Clinical Trial Data Research Articles

Pemetrexed-carboplatin salvage therapy in advanced thyroid cancers.

The overall survival of patients with advanced thyroid cancers that have progressed following targeted therapies is limited, indicating a strong need for salvage treatments. We retrospectively analyzed patients with refractory advanced thyroid cancer treated with pemetrexed-carboplatin (PC) at Mayo Clinic since 2019. Eleven patients, three with anaplastic thyroid cancer (ATC), seven with differentiated or poorly differentiated thyroid cancer (DTC), and one with oncocytic carcinoma of the thyroid, were treated with novel salvage PC. Patients with DTC (n = 7) had durable responses with a median progression-free survival of 29 months. One responder included a patient with ATC whose disease progressed following pembrolizumab/axitinib, lenvatinib, and dabrafenib/trametinib. On this fourth line treatment, the patient remains on therapy to date, over 12 months after initial response. This case series reinforces prior published phase I clinical trial data and shows that pemetrexed can have potent efficacy in the treatment of the most advanced thyroid cancers.

Nonlinear mixed-effects modeling as a method for causal inference to predict exposures under desired within-subject dose titration schemes.

The ICH E9 (R1) guidance and the related estimand framework propose to clearly define and separate the clinical question of interest formulated as estimand from the estimation method. With that it becomes important to assess the validity of the estimation method and the assumptions that must be made. When going beyond the intention to treat analyses that can rely on randomization, causal inference is usually used to discuss the validity of estimation methods for the estimand of interest. In pharmacometrics, mixed-effects models are routinely used to analyze longitudinal clinical trial data; however, they are rarely discussed as a method for causal inference. Here, we evaluate nonlinear mixed-effects modeling and simulation (NLME M&S) in the context of causal inference as a standardization method for longitudinal data in the presence of confounders. Standardization is a well-known method in causal inference to correct for confounding by analyzing and combining results from subgroups of patients. We show that nonlinear mixed-effects modeling is a particular implementation of standardization that conditions on individual parameters described by the random effects of the mixed-effects model. As an example, we use a simulated clinical trial with within-subject dose titration. Being interested in the outcome of the hypothetical situation that patients adhere to the planned treatment schedule, we put assumptions in a causal diagram. From the causal diagram, conditional independence assumptions are derived either by conditioning on the individual parameters or on earlier outcomes. With both conditional independencies unbiased estimates can be obtained.

Early adoption of triamcinolone acetonide suprachoroidal injection for uveitic macular edema: a physician survey

ObjectiveTo obtain physicians’ “real-world” perspectives on early experiences with triamcinolone acetonide suprachoroidal injection (SCS-TA) for treatment of patients with uveitic macular edema (UME).ResultsTwelve retina/uveitis specialists in the United States were surveyed about SCS-TA injection procedure and patient outcomes. Survey participants administered ≥ 291 SCS-TA injections to 243 patients with UME with various disease characteristics (etiologies, chronicity, and anatomical subtypes). Commonly reported reasons for SCS-TA adoption included potential for lowering the risk of steroid-associated intraocular pressure elevations versus intravitreal injections or implants (100%), potential for longer duration of action versus intravitreal steroid injections or implants (92%), and desire to use a new delivery modality (83%). Nearly all participants (92%) found injection procedure relatively easy post-training, with most (75%) procedurally comfortable after completing 2–5 injections. 58% of participants indicated that their patients gained 2–3 lines of vision by first follow-up visit, and 92% reported having patients who experienced 100–150 μm or greater reduction in central subfield thickness. Overall, 92% of participants were satisfied with SCS-TA treatment outcomes. Findings from this survey of early adopters of SCS-TA indicate that the suprachoroidal injection technique was easy to learn and resulted in favorable patient outcomes consistent with clinical trial data.

