Multiple Doses Research Articles

Type 2 diabetes in latin America: recommendations on the flash glucose monitoring system

ObjectiveTo establish recommendations through the consensus of a Latin American experts panel on the use of the flash glucose monitoring system (fCGM) in people living with type 2 diabetes mellitus (T2DM) regarding the benefits and challenges of using the fCGM.MethodsAn executive committee of experts was created, comprised by a panel of fifteen physicians, including endocrinologists and internal medicine physicians, with expertise in management of adult patients with T2DM. The experts were from various countries: Colombia, Chile, Peru, Mexico, Argentina, and Brazil. The modified Delphi method was used, considering a consensus level of at least 80% of the participants. A seventeen-item instrument was developed to establish recommendations on the use of fCGM in patients with T2DM in Latin American.ResultsThe number of glucose scans recommended per day with the fCGM for patients managed with oral antidiabetic drugs or basal insulin was a median of 6 scans per day, and for those managed with multiple insulin doses, a median of 10 scans per day was recommended. Additionally, a holistic and individualized management approach was recommended, taking into account new treatment directions and identifying patients who would benefit from the use of the fCGM.ConclusionContinuous use of the fCGM is recommended for people living with T2DM, regardless of their type of treatment. These metrics must be evaluated individually for each patient profile.

Once-daily oral small-molecule glucagon-like peptide-1 receptor agonist lotiglipron (PF-07081532) for type 2 diabetes and obesity: Two randomized, placebo-controlled, multiple-ascending-dose Phase 1 studies.

To investigate the effects of lotiglipron (PF-07081532), a once-daily, oral small-molecule glucagon-like peptide-1 receptor agonist, in participants with type 2 diabetes (T2D) and/or obesity. Two Phase 1 randomized, double-blind, placebo-controlled, multiple-ascending-dose studies were conducted to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of lotiglipron. Across the studies, 74 participants with T2D were treated for 28 or 42 days, and 26 participants with obesity without diabetes were treated for 42 days, following randomization to placebo or lotiglipron (target doses 10-180 mg/day, with dose titration to higher target doses). Most adverse events were mild (89.6%), with nausea the most frequently reported in both studies. There were no clinically meaningful adverse trends noted in safety laboratory tests, vital signs, or electrocardiogram parameters. In participants with T2D, lotiglipron resulted in dose-dependent reductions in mean daily glucose. The 180-mg dose was associated with least squares mean decreases from baseline in glycated haemoglobin (-1.61% [90% confidence interval {CI} -2.08, -1.14] vs. -0.61% [-1.56, 0.34] for placebo) and body weight (-5.10 kg [90% CI -6.62, -3.58] vs. -2.06 kg [90% CI -4.47, 0.36] for placebo) after 42 days; a similar magnitude of weight loss was seen in participants with obesity. The observed pharmacokinetic profile supported once-daily dosing. The profile of once-daily lotiglipron with doses up to 180 mg, as observed in these two Phase 1 studies, indicated a safety and tolerability profile consistent with the mechanism of action, with dose-dependent reductions in glycaemic indices (T2D) and body weight (both populations) after multiple doses. gov identifier: NCT04305587, NCT05158244.

Design and sample size determination for multiple-dose randomized phase II trials for dose optimization.

The U.S. Food and Drug Administration (FDA) has launched Project Optimus to shift dose selection from the maximum tolerated dose (MTD) to the dose that produces the optimal risk-benefit tradeoff. One approach highlighted in the FDA's guidance involves conducting a randomized phase II trial following the completion of a phase I trial, where multiple doses (typically including the MTD and one or two doses lower than the MTD) are compared to identify the optimal dose that maximizes the benefit-risk tradeoff. This article focuses on the design of such a multiple-dose randomized trial, specifically the determination of the sample size. We generalized the standard definitions of type I error and power to accommodate the unique characteristics of dose optimization and derived a decision rule along with an algorithm to determine the optimal sample size. The resulting design is referred to as MERIT (Multiple-dosE RandomIzed Trial design for dose optimization based on toxicity and efficacy). Simulation studies demonstrate that MERIT has desirable operating characteristics, and a sample size between 20 and 40 per dosage arm often offers reasonable power and type I errors to ensure patient safety and benefit. To facilitate the implementation of the MERIT design, we provide software, available at https://www.trialdesign.org.

Senolytic effects of exercise in human muscles require acute inflammation.

