A phase 1/2 study of pepinemab in children, adolescents, or young adults with recurrent or refractory solid tumors: A children's oncology group consortium report (ADVL1614).

PURPOSE: Pepinemab, a humanized IgG4 monoclonal antibody, targets the SEMA4D (CD100) antigen to inhibit binding to its high-affinity receptors (plexin B1/PLXNB1, plexin B2/PLXNB2) and low-affinity receptor (CD72). SEMA4D blockade leads to increased cytotoxic T-cell infiltration, delayed tumor growth, and durable tumor rejection in murine tumor models. Pepinemab was well tolerated and improved T cell infiltration in clinical studies in adults with refractory tumors. SEMA4D was identified as a strong candidate proto-oncogene in a model of osteosarcoma. Based on these preclinical and clinical data, we conducted a phase 1/2 study to determine the recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics, and immunogenicity, of pepinemab in pediatric patients with recurrent/refractory solid tumors, and activity in osteosarcoma. EXPERIMENTAL DESIGN: Pepinemab was administered intravenously on Days 1 and 15 of a 28-day cycle at 20 mg/kg, the adult RP2D. Part A (phase 1) used a Rolling 6 design; Part B (phase 2) used a Simon 2-stage design in patients with osteosarcoma. Pharmacokinetics and target saturation were evaluated in peripheral blood. RESULTS: Pepinemab (20 mg/kg) was well tolerated and no dose-limiting toxicities were observed during Part A. There were no objective responses. Two patients with osteosarcoma achieved disease control and prolonged stable disease. Pepinemab pharmacokinetics were similar to adults. CONCLUSIONS: Pepinemab (20 mg/kg) is safe, well tolerated and resulted in adequate and sustained target saturation in pediatric patients. Encouraging disease control in two patients with osteosarcoma warrants further investigation with novel combination strategies to modulate the tumor microenvironment and antitumor immune response. CLINICAL TRIAL REGISTRY: This trial is registered as NCT03320330 at Clinicaltrials.gov. DISCLAIMER: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Clinical dose rationale of tislelizumab in patients with solid or hematological advanced tumors.

Tislelizumab, an anti-programmed cell death protein 1 monoclonal antibody, has demonstrated improved survival benefits over standard of care for multiple cancer indications. We present the clinical rationale and data supporting tislelizumab dose recommendation in patients with advanced tumors. The phase I, first-in-human, dose-finding BGB-A317-001 study (data cutoff [DCO]: August 2017) examined the following tislelizumab dosing regimens: 0.5-10 mg/kg every 2 weeks (q2w), 2-5 mg/kg q2w or q3w, and 200 mg q3w. Similar objective response rates (ORRs) were reported in the 2 and 5 mg/kg q2w or q3w cohorts. Safety outcomes (grade ≥3 adverse events [AEs], AEs leading to dose modification/discontinuation, immune-mediated AEs, and infusion-related reactions) were generally comparable across the dosing range examined. These results, alongside the convenience of a fixed q3w dose, formed the basis of choosing 200 mg q3w as the recommended dosing regimen for further clinical use. Pooled exposure-response (E-R) analyses by logistic regression using data from study BGB-A317-001 (DCO: August 2020) and three additional phase I/II studies (DCOs: 2018-2020) showed no statistically significant correlation between tislelizumab pharmacokinetic exposure and ORR across multiple solid tumor types or classical Hodgkin's lymphoma, nor was exposure associated with any of the safety end points evaluated over the dose range tested. Hence, tislelizumab showed a relatively flat E-R relationship. Overall, the totality of data, including efficacy, safety, and E-R analyses, together with the relative convenience of a fixed q3w dose, provided clinical rationale for the recommended dosing regimen of tislelizumab 200 mg q3w for multiple cancer indications.

Farmacocinética de eculizumab en pacientes adultos y pediátricos con síndrome hemolítico urémico atípico y glomerulopatía C3 / Pharmacokinetics of eculizumab in adult and pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy

Objetivo analizar y describir las concentraciones de eculizumab y el bloqueo del complemento en los pacientes con síndrome hemolítico urémico atípico (SHUa) y glomerulopatía C3, y definir un margen terapéutico donde se alcance una alta probabilidad de conseguir eficacia terapéutica. Métodos estudio observacional, ambispectivo y multicéntrico que incluyó pacientes adultos y pediátricos diagnosticados de SHUa y glomerulopatía C3 desde septiembre de 2020 hasta octubre de 2022 en 5 hospitales de España. Eculizumab se administró a las dosis recomendadas por la ficha técnica. Se determinaron las concentraciones pre y posdosis de eculizumab, así como del bloqueo de la vía clásica del complemento (CH50). Se recogieron variables sociodemográficas, analíticas y clínicas, y se calcularon los parámetros farmacocinéticos. Para establecer el punto de corte de las concentraciones de eculizumab que predecían el bloqueo del complemento se realizó un análisis de curvas ROC (Receiver Operating Characteristic). Se utilizó el test de Kruskal-Wallis para contrastar las diferencias en distintos parámetros según las concentraciones de eculizumab. Resultados se incluyeron 25 pacientes, 19 adultos (76,0%) y 6 pediátricos (24,0%), con edades medianas de 43,4 (RIC 35,7-48,8) y 10,1 (RIC 9,6-11,3) años, respectivamente. De ellos, 22 (88,0%) pacientes fueron diagnosticados con SHUa y 3 (12,0%) con glomerulopatía C3. Se determinaron un total de 111 concentraciones de eculizumab. Las concentraciones predosis y posdosis medias detectadas durante la fase de mantenimiento fueron 243,8 (SD 240,6) μg/ml y 747,4 (SD 444,3) μg/ml, respectivamente (AU)

Objective The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. Methods Observational, ambispective and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in five hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre-dose and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. Results Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (IQR 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined (AU)

Comparability of Elezanumab Safety, Tolerability, and Pharmacokinetics in Healthy Japanese, Chinese, and White Participants.

Elezanumab is a fully human monoclonal antibody, which is directed against repulsive guidance molecule A. The safety, tolerability, pharmacokinetics (PK), and immunogenicity of elezanumab were assessed in 2 Phase 1 clinical studies. The objective of this study was to assess the PK, safety, tolerability, and immunogenicity following intravenous infusion of elezanumab in healthy adult Japanese, Han Chinese, and Caucasian participants as well as Western participants from the single-ascending-dose study. Elezanumab exposures were approximately 20% higher in Japanese and Han Chinese participants compared to White participants without controlling for body weight. After statistically controlling for body weight by including it as a covariate, the PK of elezanumab in White participants were comparable to those in Japanese and Han Chinese participants. The clinical implications of these exposure differences are yet to be determined. All adverse events were assessed by the investigator as having no reasonable possibility of being related to the study drugs and were mild in severity. No positive immunogenicity effect was observed that impacted elezanumab exposure or safety.

Population Pharmacokinetics of Nirsevimab in Preterm and Term Infants.

Nirsevimab, a monoclonal antibody with an extended half-life, is approved for the prevention of respiratory syncytial virus (RSV) disease in all infants in Canada, the EU, Great Britain, and the USA. A population pharmacokinetics (PK) model was built to describe the PK of nirsevimab in preterm and term infants, and to evaluate the influence of covariates, including body weight and age, in infants. Nirsevimab PK was characterized by a 2-compartment model with first-order clearance (CL) and first-order absorption following intramuscular (IM) administration. The typical CL in a 5 kg infant was 3.4 mL/day. Body weight and postmenstrual age were the primary covariates on CL, with minor effects for race, second RSV season, and antidrug antibody status (deemed not clinically relevant). Congenital heart disease (CHD) and chronic lung disease (CLD) did not significantly impact nirsevimab PK. The final population PK model, based on 8987 PK observations from 2683 participants across 5 clinical trials, successfully predicted PK in an additional cohort of 967 healthy infants. Weight-banded dosing (50 mg in infants <5 kg; 100 mg in infants ≥5 kg) was predicted to be appropriate for infants ≥1 kg in their first RSV season. Together, these data support weight-banded dosing of nirsevimab in all infants in their first RSV season, including in healthy infants, infants with CHD or CLD, and in infants born prematurely.

Development and validation of pharmacokinetics assays for a novel HER2-targeting antibody-drug conjugate (SHR-A1201): Application to its dose-escalation pharmacokinetic study.