Modelling post-chemotherapy stem cell dynamics in the bone marrow niche of AML patients

Acute myeloid leukemia (AML) is a stem cell-driven malignancy of the blood forming (hematopoietic) system. Despite of high dose chemotherapy with toxic side effects, many patients eventually relapse. The “7+3 regimen”, which consists of 7 days of cytarabine in combination with daunorubicin during the first 3 days, is a widely used therapy protocol. Since peripheral blood cells are easily accessible to longitudinal sampling, significant research efforts have been undertaken to characterize and reduce adverse effects on circulating blood cells. However, much less is known about the impact of the 7+3 regimen on human hematopoietic stem cells and their physiological micro-environments, the so-called stem cell niches. One reason for this is the technical inability to observe human stem cells in vivo and the discomfort related to bone marrow biopsies. To better understand the treatment effects on human stem cells, we consider a mechanistic mathematical model of the stem cell niche before, during and after chemotherapy. The model accounts for different maturation stages of leukemic and hematopoietic cells and considers key processes such as cell proliferation, self-renewal, differentiation and therapy-induced cell death. In the model, hematopoietic (HSCs) and leukemic stem cells (LSCs) compete for a joint niche and respond to both systemic and niche-derived signals. We relate the model to clinical trial data from literature which longitudinally quantifies the counts of hematopoietic stem like (CD34+CD38-ALDH+) cells at diagnosis and after therapy. The proposed model can capture the clinically observed interindividual heterogeneity and reproduce the non-monotonous dynamics of the hematopoietic stem like cells observed in relapsing patients. Our model allows to simulate different scenarios proposed in literature such as therapy-related impairment of the stem cell niche or niche-mediated resistance. Model simulations suggest that during the post-therapy phase a more than 10-fold increase of hematopoietic stem-like cell proliferation rates is required to recapitulate the measured cell dynamics in patients achieving complete remission. We fit the model to data of 7 individual patients and simulate variations of the treatment protocol. These simulations are in line with the clinical finding that G-CSF priming can improve the treatment outcome. Furthermore, our model suggests that a decline of HSC counts during remission might serve as an indication for salvage therapy in patients lacking MRD (minimal residual disease) markers.

International comparison and assessment of the quality of drug clinical trial implementation in China based on scientific regulatory system

Objective: To analyze the international status and level of clinical trial quality in China, and explore the advantages and value of scientific regulation of clinical research quality in China. Methods: The data is sourced from the relevant reports publicly released by the National Medical Products Administration (NMPA), the inspection reports and announcements published by the Center for Food and Drug Inspection of the NMPA, the inspection data displayed on the official website of the U.S. Food and Drug Administration (FDA), as well as clinical diagnosis and treatment guidelines issued by the National Comprehensive Cancer Network (NCCN) of United States and the Chinese Society of Clinical Oncology (CSCO) (data as of July 21, 2023). This data provides an analysis of the regulatory status of the implementation of clinical drug trials in China, inspection data, and the approval and market entry of new oncology drugs and feedback from their practical application. Results: The clinical trial quality inspection systems of China and the United States are generally aligned, with similar inspection subjects, focus areas, and public disclosure pathways. However, each has its characteristics in terms of inspection targets and types. The quality of clinical trial data in China has been continuously improving. Between 2009-2015 and 2016-July 2023, China underwent 25 and 20 FDA Bioresearch Monitoring (BIMO) inspections, respectively. The inspection results showing "No Action Indicated" (NAI) improved from 48.0% to 85.0%, while "Voluntary Action Indicated" (VAI) decreased from 44.0% to 15.0%. Official Action Indicated (OAI) measures were required in 2009 and 2012. Compared to the 2009-2015 period, there has been a clear upward trend in the quality of clinical trial data since 2016. From 2016 to July 2023, the number of new oncology drugs developed by Chinese pharmaceutical companies and included in professional guidelines has steadily increased. Specifically, 37 drugs (58.7%) were included in the 2022 edition of the CSCO guidelines, and 15 drugs (23.8%) were included in the 2023 edition of the NCCN guidelines, with 10 of these drugs featured in both guidelines. Conclusions: The implementation quality of clinical trials in China has gained a certain level of international recognition and competitiveness. This progress is attributed to national macro-level guidance, a unique institutional model, and clinical practices aligned with international standards. In the future, it will be necessary to further strengthen the scientific regulatory system and enhance clinical research capabilities to continue advancing the high-quality development of clinical trials.