Higher intensity exercise, despite causing more tissue damage, improved aging conditions. We previously observed decreased p16INK4a mRNA in human skeletal muscle after high-intensity interval exercise (HIIE), with no change following equivalent work in moderate-intensity continuous exercise. This raises the question of whether the observed senolytic effect of exercise is mediated by inflammation, an immune response induced by muscle damage. In this study, inflammation was blocked using a multiple dose of ibuprofen (total dose: 1200 mg), a commonly consumed nonsteroidal anti-inflammatory drug (NSAID), in a placebo-controlled, counterbalanced crossover trial. Twelve men aged 20-26 consumed ibuprofen or placebo before and after HIIE at 120% maximum aerobic power. Multiple muscle biopsies were taken for tissue analysis before and after HIIE. p16INK4a+ cells were located surrounding myofibers in muscle tissues. The maximum decrease in p16INK4a mRNA levels within muscle tissues occurred at 3 h post-exercise (-82%, p < 0.01), gradually recovering over the next 3-24 h. A concurrent reduction pattern in CD11b mRNA (-87%, p < 0.01) was also found within the same time frame. Ibuprofen treatment attenuated the post-exercise reduction in both p16INK4a mRNA and CD11b mRNA. The strong correlation (r = 0.88, p < 0.01) between p16INK4a mRNA and CD11b mRNA in muscle tissues suggests a connection between the markers of tissue aging and pro-inflammatory myeloid differentiation. In conclusion, our results suggest that the senolytic effect of high-intensity exercise on human skeletal muscle is mediated by acute inflammation.

COVID-19 vaccine fatigue in Scotland: how do the trends in attrition rates for the second and third doses differ by age, sex, and council area?

Abstract Vaccine fatigue is the propensity for individuals to start but not finish a vaccination program with several doses, which means they are less protected. Our study examines vaccine fatigue in the COVID-19 vaccination programme in Scotland. We model the attrition rates across multiple doses with a hierarchical binomial logistic regression model with correlated age- and area-specific random effects with conditional autoregressive priors, where inference uses integrated nested Laplace approximations. We find attrition rates smoothly decrease with increasing age, are much higher for the third dose than the second, and are generally higher for males than females.

History of Rectal Product Use and Country of Residence Influence Preference for Rectal Microbicide Dosage Forms Among Young Sexual and Gender Minorities: A Multi-country Trial Comparing Placebo Douche, Suppository, and Insert Products.

The DESIRE Study (MTN-035) explored product preference among three placebo rectal microbicide (RM) formulations, a rectal douche(RD), a suppository, and an insert, among 210 sexually active transgender people and men who have sex with men in five counties: the United States, Peru, Thailand, South Africa, and Malawi. Participants used each product prior to receptive anal sex (RAS) for 1month, following a randomly assigned sequence, then selected their preferred product via computer assisted self-interview. In-depth interviews examined reasons for preference. We compared product preference and prior product use by country to explore whether geographic location and experience with the similar products impacted preference. A majority in the United States (56%) and Peru (58%) and nearly half in South Africa (48%) preferred the douche. Most in Malawi (59%) preferred the suppository, while half in Thailand (50%) and nearly half in South Africa (47%) preferred the insert. Participants who preferred the douche described it as quick and easy, already routinized, and serving a dual purpose of cleansing and protecting. Those who preferred the insert found it small, portable, discreet, with quick dissolution. Those who preferred the suppository found the size and shape acceptable and liked the added lubrication it provided. Experience with product use varied by country. Participants with RD experience were significantly more likely to prefer the douche (p = 0.03). Diversifying availability of multiple RM dosage forms can increase uptake and improve HIV prevention efforts globally.

Effect on the splenocyte function of weaned piglets induced by continuous lipopolysaccharide injections

Abstract Introduction When piglets are exposed to pathogens for a long period, the immune system organs, among them the spleen, play a major role in combating the stress caused by those pathogens. In the present study, the effect on splenocyte function was investigated in a model of weaned piglets in which stress was induced by multiple low doses of lipopolysaccharide (LPS). Material and Methods Forty-eight 28-day-old piglets were divided into two groups: the LPS group and the control group. During the experimental period of thirteen days, the LPS group was intraperitoneally injected with LPS (100 μg/kg) once per day, and the control group was injected with the same volume of 0.9% sterile saline. On the 1st, 5th, 9th and 13th days, the piglets’ spleens were collected for isolating splenocytes. The proliferation ability of splenocytes was evaluated by the cell-counting-kit 8 method. Flow cytometry was used to detect cell cycle stage and apoptosis, and the nitric oxide level of cell supernatant was also tested. Results In the experimental group, the proliferation ability of splenocytes was enhanced, the proportion of cells in the G0/G1 phase was smaller, and cells were promoted to the S and G2/M phases. Meanwhile, apoptosis was suppressed and nitric oxide release upregulated. The results were significantly different between the LPS group and the control group on the 5th and 9th days. Conclusion The difference between the results of one group and those of the other suggest that after the 5th LPS injection, multiple low doses of LPS activated splenocytes and restored the number of splenocytes, which maintained and possibly enhanced the regulation of the immune function of the spleen.

