Clinical Development Research Articles

The establishment of reference intervals for the ClotPro thromboelastometry device in healthy dogs

AbstractObjectiveTo establish reference intervals using a new point‐of‐care thromboelastometry device in dogs for the extrinsically activated test (EX‐test), intrinsically activated test (IN‐test), fibrin polymerization test (FIB‐test), ecarin test (ECA‐test), and tissue plasminogen activator test (TPA‐test) and to investigate the effects of storage time on the results.DesignProspective clinical study in 2022.SettingUniversity teaching hospital.AnimalsForty‐eight healthy privately or university‐owned dogs were prospectively enrolled and included on the basis of normal physical examination and normal baseline laboratory results (CBC, biochemistry profile, prothrombin time, and activated partial thromboplastin time [aPTT]).InterventionsAfter a 30‐minute storage time, the EX‐test, IN‐test, FIB‐test, ECA‐test, and TPA‐test were performed on citrated blood samples. To determine the effect of storage time, 11 samples had the EX‐test, FIB‐test, and IN‐test repeated 90 and 150 minutes after sample collection.Measurements and Main ResultsTen thromboelastometry parameters were evaluated for each test. Reference intervals were calculated using the robust method for parametric data, and the robust Box–Cox transformed or nonparametric methods were used for nonparametric data. Increasing storage time resulted in more hypocoagulable tracings. A correlation was found between the IN‐test and aPTT (r = 0.62, P < 0.0001). Other weak to moderate correlations were seen between thromboelastometry parameters and platelet count and hematocrit.Conclusions and Clinical ImportanceThe development of reference intervals for the thromboelastometry device allows for the clinical use of this technology. Analyzing samples after a prolonged storage time of more than 30 minutes may result in erroneous results. Results may also be affected by an abnormal hematocrit or platelet count.

Unlocking the Potential of Pediatric Virtual Care: An e-Delphi Study on a Virtual Caregiver Participation Framework in Audiology

Purpose: Virtual service delivery models in audiology have become more accessible due to recent technological advancement and improved system-level uptake following COVID-19. Although current evidence identifies the benefits of virtual care to families with children who are d/Deaf or hard of hearing and supports its use in practice, this delivery model is still underutilized. This research aimed to gain consensus on an evidence-informed virtual caregiver participation framework developed from a scoping review of the communication sciences and disorders literature. Method: A two-round modified e-Delphi study was conducted to survey 26 knowledge users from four different countries with experience in virtual audiology care, including caregivers, audiologists, researchers, and organizational leaders. The study employed Delphi techniques, building from a scoping review to synthesize existing literature informing the knowledge gap, including online surveys and team discussions. Consensus was defined numerically (75% agreement) and by comparing and interpreting text-based responses. Results: The resulting framework grouped nine categories of caregiver participation in virtual care according to three main readiness domains: core readiness (opportunities to participate, perceived value, and willingness to participate), engagement readiness (child capacity, family–provider relationship, and role in the care process), and structural readiness (environment for participation, support, and technology). Conclusion: This work adds novel contributions to the field, through the development of a framework for caregiver participation in virtual audiology care, that can be used to support family involvement and will guide clinical tool development and future research efforts.

NSW cannabis medicines advisory service retrospective enquiry analysis to inform clinical guidance resource development

AbstractBackgroundAn innovative New South Wales government funded statewide Cannabis Medicines Advisory Service (CMAS) operated between January 2018 and June 2022. The service provided comprehensive patient‐specific and evidence‐based information to support health professionals in prescribing and patient care decisions. This study aimed to describe real‐world data collected by CMAS.MethodsA sub‐set of de‐identified, patient‐specific enquiries collected between January 2021 and June 2022 (n = 123/567; 21.7%) were analyzed using R version 4.2.1. Diagnosis, indication, and comorbidities were coded using Medical Dictionary for Regulatory Activities (MedDRA) terminology.ResultsMost patient‐specific enquiries from medical practitioners were from general practitioners (n = 103/123; 83.7%). Female (n = 53/123; 43.1%) and male (n = 59/123; 48.0%) patients were similarly represented. Sex was not specified for 8.9% (n = 11/123) of patients. The mean age of patients was 52.1 years (range <10–90). The most common three diagnoses were osteoarthritis, anxiety, and chronic pain. Indications that were most frequently reported included chronic pain, anxiety, back pain, non‐neuropathic pain, and insomnia. Comedications were most commonly non‐opioid and opioid analgesics and antidepressants. Most practitioners were considering prescribing a cannabidiol (CBD) product for their patient. Cannabinoid composition selection guidance provided by CMAS was predominantly (delta‐9‐tetrahydrocannabinol) THC:CBD ~1:1, followed by CBD‐only products. CMAS was contacted by health professionals regarding the management of potential adverse events for five patients.ConclusionThe findings of this study shed light on the information medical practitioners were seeking to inform their clinical decision‐making about medical cannabis and can inform the development of clinical guidance resources.