Atezolizumab plus bevacizumab and chemotherapy versus bevacizumab plus chemotherapy for metastatic cervical cancer: a cost-effectiveness analysis.

The objective of this study is to conduct a cost-effectiveness analysis in order to evaluate the economic advantages of incorporating atezolizumab into a standard bevacizumab plus platinum regimen for the treatment of metastatic cervical cancer from the Chinese medical system perspective. We developed a partitioned survival model based on data obtained from the recently published BEATcc clinical trial and economic cost data. Our model utilized a tree-based decision analysis approach to simulate two different treatment strategies for metastatic cervical cancer: the standard bevacizumab plus platinum regimen, and the addition of atezolizumab to the standard treatment regimen. The economic assessment data included the costs of the drugs, costs related to treatment-induced adverse events. The cost-effectiveness metrics used in the analysis were quality-adjusted life-year (QALY) and incremental cost-effectiveness ratio (ICER). The robustness of our model was assessed through sensitivity analysis. The total costs of the atezolizumab group were $128179.56, while the costs of chemotherapy group were $42065.89. The atezolizumab group gained 3.52 QALYs, whereas the chemotherapy group gained 2.35 QALY. The atezolizumab regimen resulted in an increase of 1.17 QALYs at an incremental cost of $86113.67. This led to an ICER of $73601.43, which exceeds the willingness-to-pay (WTP) threshold of $39855.79 in China. Sensitivity analysis demonstrated none of the parameters within a margin of ±25% result in significant alterations to the analysis findings. Atezolizumab plus bevacizumab and chemotherapy was not to be a cost-effective option for the treatment of metastatic cervical cancer compared to bevacizumab plus chemotherapy.

A comparative study of blood viscometers of 3 different types.

The greater the viscosity of the blood, the more difficult its flow becomes, leading to an increased incidence of diseases caused by blood circulation disorders. These diseases are commonly associated with the cardiovascular and cerebrovascular systems. High blood viscosity is a primary cause of circulatory system diseases. Studies have shown that accurately measuring blood viscosity and applying this data in clinical trials can help prevent circulatory system diseases. Viscosity data can vary depending on the measurement methods used, even when these methods are based on hydrodynamic principles. Despite using approved blood viscometers, the results often differ depending on the type of viscometer used, potentially causing confusion within the medical field. Informing the medical community about these differences and the level of error associated with each measurement method can help reduce this confusion. To our knowledge, the degree of difference in viscosity measurement results due to different measurement methods and the reasons for these differences have not yet been thoroughly explored. In this study, we selected three blood viscosity measurement methods registered with the Ministry of Food and Drug Safety of Korea to analyze the same canine blood. The viscosity measurements were carried out using each device and compared. The parallel plate and scanning capillary methods yielded similar viscosity values, while the cone plate method showed lower viscosity values. The viscosity of blood, as measured by the three viscometers, differed, indicating that more experimental data must be accumulated to evaluate the cause of these differences. In this paper, we identified several causes of inconsistency and suggested measures to avoid this confusion. However, confirming that the test results show systematic differences is expected to assist clinicians who diagnose and prescribe treatments based on blood viscosity results. The findings of this comparative study are anticipated to serve as a starting point for establishing guidelines or standards for blood viscosity measurement methods.

Extension and Further Replication of the Reliability, Criterion Validity, and Treatment Sensitivity of the PANSS10 and PANSS20 for Pediatric Trials.