Pilot PET study of vaginally administered bioadhesive nanoparticles in cynomolgus monkeys: Kinetics and safety evaluation

AbstractLong‐lasting vaginal dosage forms could improve the therapeutic efficacy of vaginal microbicides, but achieving long‐term delivery to the vaginal canal has been a significant challenge. To advance understanding of vaginal dosage retention and biodistribution, we describe a method of noninvasive imaging with 89Zr‐labeled bioadhesive nanoparticles (BNPs) in non‐human primates. We additionally examined the safety of repeated BNP application. BNPs administered vaginally to cynomolgus monkeys were still detected after 24 h (1.7% retention) and 120 h (0.1% retention). BNPs did not translocate to the uterus or into systemic circulation. Analysis of inflammatory biomarkers in the vaginal fluid and plasma suggest that BNPs are safe and biocompatible, even after multiple doses. BNPs are a promising delivery vehicle for vaginally administered therapeutics. Further studies using the non‐human primate imaging materials and methods developed here could help advance clinical translation of BNPs and other long‐lasting vaginal dosage forms.

A Post-Marketing Surveillance Study of Nusinersen for Spinal Muscular Atrophy in Routine Medical Practice in China: Interim Results.

Spinal muscular atrophy (SMA) is a rare, autosomal recessive, neuromuscular disease that leads to progressive muscular weakness and atrophy. Nusinersen, an antisense oligonucleotide, was approved for SMA in China in February 2019. We report interim results from a post-marketing surveillance phase 4 study, PANDA (NCT04419233), that collects data on the safety, efficacy, and pharmacokinetics of nusinersen in children with SMA in routine clinical practice in China. Participants enrolled in PANDA will be observed for 2years following nusinersen treatment initiation. The primary endpoint is the incidence of adverse events (AEs)/serious AEs (SAEs) during the treatment period. Efficacy assessments include World Health Organization (WHO) Motor Milestones assessment, the Hammersmith Infant Neurological Examination (HINE), and ventilation support. Plasma and cerebrospinal fluid (CSF) concentrations of nusinersen are measured at each dose visit. Fifty participants were enrolled as of the January 4, 2023, data cutoff: 10 with infantile-onset (≤ 6months) and 40 with later-onset (> 6months) SMA. All 50 participants have received at least one dose of nusinersen; 6 have completed the study. AEs were experienced by 45 (90%) participants and were mostly mild/moderate; no AEs led to nusinersen discontinuation or study withdrawal. Eleven participants experienced SAEs, most commonly pneumonia (n = 9); none were considered related to study treatment. Stability or gain of WHO motor milestone was observed and mean HINE-2 scores improved in both subgroups throughout the study. No serious respiratory events occurred,and no permanent ventilation support was initiated during the study. Pre-dose nusinersen CSF concentrations increased steadily through the loading-dose period, with no accumulation in plasma after multiple doses. Nusinersen was generally well tolerated with an acceptable overall safety profile, consistent with the known safety of nusinersen. Efficacy, safety, and nusinersen exposure are consistent with prior observations. These results support continuing PANDA and evaluation of nusinersen in Chinese participants with SMA. ClinicalTrials.gov identifier, NCT04419233.

Metabolite correlation permutation after mice acute exposure to PM2.5: Holistic exploration of toxicometabolomics by network analysis

Many environmental toxicants can cause systemic effects, such as fine particulate matter (PM2.5), which can penetrate the respiratory barrier and induce effects in multiple tissues. Although metabolomics has been used to identify biomarkers for PM2.5, its multi-tissue toxicology has not yet been explored holistically. Our objective is to explore PM2.5 induced metabolic alterations and unveil the intra-tissue responses along with inter-tissue communicational effects. In this study, following a single intratracheal instillation of multiple doses (0, 25, and 150 μg as the control, low, and high dose), non-targeted metabolomics was employed to evaluate the metabolic impact of PM2.5 across multiple tissues. PM2.5 induced tissue-specific and dose-dependent disturbances of metabolites and their pathways. The remarkable increase of both intra- and inter-tissue correlations was observed, with emphasis on the metabolism connectivity among lung, spleen, and heart; the tissues’ functional specificity has marked their toxic modes. Beyond the inter-status comparison of the metabolite fold-changes, the current correlation network built on intra-status can offer additional insights into how the multiple tissues and their metabolites coordinately change in response to external stimuli such as PM2.5 exposure.

