Lee's Pharmaceutical (China)

BackgroundIn the FUEL (Fontan Udenafil Exercise Longitudinal) trial, a positive treatment effect was identified for outcomes at the ventilatory anaerobic threshold but not for the primary outcome, oxygen consumption (Vo2) at peak exercise. This disparate response may be explained by the physiologic challenge of improving peak Vo2 in participants with near‐normal baseline exercise performance.MethodsParticipants were divided into subgroups by baseline predicted peak Vo2 (<80% versus ≥80%). Treatment effect was evaluated in those with a baseline peak Vo2 <80% predicted and linear regression was performed to examine the interaction between subgroup and response to therapy for the primary and secondary outcomes.ResultsOf the 379 participants with paired exercise data, 302 (80%) had a baseline peak Vo2 <80% predicted. In this subgroup, the primary outcome of peak Vo2 improved significantly after 6 months of udenafil treatment, when compared with placebo (0.23±4.17 mL/kg per min versus −0.90±3.74 mL/kg per min; P=0.021). Secondary outcome measures, including Vo2 at ventilatory anaerobic threshold (P=0.023), work at ventilatory anaerobic threshold (P=0.032), and the myocardial performance index (P=0.007) were all significantly improved as well. A significant interaction was found between exercise subgroups and response to udenafil for peak Vo2 (P=0.036) but not for other outcomes.ConclusionsIn this post hoc subgroup analysis, after exclusion of patients with Fontan circulation with near‐normal baseline peak Vo2, a positive treatment effect of udenafil was identified for the primary outcome of peak Vo2. The interaction between baseline peak Vo2 and treatment may have influenced the outcome of the FUEL trial.RegistrationURL: https://clinicaltrials.gov; Unique identifier: NCT0274115.

Abstract B7H3 (CD276) belongs to the B7 superfamily of immune checkpoint molecules. It is present at low levels in most normal tissues but is overexpressed in a variety of cancers, such as lung cancer, prostate cancer, breast cancer, head and neck squamous cell carcinoma, and esophageal squamous cell carcinoma. Notably, B7H3 overexpression has been found to be associated with a poor prognosis in a broad spectrum of malignant tumors, and it has become an attractive target for cancer therapy in recent years. B7H3-targeted antibody-drug conjugates (ADCs), such as DS7300, have shown positive clinical efficacy in small cell lung cancer, squamous non-small cell lung cancer, metastatic castration-resistant prostate cancer. GLR1061 is a B7H3 targeting ADC comprised of a humanized IgG1 monoclonal antibody, a cleavable linker and a novel DNA topoisomerase I inhibitor. Our independently developed topoisomerase I inhibitor had super strong cancer cell inhibition activity, which was 5 to 10 times stronger than DXd, and enhanced key advantages such as ADC bystander effect. Conjugated with B7-H3 antibody, which had superior binding and internalization, GLR1061 demonstrated more significant anti-tumor efficacy across various cancer types than DS7300 both in vitro and in vivo. In addition, in the CDX model of co-culture of antigen-positive and antigen-negative cells, GLR1061 exhibited much stronger bystander activity than DS7300, which was expected to overcome tumor heterogeneity and effectively eliminate cancer cells with different antigens expressions. In plasma stability studies, GLR1061 showed significantly lower free-payload release than DS7300 in different species (PBS, rat, monkey, and human). In a preclinical repeated-dose toxicology study in mice, GLR1061 showed good tolerability and reversible toxicity. Overall, GLR1061 demonstrated excellent specificity, efficacy, and safety as a next-generation therapy for the treatment of B7H3-positive tumors. Citation Format: Jiao Jiao, Yingjie Sun, Jiaxing Wang, Menghan Cui, Siyao Li, Wenjie Shao, Hairui Yuan, Haitong Sheng. Preclinical characterization of GLR1061, a B7H3-targeted ADC with a novel DNA topoisomerase I inhibitor, demonstrated superior bystander effect to overcome tumor heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2878.