Introduction: The Positive and Negative Syndrome Scale (PANSS) is a widely accepted outcome measure for pediatric schizophrenia trials; however, it has notable limitations. Psychometric investigations have shown a multifactorial structure and some items have limited utility assessing symptom severity in children. To address these issues, we developed and evaluated optimized 10- and 20-item PANSS short-forms (PANSS10 and PANSS20) using patient-level clinical trial data. This study further assesses these optimized forms using independent clinical trial data. Methods: We examined patient-level data from a randomized pediatric schizophrenia trial comparing paliperidone ER to aripiprazole. Data were accessed through the Yale Open Data Access (YODA) secure platform. Analyses included confirmatory factor analyses, graded response models, ω score reliability, internal consistency, sensitivity to change, and criterion validity versus the Clinical Global Impressions of Severity (CGI-S). Bland-Altman analyses examined score calibration versus the 30-item PANSS and inclusion cut scores. Results: Participants (N = 288) were ages 12 to 17 years (M = 15.3, SD = 1.46; 66% male). Total scores for the PANSS10 and PANSS20 showed strong correlations with the 30-item PANSS (0.90 and 0.97, respectively). Average inter-item correlations were 0.10 and 0.14 and ωTotal reliabilities were 0.74 and 0.85. Both PANSS10 and PANSS20 scores showed reliability >0.80-2.3 to 4.5 SD and -3.0 to 6.0 SD about mean symptom severity, respectively. Sensitivity to treatment was also similar (partial eta squared 0.23 and 0.22), as was correlation with CGI-S at baseline (0.45 and 0.48; not significantly different). The mean item-average discrepancy with the 30-item PANSS was 0.095 for PANSS10 and 0.033 for PANSS20. Conclusions: The optimized PANSS forms continue to show impressive reliability, validity, and calibration compared with the 30-item PANSS. Researchers should consider replacing the 30-item PANSS with the PANSS10 as a clinical outcome and screening measure due to its length and psychometric performance.

Uncovering the interleukin-12 pharmacokinetic desensitization mechanism and its consequences with mathematical modeling.

The cytokine interleukin-12 (IL-12) is a potential immunotherapy because of its ability to induce a Th1 immune response. However, success in the clinic has been limited due to a phenomenon called IL-12 desensitization - the trend where repeated exposure to IL-12 leads to reduced IL-12 concentrations (pharmacokinetics) and biological effects (pharmacodynamics). Here, we investigated IL-12 pharmacokinetic desensitization via a modeling approach to (i) validate proposed mechanisms in literature and (ii) develop a mathematical model capable of predicting IL-12 pharmacokinetic desensitization. Two potential causes of IL-12 pharmacokinetic desensitization were identified: increased clearance or reduced bioavailability of IL-12 following repeated doses. Increased IL-12 clearance was previously proposed to occur due to the upregulation of IL-12 receptor on T cells that causes increased receptor-mediated clearance in the serum. However, our model with this mechanism, the accelerated-clearance model, failed to capture trends in clinical trial data. Alternatively, our novel reduced-bioavailability model assumed that upregulation of IL-12 receptor on T cells in the lymphatic system leads to IL-12 sequestration, inhibiting the transport to the blood. This model accurately fits IL-12 pharmacokinetic data from three clinical trials, supporting its biological relevance. Using this model, we analyzed the model parameter space to illustrate that IL-12 desensitization occurs over a robust range of parameter values and to identify the conditions required for desensitization. We next simulated local, continuous IL-12 delivery and identified several methods to mitigate systemic IL-12 exposure. Ultimately, our results provide quantitative validation of our proposed mechanism and allow for accurate prediction of IL-12 pharmacokinetics over repeated doses.

Faricimab versus bevacizumab for neovascular age-related macular degeneration: Cost analysis based on real-world data from the Swedish Macula Registry.