Abstract C047: AGX101: Preclinical evaluation of a TM4SF1-directed tubulin inhibitor conjugate with ongoing first-in-human trial

Abstract Introduction: TM4SF1 (Transmembrane-4 L-Six-Family-Member-1) is an endothelial marker with critical roles in angiogenesis, as well as a tumor cell antigen that contributes significantly to invasion and metastasis. TM4SF1 is upregulated 20-fold in angiogenic tumor vascular endothelium compared to normal vasculature endothelium and exhibits a unique nuclear internalization pathway. AGX101 is a novel tubulin inhibitor conjugate specifically directed against TM4SF1, delivering a potent maytansinoid payload directly to the nucleus of cells within the tumor microenvironment. Delivery to both the vascular and tumor cell compartments of the tumor results in three mechanisms of action (MoAs): (1) activation of tumor immune surveillance, (2) tumor blood supply deprivation, and (3) direct tumor cell killing. Methods: TM4SF1 expression was assessed across solid tumor samples using immunohistochemistry. Safety and pharmacokinetics of AGX101 were evaluated in non-human primates, with escalating doses to determine the highest non-severely toxic dose (HNSTD). Efficacy studies were also conducted in mouse models, enabling assessment of the minimum effective dose (MED) needed to engage each of the three MoAs. The combination of HNSTD and MED enables calculation of a therapeutic index (TI). Preclinical efficacy studies used either AGX101 (in human tumor xenograft models, to study the tumor cell killing MoA) or AGXB01, a rodent surrogate of AGX101, to study vascular and immune MoAs and all three MoAs in syngeneic mouse cancer models. The potential for synergy with immune checkpoint inhibitors (ICIs) was also investigated. A first-in-human study of AGX101 in patients with advanced solid tumors with the primary objective of safety and dose-limiting toxicities (DLTs) has initiated. Results: TMFS41 is broadly expressed across solid tumors with increasing scoring intensity in higher grade tumors. In non-human primates, AGX101 exhibited a favorable safety profile, being tolerated at relatively high doses and with dose dependent, monitorable, and reversible effects. In preclinical efficacy studies, AGXB01 and AGX101 as monotherapies demonstrated robust efficacy through each of the three MoAs in multiple syngeneic, xenograft, and orthotopic tumor models in mice and rats as well as non-tumor models of angiogenesis. Measured by exposure, TI was large. Additionally, AGXB01 was shown to potentiate the effects of ICIs in syngeneic mouse models (CT26, Renca, and B16-F10), suggesting a potential synergistic approach in cancer therapy. The first dose level of AGX101 monotherapy in humans has cleared without DLTs. Conclusion: AGX101, targeting the TM4SF1 antigen, represents a promising new approach in cancer therapy. The preclinical data suggest that AGX101 could provide a significant therapeutic benefit by novel and differentiated mechanisms of action, namely selectively targeting the tumor vasculature and potentiating immune-based therapies. Further clinical development of AGX101 is ongoing. Citation Format: Ildefonso Ismael Rodriguez Rivera, Meredith S. Pelster, Shou-Ching Jaminet, Paul Jaminet, Glen J. Weiss. AGX101: Preclinical evaluation of a TM4SF1-directed tubulin inhibitor conjugate with ongoing first-in-human trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C047.

Key challenges in developing a gene therapy for Usher syndrome: machine-assisted scoping review.

