Nonclinical Data Research Articles

Functional Assessments of Gynecologic Cancer Models Highlight Differences Between Single-Node Inhibitors of the PI3K/AKT/mTOR Pathway and a Pan-PI3K/mTOR Inhibitor, Gedatolisib

Background/Objectives: The PI3K/AKT/mTOR (PAM) pathway is frequently activated in gynecological cancers. Many PAM inhibitors selectively target single PAM pathway nodes, which can lead to reduced efficacy and increased drug resistance. To address these limitations, multiple PAM pathway nodes may need to be inhibited. Gedatolisib, a well-tolerated panPI3K/mTOR inhibitor targeting all Class I PI3K isoforms, mTORC1 and mTORC2, could represent an effective treatment option for patients with gynecologic cancers. Methods: Gedatolisib and other PAM inhibitors (e.g., alpelisib, capivasertib, and everolimus) were tested in endometrial, ovarian, and cervical cancer cell lines by using cell viability, cell proliferation, and flow cytometry assays. Xenograft studies evaluated gedatolisib in combination with a CDK4/6 inhibitor (palbociclib) or an anti-estrogen (fulvestrant). A pseudo-temporal transcriptomic trajectory of endometrial cancer clinical progression was computationally modeled employing data from 554 patients to correlate non-clinical studies with a potential patient group. Results: Gedatolisib induced a substantial decrease in PAM pathway activity in association with the inhibition of cell cycle progression and the decreased cell viability in vitro. Compared to single-node PAM inhibitors, gedatolisib exhibited greater growth-inhibitory effects in almost all cell lines, regardless of the PAM pathway mutations. Gedatolisib combined with either fulvestrant or palbociclib inhibited tumor growth in endometrial and ovarian cancer xenograft models. Conclusions: Gedatolisib in combination with other therapies has shown an acceptable safety profile and promising preliminary efficacy in clinical studies with various solid tumor types. The non-clinical data presented here support the development of gedatolisib combined with CDK4/6 inhibitors and/or hormonal therapy for gynecologic cancer treatment.

Prediction of adverse drug reactions using demographic and non-clinical drug characteristics in FAERS data

The presence of adverse drug reactions (ADRs) is an ongoing public health concern. While traditional methods to discover ADRs are very costly and limited, it is prudent to predict ADRs through non-invasive methods such as machine learning based on existing data. Although various studies exist regarding ADR prediction using non-clinical data, a process that leverages both demographic and non-clinical data for ADR prediction is missing. In addition, the importance of individual features in ADR prediction has yet to be fully explored. This study aims to develop an ADR prediction model based on demographic and non-clinical data, where we identify the highest contributing factors. We focus our efforts on 30 common and severe ADRs reported to the Food and Drug Administration (FDA) between 2012 and 2023. We have developed a random forest (RF) and deep learning (DL) machine learning model that ingests demographic data (e.g., Age and Gender of patients) and non-clinical data, which includes chemical, molecular, and biological drug characteristics. We successfully unified both demographic and non-clinical data sources within a complete dataset regarding ADR prediction. Model performances were assessed via the area under the receiver operating characteristic curve (AUC) and the mean average precision (MAP). We demonstrated that our parsimonious models, which include only the top 20 most important features comprising 5 demographic features and 15 non-clinical features (13 molecular and 2 biological), achieve ADR prediction performance comparable to a less practical, feature-rich model consisting of all 2,315 features. Specifically, our models achieved an AUC of 0.611 and 0.674 for RF and DL algorithms, respectively. We hope our research provides researchers and clinicians with valuable insights and facilitates future research designs by identifying top ADR predictors (including demographic information) and practical parsimonious models.

Preclinical immunogenicity and safety of hemagglutinin-encoding modRNA influenza vaccines