To analyse the impact on cost if faricimab is used as the first-line treatment for neovascular age-related macular degeneration (nAMD) compared to standard treatment with bevacizumab. Retrospective registry study including real-world data from the Swedish Macula Registry between 2017 and 2022. The observed number of injections and visits for bevacizumab during the first two years of treatment was used (n = 437 patients). Number of faricimab injections was obtained from published clinical trial data and unit costs mostly from publicly available Swedish sources. The provider cost included medication and visit cost and societal cost included additionally patient travel cost. Costs are presented in 2023 EUR. The incremental societal cost of faricimab was 277 EUR per patient compared to bevacizumab in the base case. Medication cost was higher (1516 EUR) while visit cost (-1183 EUR) and patient travel cost (-56 EUR) were lower due to longer injection intervals. Faricimab was of similar cost as bevacizumab for patients residing far from the clinic. The faricimab injection interval and the number of bevacizumab injections were major drivers of uncertainty in the results. Faricimab represents a cost-effective alternative to bevacizumab for patients with nAMD in Sweden. Its extended treatment interval is particularly beneficial for patients living far from clinics, and if the real-life faricimab injection interval extends beyond 12 weeks. Our findings emphasize faricimab's potential to free up healthcare staff to treat a larger patient population with existing clinic resources.

Stroke-heart syndrome and early mortality in patients with acute ischaemic stroke using hierarchical cluster analysis: An individual patient data pooled analysis from the VISTA database.

The patient clinical phenotypes at particularly high risk for early cardiac complications after a recent acute ischaemic stroke (AIS), that is, stroke-heart syndrome (SHS), remain poorly defined. We utilised hierarchical cluster analysis to identify specific phenotypic profiles associated with this risk. We gathered data on patients with AIS from the Virtual International Stroke Trials Archive, a global repository of clinical trial data. We examined cardiac complications within 30 days post-stroke, including acute coronary syndrome, heart failure, arrhythmias and cardiorespiratory arrest. We employed hierarchical cluster analysis to define distinct phenotypic risk profiles. The incidence/risk of SHS and 90-day mortality were compared across these profiles. We included 12,482 patients (mean age 69 ± 12 years; 55% male), yielding five phenotypes: Profile 1 ('elderly and AF'), Profile 2 ('young and smoker'), Profile 3 ('young'), Profile 4 ('cardiac comorbidities') and Profile 5 ('hypertension with atherosclerotic comorbidities'). Profiles 4 and 1 exhibited the highest risk for SHS (adjusted HR (95% CI): 2.01 (1.70-2.38) and 1.26 (1.05-1.51), respectively, compared to Profile 3), while Profiles 5 and 2 showed moderate risk and Profile 3 had the lowest risk. Although Profiles 1 and 4 were at the highest risk for most SHS presentations, Profile 5 had the highest risk for cardiorespiratory arrest (adjusted HR (95% CI): 2.99 (1.22-7.34)). The 90-day mortality risk was stratified by phenotype, with the highest risk observed in Profiles 5, and 4. Hierarchical cluster analysis effectively identified phenotypes with the highest risk of SHS and early mortality in patients with AIS.

Etiology, Recent Advances, and Clinical Trials Data for the Treatment of Angioedema: A Review.

Angioedema is a health issue that affects parts of the body like the upper pulmonary and gastric pathways and is identified by abrupt, nonpitting enlargement of the skin, mucous membranes, or both. The swelling usually lasts a few hours to 72 hours and may appear as non-puritic, subcutaneous, or submucosal organ edema. It is characterized by localized swelling brought on by the release of histamine. Itching is rare, and usual areas of appearance include the hands, feet, face, and genitalia, with periorbital swelling being the most often. The main objective of this review article is to study in brief the classifications, etiology, pathophysiology, and clinical trial data by describing the recent advancement in the treatment of angioedema. Various research articles obtained from different journals indexed under Scopus and SCI were used to prepare the review article and for illustrative work software such as Biorender and Microsoft Word was used. Histamine-- mediated angioedema, linked to allergic reactions, coexists with urticaria. Bradykinin-mediated angioedema, exemplified by hereditary angioedema and acquired forms, lacks urticaria. Idiopathic angioedema, with uncertain etiology. Imitated angioedema results from non-IgE-mediated reactions, often induced by medications. It is a complicated medical condition with a variety of causes and mechanisms. Over time, outcomes for patients have been greatly improved by a growing understanding of its etiology, pathophysiology, and available treatments. The field of medical treatment for this difficult problem is always changing, and this is partly due to clinical trials.