Despite compelling empirical evidence demonstrating its efficacy, gene therapies for usher syndrome (USH) are not yet available for the patient's usage. This scoping review assessed the current scenario and analysed the challenges in implementing gene therapies for USH. A literature search was conducted using PubMed and Google Scholar through an artificial intelligence (AI) tool, MaiA, focusing on relevant publications from the last 10 years. We followed the methodological guidance of the Joanna Briggs Institute (JBI) and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) checklist. Of 517 records, 51 reports were considered for final analysis. It identified and categorized challenges across four key areas: preclinical, clinical, economic, and regulatory. Of all, many reports (30) highlighted the preclinical challenges where the USH gene development process encountered roadblocks. Specifically, preclinical challenges included the lack of suitable in-vivo models and effective delivery methods. Clinical challenges focused on establishing clear endpoints and long-term safety and efficacy. Economic challenges addressed diagnostic issues and manufacturing hurdles, while regulatory challenges focused on expedited evaluation processes and guidance for clinical development. Our analysis uncovered key barriers to clinical translation of USH gene therapy and strategies to address them. Researchers are employing innovative approaches, including novel delivery methods such as minigenes and nanoparticles, inventive clinical trial designs, cohesive regulatory frameworks, strategic market assessments, and collaborative research initiatives. These efforts hold promise for impactful disease-cure and modifying interventions ultimately enhancing the quality of life for USH patients.

ATMP clinical trials in the UK.

The UK advanced therapy medicinal product (ATMP) clinical trials database, produced annually by CGT Catapult, aims to assess the progress and state of the UK ATMP clinical development landscape. The aim of this article is to highlight key findings from the database and put them into context within the global landscape and various initiatives intended to attract ATMP developers to the UK. A targeted search of GlobalData's clinical trial database was performed, followed by refinement so that only trials investigating products meeting ATMP definitions were included, and that each trial was only counted once in the analysis. The 2023 data show that the number of ongoing ATMP clinical trials in the UK has remained approximately static, in contrast to a 10% reduction reported globally. Approximately 80% of these trials were commercially sponsored. Although most ATMP clinical trials are early phase, there is evidence indicating progression to later phase studies. The data indicate that the UK remains an attractive region for ATMP clinical trials. Factors including UK government investment in research, regulatory support offered by MHRA, and the Advanced Therapy Treatment Centre (ATTC) network of clinical sites, may contribute to the positive ecosystem available to developers of ATMPs.

Phase 2 Trial of Topical Application of the Hedgehog Inhibitor Patidegib in Patients With Gorlin Syndrome.

Patients with Gorlin (basal cell nevus) syndrome (GS) have numerous phenotypic abnormalities due to over-activity of the hedgehog (HH) signaling pathway, most commonly due to a heritable mutation in the PTCH1 gene, which encodes a major inhibitor of this pathway. HH inhibitors (HHi) taken orally can reverse some of the manifestations, most prominent of which is the development of numerous cutaneous basal cell carcinomas (BCCs). In order to improve the benefit:risk ratio, we have developed a gel containing a small cyclopamine-derived molecule that can be applied topically in expectation that this mode of delivery can reduce the burden of BCCs without producing the systemic adverse effects that cause patients to stop treatment with oral HHis. This study attempts to determine whether or not Patidegib Topical Gel, 2% or 4%, can accumulate in high enough concentrations to have local anti-BCC efficacy but not so high that systemic drug levels produce the adverse effects that are typical of oral HHi treatment. We conducted a small, randomized, double blinded Phase 2A trial at two sites in the United Kingdom to assess the clinical and molecular efficacy and adverse effects of 6 months of twice daily application of Patidegib Topical Gel to the entire face as well as to treatment-targeted surgically-eligible BCCs at other anatomical sites. Post hoc analyses suggested that Patidegib Topical Gel reduced the number of new surgically-eligible BCCs and the level of HH signaling with minimal adverse effects. Patidegib Topical Gel warrants further clinical development.

Preclinical pharmacology characterization of HX009, a novel PD1 x CD47 Bi-specific antibody.