Seasonal epidemics of influenza viruses are responsible for a significant global public health burden. Vaccination remains the most effective way to prevent infection; however, due to the persistence of antigenic drift, vaccines must be updated annually. The selection of vaccine strains occurs months in advance of the influenza season to allow adequate time for production in eggs. RNA vaccines offer the potential to accelerate production and improve efficacy of influenza vaccines. We leveraged the nucleoside-modified RNA (modRNA) platform technology and lipid nanoparticle formulation process of the COVID-19 mRNA vaccine (BNT162b2; Comirnaty®) to create modRNA vaccines encoding hemagglutinin (HA) (modRNA-HA) for seasonal human influenza strains and evaluated their preclinical immunogenicity and toxicity. In mice, a monovalent modRNA vaccine encoding an H1 HA demonstrated robust antibody responses, HA-specific Th1-type CD4+ T cell responses, and HA-specific CD8+ T cell responses. In rhesus and cynomolgus macaques, the vaccine exhibited durable functional antibody responses and HA-specific IFN-γ+ CD4+ T cell responses. Immunization of mice with monovalent, trivalent, and quadrivalent modRNA-HA vaccines generated functional antibody responses targeting the seasonal influenza virus(es) encoded in the vaccines that were greater than, or similar to, those of a licensed quadrivalent influenza vaccine. Monovalent and quadrivalent modRNA-HA vaccines were well-tolerated by Wistar Han rats, with no evidence of systemic toxicity. These nonclinical immunogenicity and safety data support further evaluation of the modRNA-HA vaccines in clinical studies.

405P Single- and repeat-dose nonclinical data for PGN-EDO51 demonstrated favorable pharmacology and safety profiles for the treatment of DMD

405P Single- and repeat-dose nonclinical data for PGN-EDO51 demonstrated favorable pharmacology and safety profiles for the treatment of DMD

440P Nonclinical data for PGN-EDODM1 demonstrated nuclear delivery, mechanistic and meaningful activity for the potential treatment of DM1

440P Nonclinical data for PGN-EDODM1 demonstrated nuclear delivery, mechanistic and meaningful activity for the potential treatment of DM1

An industry perspective on the FDA modernization act 2.0/3.0: Potential next steps for sponsors to reduce animal use in drug development

Abstract Pharmaceutical developers are encouraged to adopt the best practices of being purposefully thoughtful about the use of animals, seeking alternatives wherever possible. They should engage with health authorities to increase their familiarity with the methods, study designs, data outputs and the context of use for new approach methodologies (NAMs). Although current state of technology does not yet provide adequate models to fully replace in vivo studies, many models are sufficiently good for an augmented approach that will enhance our understanding of in vitro to in vivo correlations and advance the long-term goal of reducing animal use through innovative NAMs. The goal of future nonclinical safety packages is to advance the utilization of such enabling technologies towards appropriate human risk characterization. Establishing confidence in NAMs is a critical first step. For example, sponsors may include both “traditional” and NAM-based nonclinical safety data in regulatory submissions to establish confidence with health authorities. In addition, regulators should create a “safe-harbor” for hybrid nonclinical data packages to facilitate iterative learning, refinement, and implementation of NAM-based safety assessment strategies. Sponsors are urged to contribute to NAMs evolution through consortia participation, peer-reviewed publications, and documenting animal reduction in studies/programs, accelerating the eventual elimination of animal use in pharmaceutical development, as envisioned in the FDA Modernization Act 3.0.

Safety assessment of protein A and derivation of a parenteral health-based exposure limit

Protein A (PA) is a bacterial cell wall component of Staphylococcus aureus whose function is to bind to Immunoglobulin G (IgG). Given its ability to bind IgG as well as its stability and resistance to harsh acidic and basic cleaning conditions, it is commonly used in the affinity chromotography purification of biotherapeutics. This use can result in levels of PA being present in a drug product and subsequent patient exposure. Interestingly, PA was previously evaluated in clinical trials as well as supporting nonclinical studies, resulting in a database that enables the derivation of a health-based exposure limit (HBEL). Given the widespread use of PA in the pharmaceutical industry, the IQ DruSafe Impurities Safety Working Group (WG) evaluated the available information with the purpose of establishing a harmonized parenteral HBEL for PA. Based on this thorough, collaborative evaluation of nonclinical and clinical data available for PA, a parenteral HBEL of 1.2 μg/kg/dose (60 μg/dose for a 50 kg individual) is expected to be health protective for patients when it is present as an impurity in a biotherapeutic.

Considerations for occupational risk management during pregnancy: A summary of a continuing education course.

Women comprise approximately 40% of the global workforce, and many women continue to work during pregnancy. Although occupational exposure limit values (OELVs) are intended to protect all workers, many OELVs may have been established without consideration of the unique changes in pregnant workers, and many chemicals lack OELVs altogether. A short educational course was developed to address the informational needs of health professionals who have responsibility to ensure a safe workplace for pregnant employees. The course was designed to raise awareness of the key elements in risk management and their application to the pregnant worker, such as physiological changes of pregnancy that influence susceptibility to exposures; guidance for nonclinical data interpretation; exposure assessment and control strategies; and risk management in practice in a diverse regulatory environment. This paper summarizes the course content and is intended to support informed risk management decision making to protect the health of pregnant workers and their offspring.