Real World Outcomes in Patients With Recurrent, Advanced, or Metastatic Endometrial Cancer Treated With Lenvatinib Plus Pembrolizumab

AimsPatients with endometrial cancer who progress following first line therapy have improved survival outcomes with pembrolizumab and lenvatinib (pem/len) compared with standard of care chemotherapy, as demonstrated in KEYNOTE-775. This was in a group of trial patients with good performance status and excluded those with carcinosarcoma histology. In KEYNOTE-775 pem/len was associated with significant toxicity, leading to dose reductions, treatment cessation, and patient morbidity. We set out to assess the tolerability, toxicity and outcomes following pem/len for patients with recurrent, advanced or metastatic endometrial cancer in a real-world setting. Materials and methodsUK centres treating patients with pem/len for advanced endometrial cancer within the compassionate access programme were approached. Retrospective data were analysed for those treated between May 2022 and June 2023. Data on patient demographics, treatment, toxicity and outcomes were extracted from medical records. Toxicity and tolerability were compared in those over and under the age of 70. ResultsSeven centres returned data for 70 patients. Median age of patients was 68.5 years (range 45–85) with a performance status of 0–1 in 77.1% and of 2 in 22.9%. Histological subtypes included serous (34.3%), endometrioid (32.9%), carcinosarcoma (14.3%), clear cell (7.1%), mixed (2.9%) and other (8.6%). Grade ≥3 toxicity was reported in 55.7% with any-grade toxicity observed in 85.7%. In those aged ≥70 years (n = 30) the rate of grade ≥3 toxicity was 60.0%. Rates of dose reduction of lenvatinib were 64.3%, and toxicity-related treatment interruption was 45.7%. The 6-month progression-free and overall survival rates were 54.0% (95%CI: 39.0–66.8) and 70.1% (95%CI:56.5–80.1) respectively. ConclusionThis real-world, observational study of pem/len showed comparable tolerability, toxicity, and outcomes to previously reported clinical trial data. Our cohort included patients with a poorer PS and a broader range of histological subtypes including carcinosarcoma.

Changes in the Treatment and Prevention of Heart Failure Based on the 2023 Focused Update of the 2021 European Society of Cardiology Guidelines

Introduction and Objective:The 2023 update to the 2021 ESC Guidelines for diagnosing and treating acute and chronic heart failure introduces significant changes in pharmacotherapy and prevention. Staying informed about these updates is crucial given the evolving landscape of heart failure management. This review provides an overview of the latest recommendations and supporting evidence. Review Methods:A comprehensive review of scientific publications and guidelines from PubMed, Google Scholar, Clinical Key, Via Medica Journals, and relevant clinical guidelines was conducted to ensure the most recent evidence is considered. Brief Description of the State of Knowledge:Heart failure is a growing global concern. The 2023 update highlights key management changes. Recent trials, including EMPEROR-Preserved and DELIVER, show empagliflozin and dapagliflozin reduce heart failure hospitalization and cardiovascular death in patients with mildly reduced and preserved ejection fraction. The guidelines now recommend intravenous iron for patients with reduced or mildly reduced ejection fraction and iron deficiency. For those with type 2 diabetes and chronic kidney disease, SGLT2 inhibitors and finerenone, a non-steroidal mineralocorticoid antagonist, are recommended to reduce heart failure hospitalization and prevent renal function decline. Summary:The 2023 ESC Guidelines update offers revised recommendations for heart failure management and prevention, integrating the latest clinical trial data and meta-analyses. Key areas include the use of SGLT2 inhibitors, iron deficiency management, and preventive strategies for high-risk populations. Implementing these guidelines can significantly improve preventive and therapeutic outcomes for heart failure patients.