Certain immune-checkpoint inhibitors have a narrow therapeutic window (TW) as cancer therapeutics, and engineered dual-/multi-targeting agents could potentially widen the TW to bring true clinical benefits. We report a new rationally-designed bispecific-antibody (BsAb), HX009, simultaneously targeting PD1 and CD47 to improve both the efficacy and safety over the respective single-targeting agents by grafting the extracellular domain of SIRPα onto the parental anti-PD1-monoclonal antibody, HX008. This resulted in an IgG4-based "2 × 2" symmetric structure but with an intentionally-reduced CD47-binding affinity, suggesting a novel candidate cancer immunotherapy. Specifically, HX009 has binding affinity constant of 8.951 × 10-9M for human PD1 and 2.557 × 10-8M for human CD47, respectively, where the CD47 binding is significantly weaker as compared to the binding affinity of HX008 to PD1 as well as the binding affinity of SIRPα-Fc to CD47, leading to little binding to RBCs and platelets and is contrasting to many CD47-agents in development. However, HX009 effectively and simultaneously binds to the PD1 and CD47 on PD1+CD47+ T-cells via cis-binding and elicits enhanced T cell activation compared to the parental HX008. HX009 caused little cytokine-release in human peripheral blood mononuclear cells. HX009 cross-species binds to cynomolgus monkey PD1/CD47 but not to rodents, making cynomolgus monkeys the choice of species to investigate the pharmacokinetics (PK) and toxicology of HX009. HX009's anti-tumor activities were confirmed in several humanized preclinical mouse models by determining either its anti-PD1 (humanized hu-CD47-MC38 models) or anti-CD47 (HuT-102 lymphoma CDX and three PDX-AML models) functions, although limited available humanized models have hindered broadly demonstration of enhanced anti-tumor activities contributed from the dual targeting of the BsAb. The expanded DLBCL-PDX trial data suggested that both EBV-status and OX40 expression could potentially be two positive predictors for response to HX009. An intravenous (IV) infusion PK study in cynomolgus monkey revealed its largely vasculature distribution, terminal half-life (T1/2) of ~ 50h, and dose-proportional exposure without accumulation. The anti-drug antibody (ADA) was observed in all monkeys as expected, affecting the PK parameters of repeated administration. The IV single-dose toxicology study with a 14-day observation revealed a maximum tolerated dose of 150mg/kg, while the repeated-dose (once weekly for 4weeks, 5 doses in total) study showed a highest non-severely toxic dose (HNSTD) of 15mg/kg. The desired preclinical PK and safety profiles, along with its antitumor activity, support HX009's candidacy for its clinical development.

PARG inhibitor sensitivity correlates with accumulation of single-stranded DNA gaps in preclinical models of ovarian cancer

Poly (ADP-ribose) glycohydrolase (PARG) is a dePARylating enzyme which promotes DNA repair by removal of poly (ADP-ribose) (PAR) from PARylated proteins. Loss or inhibition of PARG results in replication stress and sensitizes cancer cells to DNA-damaging agents. PARG inhibitors are now undergoing clinical development for patients having tumors with homologous recombination deficiency (HRD), such as cancer patients with germline or somatic BRCA1/2-mutations. PARP inhibitors kill BRCA-deficient cancer cells by increasing single-stranded DNA gaps (ssGAPs) during replication. Here, we report that, like PARP inhibitor (PARPi), PARG inhibitor (PARGi) treatment also causes an accumulation of ssGAPs in sensitive cells. PARGi exposure increased accumulation of S-phase-specific PAR, a marker for Okazaki fragment processing (OFP) defects on lagging strands and induced ssGAPs, in sensitive cells but not in resistant cells. PARGi also caused accumulation of PAR at the replication forks and at the ssDNA sites in sensitive cells. Additionally, PARGi exhibited monotherapy activity in specific HR-deficient, as well as HR-proficient, patient-derived, or patient-derived xenograft (PDX)-derived organoids of ovarian cancer, and drug sensitivity directly correlated with the accumulation of ssGAPs. Taken together, PARGi treatment results in toxic accumulation of PAR at replication forks resulting in ssGAPs due to OFP defects during replication. Regardless of the BRCA/HRD-status, the induction of ssGAPs in preclinical models of ovarian cancer cells correlates with PARGi sensitivity. Patient-derived organoids (PDOs) may be a useful model system for testing PARGi sensitivity and functional biomarkers.