Mechanisms of Antidiabetic Effects of Medicinal Plants: A Systematic Review

Introduction: Diabetes mellitus is a worldwide concern as its rising prevalence has resulted in severe health problems. Some people employ traditional medicine to manage their diabetes. AIM: This review aims to identify medicinal plants used in diabetes management and to review their non-clinical data on its efficacy, toxicity studies, and mechanism of action. Methods: The databases used to search for information were PubMed, Scopus, ScienceDirect, and Google Scholar, reporting from Jan 2018 until Nov 2023. The search terms involved “diabetes”, “hypoglycemic” “medicinal plants”, “chemical compound”, “traditional use”, “extracts”, “reduce blood glucose” and “toxicity”. Results: A total of twenty plants were identified, showing blood glucose reduction from 14.3% to 80%, and their mechanism of action was thematically categorized under three mechanisms which are 1) insulin secretagogue, 2) insulin sensitizer, and 3) retard intestinal absorption of glucose. The plant extracts showed no sign of acute toxicity between 1.5 to 5 g/kg. Conclusion: To optimize their effectiveness, further research is required to evaluate chronic toxicity and identify plant extract bioactive compounds.

2319 Deficits comprising multi-dimensional frailty indices based on routine data: sub-analysis of a scoping review

Abstract Introduction The frailty index (FI) is a frailty assessment tool calculated as the proportion of the number of deficits, or ‘things that individuals have wrong with them’, to the total number of variables in the index. Routine health and administrative databases are valuable sources of deficits to automatically calculate FIs. There is large heterogeneity in the deficits used in FIs. This sub-analysis of a scoping review on routine data-based FIs aimed to describe and map the deficits used in multi-dimensional FIs. Methods Seven databases were searched to find literature published between 2013 and 2023. The main inclusion criterion was multi-dimensional FIs constructed from routinely collected data. Multi-dimensional FIs should have deficits in at least two of the following categories: ‘symptoms/signs’, ‘laboratory values’, ‘disease classification’, ‘disabilities’, and ‘other’. Results Of the 7526 publications screened, 57 distinct FIs were identified from 56 included studies. Most FIs were developed in the USA (n = 15) and in hospital settings (n = 19). The most dominant data source of deficits to calculate the FIs was hospital records (n = 21). Twenty-five FIs were developed for specific conditions and populations, for example, cancer, HIV, dementia, organ transplant recipients, and veterans. The median number of deficits used in the FIs was 36 (range = 5–72). Almost all the FIs (n = 56) had at least one deficit in the ‘symptoms/signs’ category, followed by ‘disease classification’ (n = 55) and ‘disabilities’ (n = 50). Approximately two-thirds of all the deficits were ‘symptoms/signs’ and ‘disease classifications’. Conclusion These findings highlight the reactive approach to frailty assessment, as most of these FIs were calculated from hospital data and used symptoms/signs and diseases as deficits. Given the heterogenous manifestations and long-term impacts of frailty, using a more proactive approach that leverages non-clinical routine data is warranted to prevent frailty development and progression.

The use of quantitative clinical pharmacology approaches to support moxidectin dosing recommendations in lactation.

Moxidectin is approved by the US Food and Drug Administration (US FDA) for the treatment of onchocerciasis (river-blindness) due to Onchocerca volvulus in patients aged 12 years and older. In onchocerciasis-endemic areas, mass drug administration (MDA) programs with ivermectin, with or without vector control, aim to control the disease, reduce morbidity, interrupt transmission, and more recently, achieve elimination. Moxidectin has the potential to be used in MDA programs. In countries where onchocerciasis is endemic, infants are often breastfed up to the age of 2 years, suggesting that some women are likely to be lactating during such periodic MDA programs. Quantitative analyses of non-clinical and clinical data using non-compartmental analysis and population based pharmacokinetic (popPK) modeling as well as physiologically based pharmacokinetic modeling (PBPK) were performed to determine the amount of moxidectin excreted in breast milk and subsequent exposures in the infant. The results of the analyses were similar. Concentrations of moxidectin in breast milk followed a similar pattern to those in plasma, with maximum concentrations occurring approximately 4 hours after dosing followed by a rapid decline in both breast milk and plasma. As early as two days after dosing, concentrations of moxidectin in breast milk were below the threshold for acceptable daily intake levels established by the European Medicines Agency (EMA) and FDA for secondary exposures from veterinary use, and below the WHO recommended relative infant dose (RID) safety threshold. The analyses were conducted to support prescribers and policy makers on dosing recommendations for moxidectin in lactation.