Streamlining Clinical Trial Data from Raw to Regulatory Submission with R Shiny and Pharmaverse

In recent years, the pharmaceutical and biotech industries have increasingly adopted open-source tools to enhance the efficiency, transparency, and reproducibility of clinical trial data analysis. R Shiny, a web application framework for R, has become a key component in creating interactive dashboards and visualizations that support real-time data exploration and decision-making. As part of the Pharmaverse ecosystem, R Shiny plays a vital role in regulatory submissions, data analysis, and reporting, offering dynamic, user-friendly interfaces for clinical trial monitoring, patient safety reporting, and efficacy analysis. This abstract explores the application of R Shiny within the Pharmaverse, emphasizing its seamless integration with tools such as Tplyr and admiral for generating CDISC-compliant SDTM and ADaM datasets. Metadata management and validation are facilitated through OAK, ensuring consistency and traceability. The automated creation of Define.xml using tools like defineR further enhances transparency and regulatory compliance. Through case studies and practical examples, this abstract highlights how R Shiny and related tools improve data transparency, accelerate decision-making, and support regulatory compliance in clinical trials. By leveraging these open-source technologies, clinical trial teams can streamline data workflows, enhance collaboration, and improve outcomes, ultimately driving innovation within the pharmaceutical industry. The integration of these tools into a cohesive framework significantly enhances the submission process to regulatory bodies like the FDA and EMA, ensuring that clinical data meets both industry and regulatory standards.

6814 Durability of Teprotumumab for the Treatment of Thyroid Eye Disease (TED) in Clinical Trials

Abstract Disclosure: G.J. Kahaly: Consulting Fee; Self; Amgen Inc. Research Investigator; Self; Amgen Inc. P.S. Subramanian: Consulting Fee; Self; Amgen Inc. Research Investigator; Self; Amgen Inc. E. Conrad: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. R.J. Holt: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. T.J. Smith: Consulting Fee; Self; Amgen Inc, Viridian, Minghui, Lassen, Lundbeck. Other; Self; US patents covering the use of IGF-1 receptor inhibitors in TED which are held by UCLA and the Lundquist Institute. Introduction: Teprotumumab has demonstrated efficacy for the treatment of thyroid eye disease (TED). To assess durability of responses to teprotumumab over the longer term, pooled clinical trial data were assessed beyond the 24-week treatment period for patients in phase 2, OPTIC, and OPTIC-X studies who received a full course of teprotumumab. Methods: Observed rates for clinical activity score (CAS, ≥2 point improvement), EUGOGO-recommended composite response, diplopia (≥1 Gorman grade improvement), proptosis (≥2 mm improvement), and Overall responder status (≥2 mm improvement proptosis and ≥2 point improvement CAS) were assessed and pooled from study baseline to Week 24 (formal study) and up to Week 72 (51 weeks post-final teprotumumab infusion). Graves’ ophthalmopathy quality-of-life (GO-QOL) scores were also examined. Additional therapies for TED administered up to Week 120 (i.e., 99 weeks post-therapy) were assessed for evidence of persistent benefit from Week 24 through Week 120. Studies differed in the timing of follow-up visits. Data were not available at every time point for all patients. Results: Response rates among patients receiving a full (8-infusion) course of teprotumumab (N=112) were largely maintained 51 weeks after the final teprotumumab infusion at study Week 72: CAS 52/57 (91.2%); composite 51/57 (89.5%); diplopia 35/48 (72.9%); proptosis 38/56 (67.9%); and Overall 37/56 (66.1%). The mean reduction in proptosis was 2.68 (SD 1.92) mm (N=56), mean GO-QOL reduction was 15.22 (SE 2.82, N=56), and disease inactivation (CAS ≤1) was detected in 40/57 (70.2%). Post-teprotumumab treatment, 17.9% (19/106) of reporting patients received additional TED treatment (systemic steroids or teprotumumab) and/or remedial periocular surgery as of 99 weeks after the last dose (to study Week 120). Conclusions: At Week 72, nearly one-year posttherapy, responses to teprotumumab were similar to those at Week 24 formal study end. Both CAS and ophthalmic composite responses were observed in 90% of observed patients. Diplopia and proptosis responses were seen in almost 70%. Additionally, 82% of patients did not require additional treatment for TED nearly two years after therapy completion. Public Presentation: 6/2/2024

Biopharmaceutical pipeline funded by venture capital firms, 2014 to 2024.