Automated synthesis of [89Zr]ZrCl4, [89Zr]ZrDFOSquaramide-bisPh(PSMA) and [89Zr]ZrDFOSquaramide-TATE

BackgroundAutomated [89Zr]Zr-radiolabeling processes have the potential to streamline the production of [89Zr]Zr-labelled PET imaging agents. Most radiolabeling protocols use [89Zr][Zr(ox)4]4− as the starting material and oxalate is removed after radiolabeling. In some instances, radiolabeling with [89Zr]ZrCl4 as starting material gives better radiochemical yields at lower reaction temperatures. In this work, a fully-automated process for production of [89Zr]ZrCl4 is reported and its use for the synthesis of [89Zr]ZrDFOSq-bisPhPSMA and [89Zr]ZrDFOSq-TATE.ResultsA simple automated process for the isolation of [89Zr]ZrCl4 by trapping [89Zr][Zr(ox)4]4− on a bicarbonate-activated strong anion exchange cartridge followed by elution with 0.1 M HCl in 1 M NaCl was developed. [89Zr]ZrCl4 was routinely recovered from [89Zr][Zr(ox)4]4− in > 95% yield in mildly acidic solution of 0.1 M HCl in 1 M NaCl using a fully-automated process. The [89Zr]ZrCl4 was neutralized with sodium acetate buffer (0.25 M) removing the requirement for cumbersome manual neutralization with strong base. The mixture of [89Zr]ZrCl4 was used for direct automated radiolabeling reactions to produce [89Zr]Zr-DFOSquaramide-bisPhPSMA and [89Zr]ZrDFOSquaramide-TATE in 80–90% over all RCY in > 95% RCP.ConclusionsThis method for the production of [89Zr]ZrCl4 does not require removal of HCl by evaporation making this process relatively fast and efficient. The fully automated procedures for the production of [89Zr]ZrCl4 and its use in radiolabeling are well suited to support the centralized and standardized manufacture of multiple dose preparations of zirconium-89 based radiopharmaceuticals.

In Vitro In Vivo Extrapolation and Bioequivalence Prediction for Immediate-Release Capsules of Cefadroxil Based on a Physiologically-Based Pharmacokinetic ACAT Model.

Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic concept, which helps to judge the effects of biopharmceutical properties of drug product such as in vitro dissolution on its pharmacokinetic and in vivo performance. With the application of virtual bioequivalence (VBE) study, the drug product development using model-based approach can help in evaluating the possibility of extending BCS-based biowaiver. Therefore, the current study was intended to develop PBPK model as well as in vitro in vivo extrapolation (IVIVE) for BCS class III drug i.e. cefadroxil.A PBPK model was created in GastroPlus™ 9.8.3 utilizing clinical data of immediate-release cefadroxil formulations. By the examination of simulated and observed plasma drug concentration profiles, the predictability of the proposed model was assessed for the prediction errors. Furthermore, mechanistic deconvolution was used to create IVIVE, and the plasma drug concentration profiles and pharmacokinetic parameters were predicted for different virtual formulations with variable cefadroxil in vitro release. Virtual bioequivalence study was also executed to assess the bioequivalence of the generic verses the reference drug product (Duricef®).The developed PBPK model satisfactorily predicted Cmax and AUC0-t after cefadroxil single and multiple oral dose administrations, with all individual prediction errors within the limits except in a few cases. Second order polynomial correlation function obtained accurately predict in vivo drug release and plasma concentration profile of cefadroxil test and reference (Duricef®) formulation. The VBE study also proved test formulation bioequivalent to reference formulation and the statistical analysis on pharmacokinetic parameters reported 90% confidence interval for Cmax and AUC0-t in the FDA acceptable limits.The analysis found that a validated and verified PBPK model with a mechanistic background is as a suitable approach to accelerate generic drug development.

Impact of interventions to reduce nosocomial transmission of SARS-CoV-2 in English NHS Trusts: a computational modelling study

BackgroundPrior to September 2021, 55,000–90,000 hospital inpatients in England were identified as having a potentially nosocomial SARS-CoV-2 infection. This includes cases that were likely missed due to pauci- or asymptomatic infection. Further, high numbers of healthcare workers (HCWs) are thought to have been infected, and there is evidence that some of these cases may also have been nosocomially linked, with both HCW to HCW and patient to HCW transmission being reported. From the start of the SARS-CoV-2 pandemic interventions in hospitals such as testing patients on admission and universal mask wearing were introduced to stop spread within and between patient and HCW populations, the effectiveness of which are largely unknown.Materials/methodsUsing an individual-based model of within-hospital transmission, we estimated the contribution of individual interventions (together and in combination) to the effectiveness of the overall package of interventions implemented in English hospitals during the COVID-19 pandemic. A panel of experts in infection prevention and control informed intervention choice and helped ensure the model reflected implementation in practice. Model parameters and associated uncertainty were derived using national and local data, literature review and formal elicitation of expert opinion. We simulated scenarios to explore how many nosocomial infections might have been seen in patients and HCWs if interventions had not been implemented. We simulated the time period from March-2020 to July-2022 encompassing different strains and multiple doses of vaccination.ResultsModelling results suggest that in a scenario without inpatient testing, infection prevention and control measures, and reductions in occupancy and visitors, the number of patients developing a nosocomial SARS-CoV-2 infection could have been twice as high over the course of the pandemic, and over 600,000 HCWs could have been infected in the first wave alone. Isolation of symptomatic HCWs and universal masking by HCWs were the most effective interventions for preventing infections in both patient and HCW populations. Model findings suggest that collectively the interventions introduced over the SARS-CoV-2 pandemic in England averted 400,000 (240,000 – 500,000) infections in inpatients and 410,000 (370,000 – 450,000) HCW infections.ConclusionsInterventions to reduce the spread of nosocomial infections have varying impact, but the package of interventions implemented in England significantly reduced nosocomial transmission to both patients and HCWs over the SARS-CoV-2 pandemic.