Social Vulnerability and Prevalence and Treatment for Mental Health and Substance Use Disorders

Community-level social vulnerability (SV) is associated with physical illness and premature mortality. Its association with mental health (MH) and substance use disorders (SUDs) needs further study. To study associations of SV with clinical diagnoses of MH disorders, SUDs, and related treatments in the US noninstitutionalized population of adults aged 18 years and older. A survey of adults in a national sample of US households between October 2020 and October 2022. Participants drawn from a multistage, clustered, and stratified area probability sample of US households were included, excluding adults older than 65 years because of the difficulty of differentiating mental disorders from symptoms of dementia. The sample also included adults living in prisons, state psychiatric hospitals, and homeless shelters who were excluded from the sample of US households used in these analyses. Each sample household was sent a letter explaining the study and offering the option to complete the household roster online, by phone, or by email. Of the 12 906 adults selected for clinical interviewing in the household sample, 4674 completed clinical interviews. Main outcomes were Structured Clinical Interview for DSM-5 past-year diagnoses of MH disorders and SUDs and responses to survey questions regarding treatment received. The Social Vulnerability Metric (SVM) and the Area Deprivation Index (ADI) were used to determine SV at the residential zip code level. The analysis involved 4674 participants (2904 [62.13%] female and 1770 [37.87%] male; mean [SD] age, 41.51 [13.41] years). Controlling for measured confounders, the SVM was significantly associated with diagnoses of schizophrenia spectrum disorder (SSD; adjusted odds ratio [aOR], 17.22; 95% CI, 3.05-97.29), opioid use disorder (OUD; aOR, 9.47; 95% CI, 2.30-39.02), stimulant use disorder (aOR, 6.60; 95% CI, 2.01-21.67), bipolar I disorder (aOR, 2.39; 95% CI, 1.19-4.80), posttraumatic stress disorder (aOR, 1.63; 95% CI, 1.06-2.50), and any MH disorder (aOR, 1.44; 95% CI, 1.14-1.83), but not major depressive disorder (MDD), generalized anxiety disorder (GAD), or any SUD. Results were similar for the ADI but generally of lower magnitude (SSD aOR, 11.38; 95% CI, 1.61-80.58; OUD aOR, 2.05; 95% CI, 0.30-14.10; stimulant use disorder aOR, 2.18; 95% CI, 0.52-9.18). Among participants with SSDs, SV was associated with reduced MH treatment (aOR, 0.001; 95% CI, 0.00-0.18) and reduced SUD treatment in participants with OUD or stimulant use disorder (aOR, 0.24; 95% CI, 0.02-2.80). In contrast to previous studies using nonclinical symptom-based survey data, we found no association between SV and GAD or MDD. By contrast, there were associations of SV with prevalence of SSD, stimulant use disorder, and OUD with corresponding decreases in treatment. These results suggest that the SVM might assist in developing more comprehensive care models that integrate medical and social care for MH disorders and SUDs.

SendigR: an R package to leverage the value of CDISC SEND datasets for cross-study analysis.

The CDISC Standard for Exchange of Nonclinical Data (SEND) data standard has created new opportunities for collaborative development of open-source software solutions to facilitate cross-study analyses of toxicology study data. A public-private partnership between BioCelerate and the FDA/Center for Drug Evaluation and Research (CDER) was established in part to develop and publicize novel methods to facilitate cross-study analysis of SEND datasets. As part of this work in collaboration with the Pharmaceutical Users Software Exchange (PHUSE), an R package sendigR has been developed to enable users to construct a relational database from a collection of SEND datasets and then query that database to perform cross-study analyses. The sendigR package also includes an integrated Python package, xptcleaner, which can be used to harmonize the terminology used in SEND datasets by mapping to CDISC controlled terminologies. The sendigR R package is freely available on the comprehensive R Archive Network (CRAN) and at https://github.com/phuse-org/sendigR. An R Shiny web application was included in the R package to enable toxicologists with no coding experience to perform historical control analyses. Experienced R programmers will be able to integrate the package functions into their own custom scripts/packages and potentially contribute improvements to the functionality of sendigR. sendigR reference manual: https://phuse-org.github.io/sendigR/. sendigR R Shiny demo app: https://phuse-org.shinyapps.io/sendigR/.

