using 16 546 head and neck CTA examination images from 14 517 patients at eight Chinese hospitals. Using an adapted, stepwise implementation and evaluation, 120 certified clinicians from 15 geographically different hospitals were recruited. Initially, the AI model was externally validated with images of 900 digital subtraction angiography-verified CTA cases (examinations) and compared with the performance of 24 clinicians who each viewed 300 of these cases (stage 1). Next, as a further external validation a multi-reader multi-case study enrolled 48 clinicians to individually review 298 digital subtraction angiography-verified CTA cases (stage 2). The clinicians reviewed each CTA examination twice (ie, with and without the AI model), separated by a 4-week washout period. Then, a randomised open-label comparison study enrolled 48 clinicians to assess the acceptance and performance of this AI model (stage 3). Finally, the model was prospectively deployed and validated in 1562 real-world clinical CTA cases. The AI model in the internal dataset achieved a patient-level diagnostic sensitivity of 0·957 (95% CI 0·939-0·971) and a higher patient-level diagnostic sensitivity than clinicians (0·943 [0·921-0·961] vs 0·658 [0·644-0·672]; p<0·0001) in the external dataset. In the multi-reader multi-case study, the AI-assisted strategy improved clinicians' diagnostic performance both on a per-patient basis (the area under the receiver operating characteristic curves [AUCs]; 0·795 [0·761-0·830] without AI vs 0·878 [0·850-0·906] with AI; p<0·0001) and a per-aneurysm basis (the area under the weighted alternative free-response receiver operating characteristic curves; 0·765 [0·732-0·799] vs 0·865 [0·839-0·891]; p<0·0001). Reading time decreased with the aid of the AI model (87·5 s vs 82·7 s, p<0·0001). In the randomised open-label comparison study, clinicians in the AI-assisted group had a high acceptance of the AI model (92·6% adoption rate), and a higher AUC when compared with the control group (0·858 [95% CI 0·850-0·866] vs 0·789 [0·780-0·799]; p<0·0001). In the prospective study, the AI model had a 0·51% (8/1570) error rate due to poor-quality CTA images and recognition failure. The model had a high negative predictive value of 0·998 (0·994-1·000) and significantly improved the diagnostic performance of clinicians; AUC improved from 0·787 (95% CI 0·766-0·808) to 0·909 (0·894-0·923; p<0·0001) and patient-level sensitivity improved from 0·590 (0·511-0·666) to 0·825 (0·759-0·880; p<0·0001). This AI model demonstrated strong clinical potential for intracranial aneurysm detection with improved clinician diagnostic performance, high acceptance, and practical implementation in real-world clinical cases. National Natural Science Foundation of China. For the Chinese translation of the abstract see Supplementary Materials section.

A Study to Evaluate the Effect of Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors on Oxidative Stress Parameters in Type 2 Diabetes Mellitus Patients.

Introduction Diabetes mellitus (DM) is a global health issue with 50 million diabetics currently residing in India. Hyperglycemia causes tissue damage due to mitochondrial overproduction of reactive oxygen species. Sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) have shown a decrease in oxidative stress by either amelioration of free-radical generation or potentiation of cellular antioxidative capacity in preclinical studies. However, there is a paucity of published clinical studies. Hence, this study was undertaken to evaluate the effect of co-administration of SGLT2i with other drugs on oxidative stress in type 2 DM (T2DM) patients. Methods A prospective, parallel, open-label study in T2DM patients attending endocrinology OPDwas conducted for a period of 12 months. At the clinician's discretion, patients were grouped as SGLT2i as an add-on to standard drugs vs standard drugs alone. Blood samples were collected at baseline and at the end of 12 weeks to estimate malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH) levels. Secondary parameters - glycemic indices and lipid profile - were estimated every four weeks. Results A total of 32 patients were enrolled in the study (16 per group). There was a significant decrease in MDA (p < 0.05) and NO (p < 0.01) and a highly significant increase in GSH (p < 0.001) at 12 weeks from baseline in the SGLT2i group. A reduction in fasting blood sugar (FBS) and post-prandial blood sugar (PPBS) and a 0.56% difference in HbA1c were also noted in the SGLT2i group.Significant lowering of low-density lipoprotein (LDL, p < 0.05) and elevation in HDL levels (p < 0.05) from baseline was seen in the SGLT2i group. Conclusion Co-administration of SGLT2i with antidiabetic drugs demonstrated a significant effect in improving oxidative stress biomarkers and glycemic and lipid profiles among T2DM patients.