e24058 Background: Breakthrough cancer pain (BTcP) can significantly impact the life quality of the cancer patient. Wide-used rapid-onset opioids (ROOs) for BTcP are transmucosal fentanyl-based preparations. Inhaled fentanyl demonstrated similar pharmacokinetic properties as intravenous administration in healthy volunteers. Fentanyl aerosol can be generated via hand-held drug-device delivery system, providing rapid, consistent multi-dose administration. Fentanyl inhalant was explored as alternative treatment of BTcP in cancer patients in this study to evaluate its efficacy, safety, and tolerability in BTcP patients with well-controlled background cancer pain. Methods: Adults ≥18 years with cancer are eligible if they were experiencing persistent cancer- or treatment-related pain with above mild severity and 1-4 episode occurrences daily. Each patient was treated and observed for 6 BTcP episodes (4 with fentanyl inhalant, 2 with placebo). During each episode, patients were allowed to inhale up to six shots within 1 hour. Pain intensity was recorded using 11-point Numerical Rating Scale (NRS) at predefined time points. The primary endpoint was the time-weighted Sum of Pain Intensity Difference scores at 30 minutes (SPID30) after the first inhalation. Results: 335 BTcP episodes in 59 patients were treated. SPID30 was analyzed using mixed model of repeated measures with treatment (fentanyl inhalant or placebo), BTcP episode, baseline pain intensity score as fixed factors, and subject as random factor. Mean SPID30 ± SD was -97.4 ± 48.43 for fentanyl-treated episodes, and -64.6 ± 40.25 for placebo-treated episodes. Based on treatment adjustment in the mixed covariance model, significant difference (p &lt; 0.001) was reported with mean treatment difference of -27.7 (LS-mean ± SD, -94.2 ± 4.49 for fentanyl and -66.5 ± 4.86 for placebo). It enlarged at 60 minutes (SPID60) with a mean treatment difference of -57.9 (LS-mean ± SD, -231.4 ±105.14 for fentanyl and -162.2 ± 91.21 for placebo, p &lt; 0.001). Significant differences in PID for episodes treated with fentanyl versus placebo were seen 4 minutes after the first dosing and maintained up to 60 minutes. Other endpoints showed statistical significance favoring fentanyl treatment, including the proportion of NRS ≤ 3, NRS pain scores decreased ≥ 33% or ≥ 50% from baseline after completion of BTcP treatment within 30 minutes of first dose, and Pain Relief Score Within 30 Minutes of the First Dose (PR30). Only 4.4% of BTcP episodes required rescue medication in fentanyl group. Major adverse events were mild or moderate in severity and were typical for opioid drugs. Conclusions: Fentanyl inhalant is safe, effective, and well-tolerated for managing BTcP. It provides a non-invasive route for systemic drug delivery and can be self-administered or given by family caregivers as personalized and regular pain management. Clinical trial information: NCT05531422 .