New Horizons of Model Informed Drug Development in Rare Diseases Drug Development.

Model-informed approaches provide a quantitative framework to integrate all available nonclinical and clinical data, thus furnishing a totality of evidence approach to drug development and regulatory evaluation. Maximizing the use of all available data and information about the drug enables a more robust characterization of the risk-benefit profile and reduces uncertainty in both technical and regulatory success. This offers the potential to transform rare diseases drug development, where conducting large well-controlled clinical trials is impractical and/or unethical due to a small patient population, a significant portion of which could be children. Additionally, the totality of evidence generated by model-informed approaches can provide confirmatory evidence for regulatory approval without the need for additional clinical data. In the article, applications of novel quantitative approaches such as quantitative systems pharmacology, disease progression modeling, artificial intelligence, machine learning, modeling of real-world data using model-based meta-analysis and strategies such as external control and patient-reported outcomes as well as clinical trial simulations to optimize trials and sample collection are discussed. Specific case studies of these modeling approaches in rare diseases are provided to showcase applications in drug development and regulatory review. Finally, perspectives are shared on the future state of these modeling approaches in rare diseases drug development along with challenges and opportunities for incorporating such tools in the rational development of drug products.

Pharmacokinetic/Pharmacodynamic modelling of Saxagliptin and its active metabolite, 5-hydroxy Saxagliptin in rats with Type 2 Diabetes Mellitus

Background and purposesIt is unclear whether the parent Saxagliptin (SAX) in vivo is the same as that in vitro, which is twice that of 5-hydroxy Saxagliptin (5-OH SAX). This study is to construct a Pharmacokinetic-Pharmacodynamic (PK-PD) link model to evaluate the genuine relationship between the concentration of parent SAX in vivo and the effect.MethodsFirst, we established a reliable Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS) method and DPP-4 inhibition ratio determination method. Then, the T2DM rats were randomly divided into four groups, intravenous injection of 5-OH SAX (0.5 mg/kg) and saline group, intragastric administration of SAX (10 mg/kg) and Sodium carboxymethyl cellulose (CMC-Na) group. Plasma samples were collected at different time points for subsequent testing. Finally, we used the measured concentrations and inhibition ratios to construct a PK-PD link model for 5-OH SAX and parent SAX.ResultsA two-compartment with additive model showed the pharmacokinetic process of SAX and 5-OH SAX, the concentration-effect relationship was represented by a sigmoidal Emax model and sigmoidal Emax with E0 model for SAX and 5-OH SAX, respectively. Fitting parameters showed SAX was rapidly absorbed after administration (Tmax=0.11 h, t1/2, ka=0.07 h), widely distributed in the body (V ≈ 20 L/kg), plasma exposure reached 3282.06 ng*h/mL, and the elimination half-life was 6.13 h. The maximum plasma dipeptidyl peptidase IV (DPP-4) inhibition ratio of parent SAX was 71.47%. According to the final fitting parameter EC50, EC50, 5−OH SAX=0.46EC50, SAX(parent), it was believed that the inhibitory effect of 5-OH SAX was about half of the parent SAX, which is consistent with the literature.ConclusionsThe PK-PD link model of the parent SAX established in this study can predict its pharmacokinetic process in T2DM rats and the strength of the inhibitory effect of DPP-4 based on non-clinical data.

US Food and Drug Administration Approval Summary: Eflornithine for High-Risk Neuroblastoma After Prior Multiagent, Multimodality Therapy.

On December 13, 2023, the US Food and Drug Administration (FDA) approved eflornithine (IWILFIN, US WorldMeds) to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy. The approval was based on an externally controlled trial (ECT) consisting of a single-arm trial, study 3(b), compared with an external control (EC) derived from a National Cancer Institute/Children's Oncology Group-sponsored clinical trial (Study ANBL0032) and supported by confirmatory evidence. In the protocol-specified primary analysis, the event-free survival hazard ratio (HR) was 0.48 (95% CI, 0.27 to 0.85) and overall survival HR was 0.32 (95% CI, 0.15 to 0.70). The most common adverse reactions (≥5%) were hearing loss, otitis media, pyrexia, pneumonia, and diarrhea. Notably, this is the first oncology drug approval which relies on an ECT as the primary clinical data to support substantial evidence of effectiveness. This was made possible by a distinctly high-quality, comparable EC data set with consistent treatment effect estimations demonstrated in multiple sensitivity and supportive analyses. Eflornithine's manageable safety profile and strong nonclinical and mechanistic data provided further support for the approval, and the evidentiary package was evaluated in the context of high unmet need in a rare, life-threatening cancer.