Protective threshold of a potent neutralizing Zika virus monoclonal antibody in rhesus macaques.

Zika virus (ZIKV) is a mosquito-borne flavivirus that caused a global pandemic in 2016-2017 with continued ongoing transmission at low levels in several countries. In the absence of an approved ZIKV vaccine, neutralizing monoclonal antibodies (mAbs) provide an option for the prevention and treatment of ZIKV infection. Previous studies identified a potent neutralizing human mAb ZIKV-117 that reduced fetal infection and death in mice following ZIKV challenge. In this study, we report exquisite potency of ZIKV-117-LALA-YTE, which has been engineered to reduce Fc receptor binding and to extend half-life, in a titration study in rhesus macaques to protect against ZIKV challenge. We show complete protection at a dose of 0.016 mg/kg ZIKV-117-LALA-YTE, which resulted in median serum concentrations of 0.13 µg/mL. The high potency of this mAb supports its potential clinical development as a novel biotherapeutic intervention for ZIKV.IMPORTANCEIn this study, we report the potency of the Zika virus (ZIKV)-specific neutralizing antibody ZIKV-117-LALA-YTE against ZIKV challenge in a titration study rhesus macaques. This high potency supports the further development of this monoclonal antibody for ZIKV.

Targeting regulated cell death pathways in cancers for effective treatment: a comprehensive review

Cancer is a complex disease characterized by specific “mission-critical” events that drive the uncontrolled growth and spread of tumor cells and their offspring. These events are essential for the advancement of the disease. One of the main contributors to these events is dysregulation of cell death pathways—such as apoptosis, necroptosis, ferroptosis, autophagy, pyroptosis, cuproptosis, parthanatos and—allows cancer cells to avoid programmed cell death and continue proliferating unabated. The different cell death pathways in cancers provide useful targets for cancer treatment. This review examines recent progresses in the preclinical and clinical development of targeting dysregulated cell death pathways for cancer treatment. To develop effective cancer therapies, it is essential to identify and target these mission-critical events that prevent tumor cells from timely death. By precisely targeting these crucial events, researchers can develop therapies with maximum impact and minimal side effects. A comprehensive understanding of the molecular and cellular mechanisms underlying these regulated cell death pathways will further the development of highly effective and personalized cancer treatments.

The distinctive pharmacokinetic profile of rezafungin, a long-acting echinocandin developed in the era of modern pharmacometrics.

Echinocandin drugs are the current first-line therapy for fungal infections caused by Candida spp. Most patients require once-daily intravenous (IV) administration in a hospital or outpatient setting for treatment, which may negatively impact their quality of life and stress healthcare resources. Similar to other echinocandins, the novel FDA-, EMA-, and Medical and Healthcare Products Regulatory Agency-approved echinocandin, rezafungin (CD101), exhibited strong antifungal activity against several fungal pathogens and a low drug-drug interaction liability, which are important for medically complex patients. A pharmacometric-based approach has been adopted throughout the development of rezafungin, which contrasts with older echinocandins where dosing regimens were largely derived empirically, and only recently based on pharmacometric guidance. This state-of-the-art approach used model-based simulations incorporating pre-clinical and clinical data as it became available to optimize the dosing regimen for rezafungin. The enhanced stability of the molecular structure and the safety profile of rezafungin allow for the administration of once-weekly IV doses, compared to the daily dosing requirement for other echinocandin drugs, with this distinctive pharmacokinetic profile of rezafungin resulting in a front-loaded dosing regimen with high exposures early in therapy for enhanced fungal killing. The long shelf-life of rezafungin makes this echinocandin more flexible in terms of storage and manufacturing. Demonstrated across clinical development, rezafungin may provide patients with next-generation first-line antifungal treatment for the treatment of candidaemia and invasive candidiasis.

DbAMP 3.0: updated resource of antimicrobial activity and structural annotation of peptides in the post-pandemic era.