8095 Background: In China, small cell lung cancer (SCLC) accounts for over 15% of lung cancers. The morbidity of SCLC has been continuously increasing. SCLC is invasive, fast-growing cancer that distinctly differs from other cancers. Approximately 70% of cases present with metastasis at diagnosis and the median overall survival rate is about 8 to 11 months with a 5-year survival rate of less than 5%. Although being sensitive to chemotherapy and radiotherapy, SCLC patients are liable to relapse and often present with drug resistance. Here we study the combination of Socazolimab, an anti-PDL1 antibody, carboplatin and etoposide to treat extensive stage small cell lung cancer. Methods: The study is a randomized, double-blinded, placebo-controlled multicenter Phase III clinical trial. Patients who have extensive-stage SCLC are eligible to the trial. Patients are randomly assigned to the study group (Socazolimab + carboplatin + etoposide) or control group (placebo + carboplatin + etoposide) at 1:1 ratio, with a treatment cycle of every 3 weeks. There are 4 cycles of chemotherapy followed by Socazolimab or placebo alone until termination events occurred or for up to 2 years. The primary endpoint is overall survival (OS). The major secondary endpoint is progression free survival (PFS). Results: There were a total of 498 patients recruited for the study with average age of 61.9 amount which 449 patients were diagnosed with stage IV SCLC. All the analysis was based on intent-to-treat (ITT). The median baseline performance status score was 1.0. The median OS of study group and control group are 13.90 months (95% CI: 12.22-15.34) and 11.58 months (95% CI: 10.64-12.81) respectively, with a P-value of 0.0316. The 24 month survival rate of study group and control group are 20.7% (95% CI:14.8-27.3) and 5.9 %(95% CI: 0.8-18.9). The median PFS of the two groups are 5.55 months (95% CI:5.06-5.82) and 4.37 months (95% CI: 4.27-4.70) with a P-value &lt; 0.0001. The treatment related adverse event were similar in both groups. Conclusions: These results show that Socazolimab plus chemotherapy continued to provide clinically meaningful improvements in OS for patients with extensive stage small cell lung cancer. Clinical trial information: NCT04878016 .

Objective: To evaluate the relationship between different indexes of weight variability and the risk of diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). Methods: A retrospective cohort study. The clinical data of 2 180 T2DM patients without DKD who underwent case management at Lee's United Clinic in Taiwan, China from 2002 to 2018 were retrospectively analyzed, including 1 103 females and 1 077 males, with an average age of (64.8±12.4) years. Regular follow-up was conducted for patients for at least 2 years, and their metabolic indexes were monitored annually. BMI variability independent of the mean (BMI-VIM), average yearly mean square successive difference (BMI-ASV), coefficient of variation (BMI-CV) and standard deviation (BMI-SD) were calculated,based on the body mass index (BMI) recorded annually by the patients. Patients were divided into four groups (Q1-Q4) based on the quartiles of the four weight variability indexes. DKD group and non-DKN group(NDKD group) were defined based on the occurrence of DKD at the end of the follow-up. Cox proportional hazards regression models were used to analyze the relationship between the four weight variability indicators and the incidence of DKD. Subgroup analysis was performed by categorizing patients into non-obesity (BMI<28 kg/m2) and obesity groups (BMI≥28 kg/m2) to investigate the impact of the four weight variability indicators on the risk of DKD. Results: After a follow-up of (4.55±2.13) years, 904 patients developed DKD. Compared with the NDKD group, patients in the DKD group had a higher proportion of females, older age, longer duration of diabetes, more insulin users, higher waist-to-hip ratio, higher levels of BMI-VIM, BMI-ASV, BMI-CV, BMI-SD, systolic blood pressure, diastolic blood pressure, and urine albumin-creatinine ratio, a lower proportion of hypoglycemic drugs, estimated glomerular filtration rate, and high-density lipoprotein cholesterol level, with statistically significant differences between the two groups(all P<0.05). Cox proportional hazards regression analysis results revealed that the risk of DKD in T2DM patients increased with the increase in BMI-SD, BMI-CV, BMI-VIM, and BMI-ASV after correcting a series of influencing factors. In the BMI-VIM subgroup, compared with the Q1 group, the risk of DKD in the Q4 group increased by 22.4% [HR=1.224 (95%CI:1.008-1.487), P=0.041]. In the BMI-ASV group, compared with the Q1 group, the risk of DKD in the Q4 group increased by 51.1% [HR=1.511 (95%CI:1.240-1.841), P<0.01]. In the BMI-CV group, compared with the Q1 group, the risk of DKD in the Q4 group increased by 22.2% [HR=1.222 (95%CI:1.006-1.485), P=0.044]. In the BMI-SD subgroup, compared with the Q1 group, the risk of DKD in the Q4 group increased by 22.2% [HR=1.222 (95%CI:1.002-1.490), P=0.048]. Sub-group analysis showed that when the non-obesity group was grouped by BMI-ASV, after correcting a series of influencing factors, compared with the Q1 group, the highest risk of DKD occurred in the Q4 group [HR=1.551 (95%CI:1.228-1.958), P<0.001];when the obesity group was grouped by BMI-ASV, after correcting a series of influencing factors, compared with the Q1 group, the highest risk of DKD occurred in the Q4 group [HR=1.703 (95%CI:1.168-2.485), P=0.006]. Conclusion: Increases in BMI-VIM, BMI-ASV, BMI-CV, and BMI-SD are associated with an increased risk of DKD in T2DM patients.