Characterization of ascending dose canine telemetry model supports its use in E14/S7B QT integrated risk assessments

IntroductionNonclinical evaluation of the cardiovascular effects of novel chemical or biological entities (NCE, NBEs) is crucial for supporting first-in-human clinical trials. One important aspect of these evaluations is the assessment of potential QT/QTc prolongation risk, as drug-induced QT prolongation can have catastrophic effects. The recent publication of E14/S7B Q&As allows for the situational incorporation of nonclinical QTc data as part of an integrated risk assessment for a Thorough QT (TQT) waiver application provided certain best practice criteria are met. Recent publications provided detailed characterization of nonclinical QTc telemetry data collected from the commonly used Latin square study design. MethodsTo understand whether data from alternate telemetry study designs were sufficient to serve as part of the E14/S7B integrated risk assessment, we report the performance and translational sensitivity to identify clinical risk of QTc prolongation risk for an ascending dose telemetry design. ResultsThe data demonstrated low variability in QTci interval within animals from day to day, indicating a well-controlled study environment and limited concern for uncontrolled effects across dosing days. Historical study variances of the ascending dose design with n = 4 subjects, measured by least significant difference (LSD) and root mean square error (RMSE) values, were low enough to detect a + 10 ms QTci interval change, and the median minimum detectable difference (MDD) for QTci interval changes was <10 ms. Furthermore, concentration-QTci (C-QTci) assessments to determine +10 ms QTci increases for known hERG inhibitors were comparable to clinical CC values listed in the E14/S7B training materials, supporting the use of the ascending dose design in an E14/S7B integrated risk assessment. DiscussionThese findings suggest that the ascending dose design can be a valuable tool in nonclinical evaluation of QT/QTc prolongation risk and the support of TQT waiver applications.

Optimizing Early Clinical Investigations in Cancer Immunotherapy: The Translational Journey of RG6292, a Novel, Selective Treg-Depleting Antibody.

The multifaceted IL-2/IL-2R biology and its modulation by promising therapeutic agents are highly relevant topics in the cancer immunotherapy field. A novel CD25-Treg-depleting antibody (Vopikitug, RG6292) has been engineered to preserve IL-2 signaling on effector T cells to enhance effector activation and antitumor immunity, and is currently being evaluated in the clinic. The Entry into Human-enabling framework described here investigated the characteristics of RG6292, from in vitro quantification of CD25 and RG6292 pharmacology using human tissues to in vivo assessment of PK/PD/safety relationships in cynomolgus monkeys as non-human primate species (NHP). Fundamental knowledge on CD25 and Treg biology in healthy and diseased tissues across NHP and human highlighted the commonalities between these species in regard to the target biology and demonstrated the conservation of RG6292 properties between NHP and human. The integration of in vitro and in vivo PK/PD/safety data from these species enabled the identification of human relevant safety risks, the selection of the most appropriate safe starting dose and the projection of the pharmacologically-relevant dose range. The first clinical data obtained for RG6292 in patients verified the appropriateness of the described approaches as well as validated the full clinical relevance of the projected safety, PK, and PD profiles from animal to man. This work shows how the integration of mechanistic non-clinical data increases the predictive value for human, allowing efficient transition of drug candidates and optimizations of early clinical investigations.