Neurological Presentation of Lead Toxicity: A Case Report

Acute encephalopathy, caused by infectious agents, metabolic or mitochondrial dysfunction, brain tumor, or prolonged exposure to toxic elements, is a significant cause of morbidity and mortality in young children. Lead encephalopathy that occurs due to prolonged lead ingestion or exposure in children is not uncommon, and many such cases have been reported in the past. This report shares the authors’ experience of the missed diagnosis of lead encephalopathy, its red flags, and its relation to pica as a root cause. A 14-month-old boy, resident of Delhi, India, was admitted with vomiting, irritability, and two episodes of abnormal limb movements, with the first symptom starting when he was 11 months old. His case was initially treated as acute disseminated encephalomyelitis, but he showed no improvement. The child was then referred to the Sir Ganga Ram Hospital, New Delhi, India. The boy presented with severe anemia, along with basophilic stippling on the peripheral smear during routine investigations. Suspecting lead poisoning, blood lead levels were checked, and were found to be grossly elevated. The child was then started on chelation therapy. Multiple doses of chelation (dimercaprol and D-penicillamine) were given, and sequential blood lead levels were monitored, which showed a marked decrement. The child was discharged, and is being monitored routinely. Lead poisoning remains a neglected public health issue, especially in children, and delay in identification can cause significant morbidity and mortality. Pediatricians and general practitioners must be aware of this risk, especially in children with iron deficiency anemia exhibiting pica.

Multiple dosing of immediate-release hydrocortisone is associated with a greater risk of hypothalamic-pituitary-adrenal axis suppression when compared to low-dose prednisolone when weaning in steroid-induced adrenal insufficiency

Multiple dosing of immediate-release hydrocortisone is associated with a greater risk of hypothalamic-pituitary-adrenal axis suppression when compared to low-dose prednisolone when weaning in steroid-induced adrenal insufficiency

Ototoxicity: a high risk to auditory function that needs to be monitored in drug development.

Hearing loss constitutes a major global health concern impacting approximately 1.5 billion people worldwide. Its incidence is undergoing a substantial surge with some projecting that by 2050, a quarter of the global population will experience varying degrees of hearing deficiency. Environmental factors such as aging, exposure to loud noise, and the intake of ototoxic medications are implicated in the onset of acquired hearing loss. Ototoxicity resulting in inner ear damage is a leading cause of acquired hearing loss worldwide. This could be minimized or avoided by early testing of hearing functions in the preclinical phase of drug development. While the assessment of ototoxicity is well defined for drug candidates in the hearing field - required for drugs that are administered by the otic route and expected to reach the middle or inner ear during clinical use - ototoxicity testing is not required for all other therapeutic areas. Unfortunately, this has resulted in more than 200 ototoxic marketed medications. The aim of this publication is to raise awareness of drug-induced ototoxicity and to formulate some recommendations based on available guidelines and own experience. Ototoxicity testing programs should be adapted to the type of therapy, its indication (targeting the ear or part of other medications classes being potentially ototoxic), and the number of assets to test. For multiple molecules and/or multiple doses, screening options are available: in vitro (otic cell assays), ex vivo (cochlear explant), and in vivo (in zebrafish). In assessing the ototoxicity of a candidate drug, it is good practice to compare its ototoxicity to that of a well-known control drug of a similar class. Screening assays provide a streamlined and rapid method to know whether a drug is generally safe for inner ear structures. Mammalian animal models provide a more detailed characterization of drug ototoxicity, with a possibility to localize and quantify the damage using functional, behavioral, and morphological read-outs. Complementary histological measures are routinely conducted notably to quantify hair cells loss with cochleogram. Ototoxicity studies can be performed in rodents (mice, rats), guinea pigs and large species. However, in undertaking, or at the very least attempting, all preclinical investigations within the same species, is crucial. This encompasses starting with pharmacokinetics and pharmacology efficacy studies and extending through to toxicity studies. In life read-outs include Auditory Brainstem Response (ABR) and Distortion Product OtoAcoustic Emissions (DPOAE) measurements that assess the activity and integrity of sensory cells and the auditory nerve, reflecting sensorineural hearing loss. Accurate, reproducible, and high throughput ABR measures are fundamental to the quality and success of these preclinical trials. As in humans, in vivo otoscopic evaluations are routinely carried out to observe the tympanic membrane and auditory canal. This is often done to detect signs of inflammation. The cochlea is a tonotopic structure. Hair cell responsiveness is position and frequency dependent, with hair cells located close to the cochlea apex transducing low frequencies and those at the base transducing high frequencies. The cochleogram aims to quantify hair cells all along the cochlea and consequently determine hair cell loss related to specific frequencies. This measure is then correlated with the ABR & DPOAE results. Ototoxicity assessments evaluate the impact of drug candidates on the auditory and vestibular systems, de-risk hearing loss and balance disorders, define a safe dose, and optimize therapeutic benefits. These types of studies can be initiated during early development of a therapeutic solution, with ABR and otoscopic evaluations. Depending on the mechanism of action of the compound, studies can include DPOAE and cochleogram. Later in the development, a GLP (Good Laboratory Practice) ototoxicity study may be required based on otic related route of administration, target, or known potential otic toxicity.