Antimicrobial resistance is one of the most urgent global health threats, especially in the post-pandemic era. Antimicrobial peptides (AMPs) offer a promising alternative to traditional antibiotics, driving growing interest in recent years. dbAMP is a comprehensive database offering extensive annotations on AMPs, including sequence information, functional activity data, physicochemical properties and structural annotations. In this update, dbAMP has curated data from over 5200 publications, encompassing 33,065 AMPs and 2453 antimicrobial proteins from 3534 organisms. Additionally, dbAMP utilizes ESMFold to determine the three-dimensional structures of AMPs, providing over 30,000 structural annotations that facilitate structure-based functional insights for clinical drug development. Furthermore, dbAMP employs molecular docking techniques, providing over 100 docked complexes that contribute useful insights into the potential mechanisms of AMPs. The toxicity and stability of AMPs are critical factors in assessing their potential as clinical drugs. The updated dbAMP introduced an efficient tool for evaluating the hemolytic toxicity and half-life of AMPs, alongside an AMP optimization platform for designing AMPs with high antimicrobial activity, reduced toxicity and increased stability. The updated dbAMP is freely accessible at https://awi.cuhk.edu.cn/dbAMP/. Overall, dbAMP represents a comprehensive and essential resource for AMP analysis and design, poised to advance antimicrobial strategies in the post-pandemic era.

Quantitative Structure-Activity Relationship Models to Predict Cardiac Adverse Effects.

Drug-induced cardiotoxicity represents one of the most common causes of attrition of drug candidates in preclinical and clinical development. For this reason, the evaluation of cardiac toxicity is essential during drug development and regulatory review. In the present study, drug-induced postmarket adverse event combinations from the FDA Adverse Event Reporting System were extracted for 2002 drugs using 243 cardiac toxicity-related preferred terms (PTs). These PTs were combined into 12 groups based on their clinical relevance to serve as training sets. The optimal classification scheme was determined using a combination of data sources that included drug labeling information, published literature, clinical study data, and postmarket surveillance data. Two commercial QSAR platforms were used to construct 12 models, including general cardiac toxicity, cardiac ischemia, heart failure, cardiac valve disease, myocardial disease, pericardial disease, structural heart disease, cardiac arrhythmia, Torsades de Pointes, long QT syndrome, atrial fibrillation and ventricular arrhythmia, and cardiac arrest. The cross-validated performance for the new models reached a sensitivity of up to 80% and negative predictivity of up to 80%. These new models covering a wide range of cardiac endpoints will provide fast, reliable, and comprehensive predictions of potential cardiotoxic compounds in drug discovery and regulatory safety assessment.

Meta-Analysis of Exposure-Adverse Event Relationships for Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) have become a vital class of therapeutics in oncology because of their ability to selectively deliver potent drug molecules to tumor cells. However, ADC-associated toxicities cause high failure rates in the clinic and hinder their full potential. Due to the complex structure and pharmacokinetics of ADCs, it is challenging to identify the drivers of their toxicities. Here, quantitative analysis was performed to correlate the incidence of clinical adverse events (AEs) with nine different commonly measured exposure parameters collected from study-level summary data. We considered ADC analytes for different classes of ADCs, to identify ADC analytes that are strongly associated with the AEs for ADCs. Published clinical exposure and safety data for any grade and grade ≥3 AEs from 40 publications across six ADCs and three payloads were collected and analyzed. Exposure-AE relationships were quantified using logit models, and the strength of the correlations and rank order were determined. The analysis suggests that deruxtecan ADC-related toxicities correlated most strongly with the exposure of the free payload; monomethyl auristatin E (MMAE) ADC-related toxicities correlated with the free MMAE area under the curve; and pyrrolobenzodiazepine ADC-related toxicities correlated with no specific analyte but the dose. These findings agree with the published literature and support the notion that AE profiles are often shared by ADCs that deliver the same cytotoxic payload. The exposure-AE relationships presented here, together with identification of the most informative ADC analytes, may facilitate more focused mechanistic studies on the drivers of clinical AEs and could support dosing decisions during clinical development of ADCs.