Efficacy and Safety of Dapagliflozin in Patients With Acute Heart Failure

BackgroundThe primary goals during acute heart failure (AHF) hospitalization are decongestion and guideline-directed medical therapy (GDMT) optimization. Unlike diuretics or other GDMT, early dapagliflozin initiation could achieve both AHF goals. ObjectivesThe authors aimed to assess the diuretic efficacy and safety of early dapagliflozin initiation in AHF. MethodsIn a multicenter, open-label study, 240 patients were randomized within 24 hours of hospital presentation for hypervolemic AHF to dapagliflozin 10 mg once daily or structured usual care with protocolized diuretic titration until day 5 or hospital discharge. The primary outcome, diuretic efficiency expressed as cumulative weight change per cumulative loop diuretic dose, was compared across treatment assignment using a proportional odds model adjusted for baseline weight. Secondary and safety outcomes were adjudicated by a blinded committee. ResultsFor diuretic efficiency, there was no difference between dapagliflozin and usual care (OR: 0.65; 95% CI: 0.41-1.02; P = 0.06). Dapagliflozin was associated with reduced loop diuretic doses (560 mg [Q1-Q3: 260-1,150 mg] vs 800 mg [Q1-Q3: 380-1,715 mg]; P = 0.006) and fewer intravenous diuretic up-titrations (P ≤ 0.05) to achieve equivalent weight loss as usual care. Early dapagliflozin initiation did not increase diabetic, renal, or cardiovascular safety events. Dapagliflozin was associated with improved median 24-hour natriuresis (P = 0.03) and urine output (P = 0.005), expediting hospital discharge over the study period. ConclusionsEarly dapagliflozin during AHF hospitalization is safe and fulfills a component of GDMT optimization. Dapagliflozin was not associated with a statistically significant reduction in weight-based diuretic efficiency but was associated with evidence for enhanced diuresis among patients with AHF. (Efficacy and Safety of Dapagliflozin in Acute Heart Failure [DICTATE-AHF]; NCT04298229)

Real-life experience with inotersen at CEPARM, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro.

Hereditary transthyretin amyloidosis (ATTRv) is an inherited, progressive, and fatal disease still largely underdiagnosed. Mutations in the transthyretin (TTR) gene cause the TTR protein to destabilize, misfold, aggregate, and deposit in body tissues, which makes ATTRv a disease with heterogeneous clinical phenotype. To describe the long-term efficacy and safety of inotersen therapy in patients with ATTRv peripheral neuropathy (ATTRv-PN). Patients who completed the NEURO-TTR pivotal study and the NEURO-TTR OLE open-label extension study migrated to the present study and were followed-up for at least 18 more months to an average of 67 months and up to 76 months since day 1 of the inotersen therapy (D1-first dose of inotersen). Disease progression was evaluated by standard measures. Ten ATTRv-PN patients with Val30Met mutation were included. The mean disease duration on D1 was of 3 years, and the mean age of the patients was of 46.8 years. During an additional 18-month follow up, neurological function, based on the Neuropathy Impairment Score and the Polyneuropathy Disability Score, functionality aspects (Karnofsky Performance Status), and nutritional and cardiac aspects were maintained. No new safety signs have been noted. The treatment with inotersen was effective and well tolerated for the average of 67 months and up to 76 months. Our results are consistent with those of larger phase-III trials.

Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial

In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome. The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 μg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0-4) from baseline to weeks 21-24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed. Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21-24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of -1·7 (95% CI -2·0 to -1·3) for odevixibat and -0·8 (-1·3 to -0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline -0·9 [95% CI -1·4 to -0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 μmol/L [SD 115] with odevixibat vs 246 μmol/L [121] with placebo) to the average of weeks 20 and 24 (149 μmol/L [102] vs 271 μmol/L [167]; LS mean change -90 μmol/L [95% CI -133 to -48] with odevixibat vs 22 μmol/L [-35 to 80] with placebo; difference in LS mean change -113 μmol/L [95% CI -179 to -47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths. Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study. Albireo Pharma, an Ipsen company.