Venture capital (VC) firms fund biopharmaceutical research and development (R&D) while incurring substantial financial risk. VC firms seek to invest in clinical areas with the greatest potential for financial return. Using a combination of data for clinical trials and VC investment deals between January 2014 and March 2024, we found that approximately 75% of VC investments were allocated to clinical trials studying small-molecule drugs compared to biologics or gene therapies, without substantial changes over the study period. Most of VC firms' investment in biopharmaceutical R&D was concentrated in phase 1 and phase 2 clinical trials. This trend has increased in recent years, with phase 1 trials accounting for nearly half of total deals and capital investments in 2023. VC investments were concentrated in several therapeutic areas, including cancer.

Pharmacoeconomic Analysis of the Use of C1-inhibitor in Treatment of Hereditary Angioedema: Clinical Trial Data in Belarus

Pharmacoeconomic Analysis of the Use of C1-inhibitor in Treatment of Hereditary Angioedema: Clinical Trial Data in Belarus

Neoadjuvant Pembrolizumab Plus Chemotherapy in Early-Stage Triple-Negative Breast Cancer: A Nationwide Retrospective Turkish Oncology Group Study

Background/Objectives: Following the results of the phase 3 KEYNOTE-522 trial, the U.S. Food and Drug Administration approved pembrolizumab, a humanized IgG4 kappa monoclonal antibody, in combination with neoadjuvant chemotherapy as a new standard of care for high-risk early-stage triple-negative breast cancer (TNBC). This retrospective, multicenter study in Türkiye assessed the real-world efficacy and safety of neoadjuvant pembrolizumab combined with chemotherapy in early-stage TNBC. Methods: The study included 108 patients treated between 2021 and 2023 across 14 oncology centers. Three distinct neoadjuvant regimens incorporating pembrolizumab were administered at the discretion of the treating physicians. The primary outcomes were the pathological complete response (pCR) rate after neoadjuvant therapy and the 2-year event-free survival (EFS) and overall survival (OS) rates. Results: The observed pCR rate was 63.9%, closely mirroring the 64.8% reported in the KEYNOTE-522 trial. At the two-year mark, the EFS rate was 87.2% and the OS rate was 92.3%. Multivariable analysis identified pCR as the sole independent predictor of both EFS and OS. The safety profile was consistent with previous clinical trial data, with most adverse events being of grade 1–2 in severity. Conclusions: These findings provide valuable real-world confirmation of the efficacy and safety of neoadjuvant pembrolizumab–chemotherapy in early-stage TNBC, complementing evidence from randomized trials.

New Drug Development Strategy in Japan: Flexibility in Guideline Adherence.

Recently, a new type of drug lag, known as "drug loss" has emerged in Japan. It is a condition where the development of a drug approved in other countries has not been initiated in Japan. For 265 new drugs approved in the United States or Europe during 2010-2020, only 31% had commenced development in Japan as of December 31, 2020. A characteristic feature of Japanese guidelines on new drug development is that, in principle, clinical trial data in Japanese participants are required in each study phase. Given key players in new drug development are shifting from large pharmaceutical companies to emerging biopharma companies, primarily based outside Japan, the necessity for Japanese data may contribute to the drug lag. This study aimed to clarify the guideline adherence to new drug applications in Japan. Of the 159 new drugs approved in Japan between April 2019 and March 2024, the clinical data packages for almost all drugs included both pharmacokinetic (PK) data and efficacy and safety data in Japanese participants, irrespective of the study phase or design. We identified three flexible development approaches: the absence of Japanese dose-response data (39.6%), absence of Japanese confirmatory data generated from phase III randomized controlled trials (35.2%), and post-hoc Japanese PK data (43.0%, 34/79). Biologics, orphan drug designation, antineoplastic agents, and same applicant and originator were identified as factors significantly associated with these flexibilities. The results will help foreign companies, including emerging biopharmas, in formulating effective new drug development strategies, potentially alleviating the drug lag in Japan.