Abstract 4139191: ETX-258 - A GalOmic™ siRNA for the Treatment of Heart Failure Following Myocardial Infarction

Introduction: Heart failure with reduced ejection fraction (HFrEF) remains a significant clinical challenge, evidenced by high hospitalization rates and five-year mortality. Current treatments are limited by side effects, poor patient compliance, and the necessity for gradual drug titration. These challenges highlight the need for new therapies that are both safe and effective in targeting the structural remodeling pivotal to disease progression post-myocardial infarction (MI). e-therapeutics (ETX) uniquely combines computation and RNAi to discover life-transforming medicines. ETX’s RNAi platform, GalOmic™, enables generation of specific, potent, and long-acting siRNA therapies that effectively silence novel gene targets in hepatocytes. This highly specific mechanism of action limits unwanted side effects, positioning it as a promising approach to HFrEF treatment. Methods: Potent siRNAs against a hepatic target with cardioprotective potential were designed in silico. Candidate siRNAs were screened in vitro in HEK293 cells and in vivo in C57BL/6J mice to select the lead GalOmic™ siRNA, ETX-258. MI was induced by ligation of the left anterior descending artery in C57BL/6J mice after which ETX-258 was injected subcutaneously weekly for 6 weeks. Eplerenone, a mineralocorticoid receptor antagonist which is part of the current treatment regimen for HFrEF, was used as a comparator. Cardiac function was assessed by echocardiography at 2-, 4- and 6-weeks post-MI. Cardiac damage and structural remodeling were evaluated using circulating biomarkers of cardiac function and histological assessment. Results: ETX-258 was selected as a highly active siRNA for the treatment of heart failure with a long duration of action. Post-MI treatment with ETX-258 significantly improved key echocardiographic parameters of cardiac function, including ejection fraction and total cardiac output, achieving results comparable to eplerenone. Additionally, both structural cardiac parameters and markers of damage and remodeling showed significant improvements, reaching similar levels in both ETX-258 and eplerenone-treated mice. Conclusions: High unmet need remains for HFrEF patients despite existing therapies. These results highlight the potential of ETX-258 to improve cardiac function and pathogenic structural remodeling post-MI. This, paired with the long duration of action and favorable safety profile of GalOmic™ siRNAs, makes ETX-258 a promising candidate for further clinical development.

Globalization in clinical drug development for sickle cell disease.

Globalization in clinical drug development for sickle cell disease.

A guide for blood-brain barrier models.

Understanding the intricate mechanisms underlying brain-related diseases hinges on unraveling the pivotal role of the blood-brain barrier (BBB), an essential dynamic interface crucial for maintaining brain equilibrium. This review offers a comprehensive analysis of BBB physiology, delving into its cellular and molecular components while exploring a wide range of in vivo and in vitro BBB models. Notably, recent advancements in 3D cell culture techniques are explicitly discussed, as they have significantly improved the fidelity of BBB modeling by enabling the replication of physiologically relevant environments under flow conditions. Special attention is given to the cellular aspects of in vitro BBB models, alongside discussions on advances in stem cell technologies, providing valuable insights into generating robust cellular systems for BBB modeling. The diverse array of cell types used in BBB modeling, depending on their sources, is meticulously examined in this comprehensive review, scrutinizing their respective derivation protocols and implications. By synthesizing diverse approaches, this review sheds light on the improvements of BBB models to capture physiological conditions, aiding in understanding BBB interactions in health and disease conditions to foster clinical developments.

Immunogenicity assessment strategy for a chemically modified therapeutic protein in clinical development

The clinical immunogenicity assessment for complex multidomain biological drugs is challenging due to multiple factors that must be taken into consideration. Here, we describe a strategy to overcome multiple bioanalytical challenges in order to assess anti-drug antibodies (ADA) for a novel and unique chemically modified protein therapeutic. A risk-centered approach was adopted to evaluate the immunogenic response to a modified version of human growth differentiation factor 15 (GDF15) connected to an albumin-binding fatty acid via a polyethylene glycol (PEG) linker. Key steps include monitoring anti-drug antibodies (ADAs), using a standard tiered approach of screening and confirmation. To deepen our understanding of ADA response, as a third tier of immunogenicity assessment, novel extensive characterization using a set of assays was developed, validated, and used routinely in clinical sample analysis. This characterization step included performance of titration, mapping of ADA response including anti-GDF15 and anti-PEG–fatty-acid antibody characterization, and assessment of the neutralizing anti-drug antibodies (NAbs) using cell-based assays for immunogenicity in parallel. The analytical methods were applied during two clinical trials involving both healthy volunteers and overweight or obese patients. We observed low incident rates for ADA and no ADAs against the PEG linker with fatty acid conjugation. In one of the clinical studies, we identified neutralizing ADAs. The proposed novel strategy of extensive characterization proved effective for monitoring the presence of ADAs and NAbs and can be used to support clinical development of a broad range of chemically modified proteins and multidomain biotherapeutics.