Eculizumab in Adolescent Patients with Refractory Generalized Myasthenia Gravis: A Phase 3, Open-Label, Multicenter Study

ObjectiveJuvenile generalized myasthenia gravis (gMG) is an extremely rare condition which would benefit from new targeted treatment approaches. This study evaluated the efficacy and safety of eculizumab, a terminal complement C5 inhibitor. MethodsAdolescents aged 12–17 years with refractory gMG and a positive serologic test for anti-acetylcholine receptor (AChR) antibodies, received eculizumab [weekly induction (1–2 doses of 600 mg or 4 doses of 900 mg) followed by maintenance doses (300–1200 mg) every 2 weeks for up to 26 weeks] in a Phase 3, open-label multicenter study (NCT03759366). Change from baseline to Week 26 in Quantitative Myasthenia Gravis (QMG) total score (primary endpoint) and secondary endpoints including Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score; Myasthenia Gravis Composite score; Myasthenia Gravis Foundation of America post-intervention status; EuroQol 5-Dimensions (Youth) and Neurological Quality-of-Life Pediatric Fatigue questionnaire scores; pharmacokinetics, pharmacodynamics; and safety, were recorded. ResultsEleven adolescents (mean±SD age 14.8±1.8 years) were enrolled; 10 completed the primary evaluation period. Least-squares mean changes from baseline at Week 26 were -5.8 (SE 1.2; P=.0004) for QMG total score and -2.3 (SE 0.6; P=.0017) for MG-ADL total score. Overall, the primary and all secondary efficacy endpoint analyses met statistical significance from the first assessment, and were sustained throughout. Complete terminal complement inhibition was sustained through 26 weeks in all patients. Treatment-emergent adverse events were all mild/moderate and predominantly unrelated to eculizumab. ConclusionsEculizumab was effective in reducing disease burden and was well tolerated in adolescents with refractory AChR antibody-positive gMG.

A multicenter, open-label long-term safety study of rimegepant for the acute treatment of migraine.

The present study evaluated the long-term safety and tolerability of rimegepant, an orally administered small molecule calcitonin gene-related peptide receptor antagonist, in people with migraine. This multicenter, long-term, open-label safety study included adults (≥18 years) with ≥1 year history of migraine who were sequentially enrolled into three groups: participants in the first two groups had either 2-8 or 9-14 moderate to severe migraine attacks per month by history and treated as needed (pro re nata [PRN]) with one rimegepant 75 mg oral tablet up to once per calendar day for 52 weeks (PRN 2-8 and PRN 9-14); a third group, included to collect safety data during higher-frequency dosing, had 4-14 moderate to severe migraine attacks per month by history and who took one rimegepant tablet every other day as scheduled dosing plus PRN dosing of one rimegepant tablet for migraine attacks of any severity on nonscheduled dosing days for 12 weeks (every other day (EOD) + PRN). Overall, 1800 participants self-administered rimegepant (PRN 2-8: n = 1033; PRN 9-14: n = 481; EOD + PRN: n = 286). The most common on-treatment adverse events (AEs) were upper respiratory tract infection (8.8%), nasopharyngitis (6.8%) and sinusitis (5.1%). Most AEs were mild or moderate and considered unrelated to rimegepant. Serious AEs considered possibly (n = 1) or unlikely (n = 9) related to rimegepant were reported in ten (0.6%) participants. No signal of drug-induced liver injury because of rimegepant was identified. Rimegepant 75 mg up to once per day as EOD + PRN for 12 weeks or PRN for up to 52 weeks was safe and well tolerated. No signal of hepatotoxicity, potential drug abuse, or medication-overuse headache was identified.Trial registration: Clinicaltrials.gov: NCT03266588.

Immunogenicity, efficacy, and safety of biosimilar insulin glargine (Gan & Lee glargine) compared with originator insulin glargine (Lantus®) in patients with type 2 diabetes after 26 weeks' treatment: A randomized open label study.

To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus. This was a phase 3, multicenter, open-label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment-induced anti-insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment-induced AIA development to the prespecified margins. The percentages of participants positive for treatment-induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of -2.1 percentage points and a 90% CI (-7.6%, 3.5%) (predefined similarity margins: -10.7%, 10.7%). The difference in glycated haemoglobin was -0.08% (90% CI, -0.23, 0.06). The overall percentage of participants with any treatment-emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups. GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy,and safety, based on the current study.

CT-guided ozone-mediated lumbar-renal sympathetic denervation for resistant hypertension treatment: A pilot single-arm clinical trial