Abstract PO3-19-07: AC699-001, a first in human Phase 1 trial utilizing a novel estrogen receptor chimeric degrader in patients with advanced or metastatic breast cancer

Abstract Background Estrogen receptors (ER) are hormone-regulated transcription factors that play a critical role in breast cancer initiation and proliferation. Modulation of estrogen activity with therapeutics such as tamoxifen and aromatase inhibitors have been the mainstay therapeutic strategy for ER-positive breast cancer. Several ER-directed therapies have been developed to antagonize the oncogenic ER function, including Selective ER Degraders (SERDs) such as fulvestrant which is approved to treat patients with advanced or metastatic breast cancer. However, it requires intramuscular injection and has poor solubility, thereby limiting its administered dose and therefore its efficacy. In addition to SERDs, a newly emerging technology, E3 ligase-engaged chimeric degraders, has been used to induce potent and deeper ER degradation. Empowered by Accutar's proprietary Protein-Protein Interaction Targeting Chimeras (PPI-TAC) platform, AC699 was meticulously designed as a chimeric degrader to target and degrade the protein of interest, ERα. By effectively linking an ER ligand to an E3-ligase recruiting ligand, AC699 brings ERα in proximity to an E3 ligase, thereby inducing subsequent ubiquitination and degradation of ERα. Notably, chimeric ER degraders possess the unique advantage of degrading the ER protein without the inherent risk of activating an ER signal. Moreover, these molecules are not degraded alongside the target protein allowing for their efficient recycling within the cell. This direct mechanism enables chimeric ER degraders to achieve potent ER degradation with increased specificity, thereby potentially providing a higher therapeutic index compared to SERDs. This abstract describes a first-in-human Phase 1 trial of AC699, a novel ER degrader. Study Description The AC699-001 Phase 1 dose escalation study will enroll up to 60 patients with locally advanced or metastatic ER-positive, human epidermal growth factor receptor 2-negative, breast cancer. Patients must have progressed on standard treatment including at least two prior endocrine regimens or at least one prior line of therapy if combined with a CDK4/6 inhibitor. Prior chemotherapy is not required but must not exceed three prior cytotoxic regimens. Patients must have at least one measurable lesion or at least one predominantly lytic bone lesion. AC699 is given orally, once daily, with doses ranging from 100 mg to 600 mg in a standard 3+3 dose escalation design. The primary objective is to evaluate the safety and tolerability of AC699 using CTCAE 5.0. Secondary objectives include assessing preliminary anti-tumor activity according to RECIST 1.1 and characterizing the pharmacokinetic profile of single and multiple doses of AC699. Enrollment began in December 2022 with five sites in the United States planned. NCT05654532. Citation Format: Manish R Patel, Rachel Layman, Joy Nolte Fong, Hui Zhang, Su Kim, Erika Hamilton. AC699-001, a first in human Phase 1 trial utilizing a novel estrogen receptor chimeric degrader in patients with advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-19-07.