Abstract PO3-04-13: SUMIT-ELA: Phase 1b/2 combination of cyclin-dependent kinase 7 inhibitor (CDK7i) samuraciclib and selective estrogen receptor degrader (SERD) elacestrant in advanced hormone receptor positive (HR+) breast cancer after CDK4/6i

Abstract Background: CDK7 has 3 critical roles in cancer: enhanced transcription of oncogenes and upregulation of anti-apoptotic genes, acceleration of the cell cycle through phosphorylation of other CDKs and driving estrogen receptor (ER) resistance to hormonal therapy. Inhibition of CDK7 is therefore a potential novel anti-cancer therapeutic strategy. Samuraciclib (CT7001), a once daily oral CDK7 inhibitor has demonstrated a favorable safety profile and clinical activity in combination with fulvestrant (SERD) in patients with HR+/HER2- advanced breast cancer who have previously been treated with a CDK4/6 inhibitor [1]. Extended benefit was observed in patients with no TP53-mutation per circulating tumor DNA (ctDNA) analysis detectable at baseline. Limitations in the pharmacokinetic (PK) properties and route of administration (intramuscular only) of fulvestrant mean that oral alternatives are desirable. Recently, the EMERALD phase 3 study of the oral SERD elacestrant demonstrated a significant PFS benefit over standard of care endocrine treatment in the ER+/HER2- advanced or metastatic breast cancer population previously treated with a CDK4/6 inhibitor. [2]. Non-clinical data indicate that the underlying biology driving samuraciclib combination with endocrine therapy translates from fulvestrant to elacestrant, clinical evaluation is warranted [3]. This open-label Phase 1b dose escalation and Phase 2 dose expansion study will evaluate the safety, efficacy and pharmacokinetics of samuraciclib in combination with elacestrant. ctDNA analysis is informative for both elacestrant and samuraciclib, via ESR1-mutation status and TP53-mutation status respectively, and is an integral part of the study design. Trial Design: Eligible patients will provide written informed consent, be aged 18 years or older, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to resection or radiotherapy of curative intent, have received an aromatase inhibitor in combination with a CDK4/6 inhibitor in either the adjuvant or advanced setting, be receiving a luteinizing hormone-releasing hormone agonist if pre/perimenopausal and have RECIST v1.1 evaluable disease. Prior SERD, mammalian target of rapamycin inhibitor (mTORi) or chemotherapy for advanced breast cancer are not permitted. The study will enrol ~48 patients. All patients will undergo baseline Guardant360 ctDNA analysis to establish their ESR-1 and TP53-mutation status. Patients will undergo RECIST v1.1 evaluation at baseline every 8-weeks until week 48, followed by every 12-weeks thereafter. Initially both samuraciclib and elacestrant will be administered once daily in a dose escalation/de-escalation approach under supervision of the study Safety Review Committee. The primary endpoint in Phase 1b is the identification of tolerable combination dose levels for both samuraciclib and elacestrant and in Phase 2 expansion to quantify the progression free survival benefit of the combination. Secondary endpoints are tolerability, clinical benefit response at 24 weeks, overall response rate, duration of response, best percent change in tumor size, pharmacokinetics and correlations between ctDNA detectable ESR1 and TP53 mutations and efficacy/safety finding in this patient population. The study opened for recruitment in June 2023.

Preclinical Pharmacokinetics and Pharmacology Study of RC98: A Programmed Cell Death Ligand 1 Monoclonal Antibody in Cynomolgus Monkeys.

RC98 is the monoclonal antibody against Programmed Cell Death Ligand 1 (PD-L1). Relevant reports have confirmed that the influence of PD-L1 expressed by tumor cells on antitumor CD8+ T cell responses is well characterized, but the impact of PD-L1 expressed by immune cells has not been well defined. This study aimed to design a Pharmacokinetics/Pharmacology (PK/PD) study of RC98 in normal cynomolgus monkeys to research the effect on the immune system. RC98 and vehicle were administered to cynomolgus monkeys at 15 mg/kg via intravenous infusion once a week for 4 weeks to evaluate the relationship between PK and PD. The pharmacodynamic activity was measured by the PD-L1 receptor occupancy (RO) in CD3+ T cells, A T-cell-dependent antibody response (TDAR), and the concentration of soluble PD-L1. The pharmacokinetic result showed that the exposure from the last administration was lower than that of the first administration, probably due to immunogenicity production. There was a strong correlation between systemic exposure and RO in CD3+ T cells but decreased RO levels after the last dose, which indirectly reflected the activation of T cells. The keyhole limpet hemocyanin (KLH)-induced TDAR in the RC98 group was higher than in the vehicle group. The concentration of soluble PD-L1 had increased feedback with RC98, and the concentration of soluble PD-L1 was maintained at a higher level after multiple doses than before dosing. These data indicate that the immune system was clearly activated. In addition, the non-clinical data could provide a basis for its efficacy evaluation in clinical trials.