IntroductionThe study (ClinicalTrials.gov, NCT04346914) is an open label, single-arm, phase 1b clinical trial investigating the safety, tolerability, and efficacy of the recombinant human anti–programmed death-ligand 1 monoclonal antibody socazolimab in combination with carboplatin and etoposide in the first-line treatment of extensive-stage SCLC. Good safety and efficacy were found in previous phase 1 clinical trials of other cancers, such as cervix cancer. MethodsPatients received socazolimab (5 mg/kg) every three weeks until disease progression or physician decision. Carboplatin (area under the curve: 5) was also administered every three weeks and etoposide (100 mg/m2) on days 1, 2, and 3 of the treatment cycle. The primary purpose of the study was safety measured by the Common Terminology Criteria for Adverse Events. Secondary purposes included objective response rate, progression-free survival, duration of response, and overall survival. ResultsFrom April 15, 2020 (enrollment date), to December 30, 2021 (data cutoff), 20 patients with extensive-stage SCLC were administered with socazolimab, carboplatin, and etoposide. Objective response rate was 70.0% (95% confidence interval [CI]: 45.72%–88.11%). Median progression-free survival was 5.65 months (95% CI: 4.14–6.54), and the median duration of response was 4.29 months (95% CI: 2.76–5.85). Median overall survival was 14.88 months (95% CI: 10.09–not evaluated). The highest incidence of treatment-related adverse events included anemia (100%), decreased neutrophil count (95%), decreased platelet count (95%), and decreased white blood cell count (95%), which occurred during combination therapy. The most common grade 3 or 4 treatment-related adverse events were neutropenia (90%), decreased white blood cell count (65%), decreased platelet count (50%), and anemia (30%), which were also common adverse reactions of chemotherapy. No adverse events leading to death had occurred. ConclusionsResults revealed that the combination therapy of socazolimab, carboplatin, and etoposide had preliminarily confirmed the safety of socazolimab in the first-line treatment of SCLC combined with EC chemotherapy. Currently, a phase 3, randomized, placebo-controlled trial (ClinicalTrials.gov, NCT04878016) is being conducted with 498 patients.

5526 Background: The study (NCT03676959) is an open-label, phase I study investigating the safety and efficacy of the recombinant, fully human anti-programmed death-ligand 1 (PD-L1) monoclonal antibody socazolimab for recurrent or metastatic cervical cancer. Methods: Patients received socazolimab every 2 weeks until disease progression. The study was divided into a dose-escalation phase and a dose-expansion phase. Safety and tolerability were primary endpoints of the dose-escalation phase. Primary endpoints of the dose-expansion phase were safety and overall response rate (ORR) of the 5mg/kg dose. Efficacy was assessed by a third-party independent review committee (IRC) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as the evaluation standard. Pharmacokinetics and pharmacodynamics were also studied. Results: One hundred four patients were enrolled. Twelve patients were included in the dose-escalation phase, with one complete and two partial responses in the 5mg/kg treatment group. Ninety-two patients (5mg/kg) were enrolled in the dose-expansion phase, with 54 patients (59.3%) expressing baseline PD-L1-positive tumors. ORR was 15.4% (95% CI, 8.7 to 24.5%). Median PFS was 4.44 months (95% CI, 2.37 to 5.75 months), and the median OS was 14.72 months (95% CI, 9.59 to NE months). ORRs for PD-L1-positive and PD-L1-negative patients were 16.7% and 17.9%, respectively. Treatment-related grade 3 to 4 adverse events occurred in 7.7% of patients. No treatment-related deaths had occurred. Conclusions: Our study demonstrates that socazolimab has remarkable safety and efficacy for the treatment of recurrent or metastatic cervical cancer and exhibits a safety profile similar to other anti–PD-1/PD-L1 monoclonal antibodies. Clinical trial information: NCT03676959. [Table: see text]