Abstract RF01-01: SERENA-3: A randomized pre-surgical window of opportunity study assessing dose and duration of camizestrant treatment in post-menopausal women with ER-positive, HER2-negative primary breast cancer

Abstract Background Camizestrant, a next-generation oral selective estrogen receptor (ER) degrader (SERD) and pure ER antagonist, has demonstrated statistically significant and clinically meaningful progression-free survival (PFS) benefit over fulvestrant at both 75 and 150 mg once-daily doses in the Phase 2 SERENA-2 (NCT04214288) study in post-menopausal women with ER+ HER2- advanced breast cancer. SERENA-3 (NCT04588298) was established to explore the biological effects of three camizestrant dose levels in post-menopausal women with ER+ HER2- primary breast cancer. Methods Post-menopausal women with ER+ HER2- primary breast cancer scheduled to undergo curative intent surgery were randomly assigned in Stages 1 and 2 to pre-surgical treatment with camizestrant at 75, 150 or 300 mg once daily for 5 to 7 days or, in a sequential Stage 3, randomly assigned to camizestrant at 75 or 150 mg once daily for 12 to 15 days. Image-guided tumor biopsies were accessed as pre-treatment samples, while on-treatment ultrasound-guided tumor biopsies were obtained on the last day of camizestrant treatment. The primary objective was to explore the effect of camizestrant on ER expression by comparison of pre-treatment and on-treatment biopsies as assessed by immunohistochemistry (IHC) H-score. Secondary objectives included assessment of Ki67 and progesterone receptor (PgR) expression, and also of safety and tolerability, with exploratory pharmacodynamic (PD) assessment using other transcriptomic and proteomic technologies. The study was undertaken in 17 centers across 3 countries (Georgia, Mexico and the United Kingdom). Results 135 patients were randomized and received treatment. 76 patients received camizestrant for 5 to 7 days at doses of 75 mg (n=30), 150 mg (n=33), and 300 mg (n=13); 59 received camizestrant for 12 to 15 days at doses of 75 mg (n=30) and 150 mg (n=29). Baseline disease characteristics, and ER, Ki67 and PgR levels were well balanced across arms and stages. Pharmacokinetic (PK) observations in all stages were commensurate with steady-state predictions derived from previous studies. PD data for ER and Ki67 are shown in Table 1. Camizestrant reduced ER H-score by approximately 65% irrespective of dose or duration. While the 75 mg dose reduced Ki67 score to a lesser degree than 150 mg and 300mg after 5–7 days exposure, after 12–15 days exposure 75 and 150 mg reduced Ki76 score to a similar substantial degree (82% reduction). PD results assessed by additional transcriptomics and proteomics assays were concordant with the IHC analyses. No serious adverse events were reported. All treatment-emergent adverse events were grade 1, apart from one patient with a grade 2 visual impairment, and one patient with grade 3 diarrhea. Conclusions SERENA-3 is the first study investigating the effect of multiple dose levels of camizestrant with different treatment durations on ER, Ki67 and PgR expression in post-menopausal women with primary ER+ HER2˗ breast cancer. SERENA-3 demonstrated that the 75 mg dose of camizestrant achieves maximal levels of ER degradation and Ki67 suppression. Together with SERENA-2, this provides strong evidence supporting 75 mg as the optimal dose of camizestrant, including for the early disease setting, and highlights the additive value of a specifically designed multi-dose pre-surgical PD study for optimal dose selection. Table 1 Citation Format: John Robertson, Teimuraz Gogitidze, Zaza Katashvili, Juan Enrique Bargallo Rocha, Ekaterine Arkania, Iain Moppett, Kwok-Leung Cheung, Gia Nemsadze, Maxine Ajimi, Itziar Irurzun-Arana, Justin Lindemann, Teresa Klinowska, Alastair Mathewson, Christopher Morrow, Myria Nikolaou, Giorgi Dzagnidze. SERENA-3: A randomized pre-surgical window of opportunity study assessing dose and duration of camizestrant treatment in post-menopausal women with ER-positive, HER2-negative primary breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF01-01.

Abstract PO4-18-11: Phase 1 study of the tissue factor-targeting antibody-drug conjugate XB002 in patients with advanced solid tumors (JEWEL-101): Design of the triple-negative and hormone receptor-positive breast cancer expansion cohorts