Exploring Design-Based Research as a framework for addressing pedagogical problems faced by higher education

Design-Based Research presents a pragmatic approach to addressing both pedagogical problems and innovations within a rigorous framework that aims to build transferable practice. This panel discussion will explore four examples of implementing DBR in various higher education contexts and draw participants into a discussion of how they might apply DBR to address identified pedagogical problems or innovations in their own contexts. Why DBR? This panel discussion is a focal point for exploring how design-based research (DBR) in higher education in 2024, can address pedagogical problems brought about by the global pandemic and the explosion of generative artificial intelligence use in assessment and learning (For examples). In a period of continuous disruption in higher education, flexible and ethical research strategies that embrace unexpected influences in teaching and learning is paramount (Cochrane et al., 2023), leading to a new generation of educational researchers embracing DBR. Furthermore, practical examples demonstrating students as partners in curriculum design to inform ‘what works’ in practice are essential for researchers to gain confidence in adopting research-teaching-practice methods of inquiry (Bakker, 2018; Cochrane & Munn, 2020). Understanding how the processes and outputs of DBR can meet these needs is crucial to alleviating both business and educational tensions about timing, funding, resources, and workload planning (Cochrane, 2022; McKenney & Reeves, 2019; Reeves & Lin, 2020). At the core of DBR is the opportunity to explore pedagogical problems or innovation through four phases: problem analysis, develop solutions to the identified problem, explore and evaluate the impact of the design in iterative interventions in real learning situations, leading to the development of transferable design principles and theory building (McKenney & Reeves, 2019) Various research methods can be applied to progressively ask participant perspectives, including students, teachers and learning designers, on appropriate approaches or technologies to solve an identified problem (McKenney & Reeves, 2019). The intended outcome of this panel discussion is to collaborate with participants in implementing DBR in higher education in response to specific pedagogical problems identified by the participants. Beginning with a brief background to DBR followed by four examples to stimulate discussion on its application in broader contexts to address identified problems in curriculum design. Relevance to Higher Education The relevance of debating the role of design-based research in higher education in 2024 is to stimulate discussion for how this pragmatic research approach informs ‘what works’ in situated learning contexts to develop cutting edge design principles and theory that can be transferrable (Galvin & Cochrane, 2023). The methodological framework of DBR invites students, teachers, and learning designers to collaborate from the conception of a design artefact or educational approach to solve a learning problem through to iterative stages of delivery. Following a new normal in higher education where change is inevitable, and fast-paced, research design that does not shy away from the progressive and ‘messy’ elements of educational settings to improve real time learning is essential. Finding a balance between naturalistic and interventionist research methods to explore this complexity is a way forward that DBR can provide. It is acknowledged that greater understanding for the value of DBR and how to plan practical stages with multiple participants is needed for teachers, researchers, and leaders in higher education to confidently adopt this approach (Haagen-Schützenhöfer et al., 2024). Opening discussion with peers models the collaborative ethos of DBR and opens potential connections and networking avenues to establish and generate knowledge for DBR in higher education. The Panel Members The panel will be comprised of project leaders from four DBR projects: Clinical reasoning development, interdisciplinary engineering education, biomechanics, performance anxiety. These projects were introduced in a concise paper for the ASCILITE 2023 conference (Cochrane et al., 2023) and the authors are in the process of collaborating on a full journal article analysing these DBR projects (Cochrane et al., 2024) that should be published in time for the ASCILITE 2024 conference.