Uncontrolled bleeding associated with trauma and surgery is the leading cause of preventable death. Batroxobin, a snake venom-derived thrombin-like serine protease, has been shown to clot fibrinogen by cleaving fibrinopeptide A in a manner distinctly different from thrombin, even in the presence of heparin. The biochemical properties of batroxobin and its effect on coagulation have been well characterized in vitro. However, the efficacy of batroxobin on hemostatic clot formation in vivo is not well studied due to the lack of reliable in vivo hemostasis models. Here, we studied the efficacy of batroxobin and slounase, a batroxobin containing activated factor X, on hemostatic clot composition and bleeding using intravital microcopy laser ablation hemostasis models in micro and macro vessels and liver puncture hemostasis models in normal and heparin-induced hypocoagulant mice. We found that prophylactic treatment in wild-type mice with batroxobin, slounase and activated factor X significantly enhanced platelet-rich fibrin clot formation following vascular injury. In heparin-treated mice, batroxobin treatment resulted in detectable fibrin formation and a modest increase in hemostatic clot size, while activated factor X had no effect. In contrast, slounase treatment significantly enhanced both platelet recruitment and fibrin formation, forming a stable clot and shortening bleeding time and blood loss in wild-type and heparin-treated hypocoagulant mice. Our data demonstrate that, while batroxobin enhances fibrin formation, slounase was able to enhance hemostasis in normal mice and restore hemostasis in hypocoagulant conditions via the enhancement of fibrin formation and platelet activation, indicating that slounase is more effective in controlling hemorrhage.

Background and objective: The incidence of epilepsy in elderly stroke patients has been significant attention because planning future needs for health services and improved primary and secondary prevention of stroke are important. We evaluated the relationship between stroke and the subsequent development of epilepsy within 10 years follow-up. Methods: This retrospective, nationwide, longitudinal study used National Health Insurance Service -Senior cohort (NHIS-Senior) 2002-2013, which was released by the KNHIS in 2016, comprising 550,000 random subjects who were selected from over than 60 years old. This study included a cohort of 42,925 patients who were first diagnoses as stroke between 2004 and 2006. To match each stroke patient, 218,478 control subjects were selected from the data-base. Results: In this cohort, the prevalence of stroke was higher in female(62%) than in male(38%). A higher prevalence of stoke was observed in the 60-70 years age and more than 80 years age group in urban area. The incidence of stroke was increased from 2002 to 2009, but decreased from 2010 to 2013. The diagnosis of epilepsy was done at averagely 20 months after the diagnosis of stroke. Cox regression analysis showed that the HR of epilepsy was 7.658 times greater for patients with stroke (95% CI: 7.402-7.923) than for control group after adjusting for other risk factors. The HR of epilepsy was 1.08 (95% CI: 1.045-1.116) in female patients, 1.66(95% CI: 1.607-1.715) in diabetic patients, 1.679(95% CI: 1.625-1.734) in hypertensive patients, 1.831(95% CI: 1.626-2.062) in chronic kidney disease and 1.647(95% CI: 1.593-1.703) in hypercholesterol patients. Conclusion: Our findings suggest that stoke may be independent risk factor for epilepsy in elderly patients(HR 7.658, 95% CI: 7.402-7.923). So we need to control and pay attention to epilepsy in elderly stroke patients.