Abstract Background: Tissue factor (TF) is a transmembrane protein that functions as a factor VIIa receptor, initiating the extrinsic coagulation cascade. TF is aberrantly expressed in multiple solid tumors, including breast cancer (BC), and its expression is associated with disease progression and poor prognosis (van den Berg et al. Blood 2012). Microtubule-targeting agents are a cornerstone of treatment for metastatic BC. XB002 is a novel antibody-drug conjugate (ADC) composed of a high-affinity TF-directed human monoclonal antibody conjugated to the zovodotin linker-payload. Zovodotin consists of an auristatin-based payload and a protease-cleavable linker and is designed to lower off-target deconjugation and improve tolerability compared with other microtubule inhibitor linker-payloads. In preclinical studies, XB002 did not interfere with coagulation and demonstrated antitumor activity with an encouraging safety profile. XB002 is being evaluated in JEWEL-101, an ongoing trial in patients (pts) with advanced solid tumors, including BC. Preliminary results from the dose-escalation stage of JEWEL-101 showed XB002 was well tolerated at multiple dose levels with no bleeding events or treatment-related peripheral neuropathy (PN) and low-grade ocular toxicity (Ulahannan et al. ENA 2022). Presented here is the study design of the tumor-specific expansion stage, including triple-negative BC (TNBC) and hormone receptor-positive BC (HR+ BC) cohorts. Trial design and statistical methods: JEWEL-101 (NCT04925284) is a multicenter, open-label, phase 1 trial evaluating the safety, tolerability, pharmacokinetics (PK), and antitumor activity of XB002 in advanced solid tumors. Single-agent XB002 at the recommended dose will be assessed in the BC expansion cohorts utilizing Simon’s Two-Stage design. Eligibility criteria: The trial will enroll adult pts with TNBC (ER-/PR-/HER-2-negative or low) and HR+ BC (ER+ and/or PR+ and HER-2-negative or low) into 2 separate cohorts. HER-2 negativity is defined as either HER-2 negative or low by local ISH or IHC assessment. For both cohorts, pts must have received 1–3 lines of prior systemic anticancer therapies for locally advanced or metastatic disease. Pts in the HR+ BC cohort must have received prior endocrine therapy and CDK4/6 inhibitor. All pts must have cytologically or histologically and radiologically confirmed BC that is inoperable, locally advanced, metastatic, or recurrent. Documented radiographic progression during or following their last systemic anticancer therapy is required. All pts must also have measurable disease per RECIST 1.1 by investigator assessment, archival (&amp;lt; 2 years) or fresh tumor tissue, ECOG PS 0 or 1, and adequate organ and marrow function. Pts with grade 1 PN are allowed. Concomitant anticoagulation therapy while receiving XB002 is permitted if clinically indicated. Key exclusions are prior use of TF-targeting or auristatin derivate-based ADC; uncontrolled, significant intercurrent or recent illness, including acute or chronic significant ocular disorders; major surgery within 4 weeks; and corrected QT interval calculated by the Fridericia formula &amp;gt;480 ms per ECG. Specific aims: The primary objective of the expansion stage is to evaluate the preliminary efficacy of XB002 by estimating the objective response rate per RECIST 1.1 as assessed by the investigator. Secondary objectives include safety and tolerability, PK, immunogenicity, progression-free survival, duration of response, and overall survival. Accrual: Up to 28 pts will be enrolled into each BC cohort. Enrollment is planned across sites in the US, Europe, and Asia-Pacific. Contact information: Exelixis Clinical Trials, druginfo@exelixis.com, 1-888-393-5494 Citation Format: Susanna Ulahannan, Melissa Johnson, Mia Weiss, Andrae Vandross, Sofia Vidal-Cardenas, Mustafa Syed, Anthony Tolcher. Phase 1 study of the tissue factor-targeting antibody-drug conjugate XB002 in patients with advanced solid tumors (JEWEL-101): Design of the triple-negative and hormone receptor-positive breast cancer expansion cohorts [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-18-11.

Safety, tolerability, and pharmacokinetics of single- and multiple-ascending doses of olamkicept: Results from randomized, placebo-controlled, first-in-human phase I trials.

Olamkicept selectively inhibits the cytokine interleukin-6 (IL-6) trans-signaling pathway without blocking the classic pathway and is a promising immunoregulatory therapy for inflammatory bowel disease (IBD). These first-in-human, randomized, placebo-controlled, single- (SAD) and multiple-ascending dose (MAD) trials evaluated olamkicept safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics. Doses tested in the SAD trial included seven single intravenous doses (0.75, 7.5, 75, 150, 300, 600, and 750 mg) and one subcutaneous (SC) dose (60 mg) given to healthy subjects (N = 64), and three intravenous doses (75 mg, 300 mg, and 750 mg) given to patients with Crohn's disease (CD; N = 24). Doses tested in the MAD trial included multiple intravenous doses (75, 300, and 600 mg once weekly for 4 weeks) given to healthy subjects (N = 24). No severe or serious treatment-emergent adverse events (TEAEs) were recorded. The most common TEAEs were headache, nasopharyngitis, and myalgia in the SAD trial, and diarrhea, headache, and cough in the MAD trial. Infusion-related reactions occurred in one and two subjects in the SAD and MAD trial, respectively, leading to treatment discontinuation in the MAD trial. Olamkicept showed dose-independent pharmacokinetics after single and multiple administrations, and there was no major difference in systemic exposure between healthy subjects and patients with CD. Complete target engagement (inhibition of phosphorylation of signal transducer and activator of transcription-3) was achieved in blood around or above olamkicept serum concentrations of 1-5 μg/mL. Overall, these results suggest that olamkicept is safe and well-tolerated in healthy subjects and patients with CD after single intravenous/SC and multiple intravenous administrations.