BackgroundRenal sympathetic denervation (RDN) reduces blood pressure (BP). MethodsThis single-arm open-label study enrolled patients with resistant hypertension (RH) and treat them by CT-guided ozone mediated lumbar-renal sympathetic denervation (L-RDN). The primary endpoint was to assess the changes of BP over 24-h ambulatory BP monitoring (ABPM) and to evaluate the anti-hypertensive medication burden (AHMB) at 3-month follow-up. This study was registered in Chictr.org.cn (ChiCTR2300071375). Results17 patients (mean age 65.12 ± 10.77 years) with AHMB of 4.12 ± 1.11 were enrolled. After the procedure, 7 patients (46.7 %) matched the criteria for antihypertensive medication reduction. The AHMB decreased to 3.87 ± 0.96 for the whole objectives and from 3.87 ± 0.96 to 3.55 ± 0.78 for patients with normal baseline renal function. On top of the lessened AHMB, L-RDN further reduced morning systolic BP (SBP) by −8.6 ± 4.0 mmHg (p = 0.034) and diastolic BP (DBP) by −4.6 ± 2.1 mmHg (p = 0.032) for all participants and morning SBP by −13.2 ± 3.6 mmHg (p < 0.001), morning DBP by −6.2 ± 2.4 mmHg (p = 0.011) and daytime SBP by −4.1 ± 1.6 mmHg (p = 0.009) for those with normal baseline renal function at 3-month of follow-up. No adverse events were reported intra- and post operation. ConclusionsCT-guided ozone-mediated L-RDN might be an innovative approach of RDN for treating RH. Confirmatory studies are warranted.

510 Dopaminergic Neuronal Cell Therapy for Parkinson’s Disease: Results From a Phase 1 Study of Bemdaneprocel

INTRODUCTION: None of the available therapies for PD directly address the loss of dopaminergic neurons. Bemdaneprocel is an investigational cellular therapy composed of midbrain dopaminergic neuronal cells derived from human embryonic stem cells. METHODS: In this open-label study 12 subjects have received 1 of 2 doses of bemdaneprocel to the putamen bilaterally, along with a 1-year immunosuppression regimen. Safety and tolerability have been assessed, along with assessments of engraftment and clinical impact. RESULTS: At screening, the average age was 66.4 yrs and the mean time since diagnosis was 9.1 yrs. All subjects presented at screening with a Hoehn and Yahr stage of 2 in the on-medication state. The mean MDS-UPDRS part III score was 46.6 (15-73) when assessed in the off-medication state, and patients presented with 4.3 (1.4-6.2) average daily hours of OFF time as assessed by PD diaries. In both cohorts, the safety profile is favorable with the vast majority of reported treatment-emergent AEs being mild to moderate. All but one AE deemed potentially related to the intervention were attributed to the immunosuppression regimen. There were no AEs reported as possibly related to the cell therapy. Patients enrolled in both cohorts to date have demonstrated clinical improvement as measured by the MDS-UPDRS, PD diaries, PDQ-39, and others. F-DOPA PET imaging supports evidence of engraftment, survival and functionality of the cells at 1 year. CONCLUSIONS: Results from at least 1 year of follow-up in this phase 1 study will be presented. An acceptable safety profile, evidence of sustained engraftment, and positive exploratory clinical outcomes in this study support further investigation of bemdaneprocel for the treatment of PD. Unpublished data, will be partly shown in a poster at MDS

Efficacy and Safety of Bleselumab in Preventing the Recurrence of Primary Focal Segmental Glomerulosclerosis in Kidney Transplant Recipients: A Phase 2a, Randomized, Multicenter Study.

Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease and frequently recurs after kidney transplantation. Recurrent FSGS (rFSGS) is associated with poor allograft and patient outcomes. Bleselumab, a fully human immunoglobulin G4 anti-CD40 antagonistic monoclonal antibody, disrupts CD40-related processes in FSGS, potentially preventing rFSGS. A phase 2a, randomized, multicenter, open-label study of adult recipients (aged ≥18 y) of a living or deceased donor kidney transplant with a history of biopsy-proven primary FSGS. The study assessed the efficacy of bleselumab combined with tacrolimus and corticosteroids as maintenance immunosuppression in the prevention of rFSGS >12 mo posttransplantation, versus standard of care (SOC) comprising tacrolimus, mycophenolate mofetil, and corticosteroids. All patients received basiliximab induction. The primary endpoint was rFSGS, defined as proteinuria (protein-creatinine ratio ≥3.0 g/g) with death, graft loss, or loss to follow-up imputed as rFSGS, through 3 mo posttransplant. Sixty-three patients were followed for 12 mo posttransplantation. Relative decrease in rFSGS occurrence through 3 mo with bleselumab versus SOC was 40.7% (95% confidence interval, -89.8 to 26.8; P = 0.37; absolute decrease 12.7% [95% confidence interval, -34.5 to 9.0]). Central-blinded biopsy review found relative (absolute) decreases in rFSGS of 10.9% (3.9%), 17.0% (6.2%), and 20.5% (7.5%) at 3, 6, and 12 mo posttransplant, respectively; these differences were not statistically significant. Adverse events were similar for both treatments. No deaths occurred during the study. In at-risk kidney transplant recipients, bleselumab numerically reduced proteinuria occurrence versus SOC, but no notable difference in occurrence of biopsy-proven rFSGS was observed.