Approximately 25% of breast cancer patients with HER2 overexpression tend to have a high risk of disease progression and death. Various HER2-targeting therapies have been approved for treatment. Recently, a novel antibody-drug conjugate, SHR-A1201, is being researched and developed. For the pharmacokinetic study of SHR-A1201, suitable bioanalytical methods are needed for quantifying unconjugated cytotoxin, cytotoxin-conjugated antibodies and total antibodies. In this research, bioanalytical methods involving a highly sensitive LC-MS/MS assay for unconjugated cytotoxic payload DM1 in human plasma, ELISA strategies for DM1-conjugated trastuzumab and total trastuzumab in human serum were developed, validated and successfully applied to a phase I dose-escalation pharmacokinetic study of SHR-A1201. The pharmacokinetic properties and exposure-to-dose proportionality was evaluated for SHR-A1201. According to the bioanalytical method validation guidance, the bioanalytical methods were fully validated and the validation results met the acceptance criteria. The nonspecific binding of DM1 and dimer was avoided for the LC-MS/MS assay. In the dose-escalation pharmacokinetic study of SHR-A1201, a potential dose-proportional pharmacokinetics was observed over the dose from 1.2 mg/kg to 4.8 mg/kg. The validated bioanalytical strategies are robust and reproducible and these bioanalytical methods will contribute to better understanding of the pharmacokinetic properties of SHR-A1201.

Lanadelumab in Patients 2 to Less Than 12 Years Old With Hereditary Angioedema: Results From the Phase 3 SPRING Study.

BACKGROUND: Symptoms of hereditary angioedema (HAE) often first occur during childhood, and HAE attacks in children can be severe and substantially affect health-related quality of life (HRQoL). However, there are no approved long-term prophylaxis treatments for children aged less than 6 years. OBJECTIVE: The SPRING Study (NCT04070326) evaluated the safety, pharmacokinetics, and efficacy of lanadelumab and HRQoL in patients aged 2 to less than 12 years. METHODS: Over 52 weeks of treatment, patients aged 2 to less than 6 years received lanadelumab 150 mg every 4 weeks (Q4W) and patients aged 6 to less than 12 years received 150 mg every 2 weeks (Q2W) but could switch to Q4W if they were attack-free for 26 weeks. RESULTS: We enrolled 21 patients (aged 2 to less than 6 years: n = 4; aged 6 to less than 12 years: n = 17), 20 of whom completed the study. There were no reported serious treatment-emergent adverse events or discontinuations resulting from such events. Treatment-emergent adverse events were reported for 17 patients (81.0%). The most common TEAE was injection site pain. Overall systemic exposure was comparable for both age groups. The mean (SD) attack rate during treatment decreased by 94.8% from baseline (1.84 [1.53] to 0.08 [0.17] attacks/mo), and 16 (76.2%) patients were attack-free. The attack rate reduction in both age groups was similar during the first 26-week fixed-dosing treatment. Seven patients switched from Q2W to Q4W and remained attack-free. A large, clinically meaningful increase in the Pediatric Quality of Life Inventory Generic Core Scale Total Score and a large increase in the Pediatric Quality of Life Inventory Generic Core Scale-Family Impact Module Total Score from baseline to end of study (better HRQoL) were observed. CONCLUSIONS: Findings support safety, efficacy, and improved HRQoL with lanadelumab 150 mg Q2W and Q4W regimens for the prevention of HAE attacks in patients aged 2 to less than 12 years.

Spesolimab: a comprehensive review on the anti-IL-36 receptor antibody in dermatology.

Interleukin-36 (IL-36) cytokines contribute to the pathogenesis of various inflammatory skin conditions and are potential therapeutic targets. Spesolimab is a monoclonal antibody that inhibits IL-36 signaling recently approved by the Food and Drug Administration for the management of generalized pustular psoriasis flares in adults. Clinical trials are evaluating the efficacy of this monoclonal antibody in a few other dermatological conditions. Here, this review comprehensively summarizes the safety and efficacy of spesolimab treatment in various dermatological conditions.

Pharmacokinetics (PK) of Tiragolumab in First-in-Human Study in Patients with Mixed Solid Tumors (GO30103).

Tiragolumab is a first-in-class, fully human IgG1/kappa anti-TIGIT monoclonal antibody that blocks the binding of TIGIT to CD155 (the poliovirus receptor). We summarize the pharmacokinetics (PK) data from the phase 1a/1b GO30103 study of Q3W (every 3 weeks) sequential dosing of tiragolumab (2, 8, 30, 100, 400, 600, or 1200 mg) followed by atezolizumab (1200 mg), Q4W (every 4 weeks) sequential dosing (tiragolumab 840 mg followed by atezolizumab 1680 mg), and Q4W co-infusion (tiragolumab 840 mg plus atezolizumab 1680 mg). Serum samples were collected at multiple time points following tiragolumab and atezolizumab intravenous infusion in patients with solid tumors for PK and immunogenicity assessment. The serum PK profile of tiragolumab appeared to be biphasic, with a rapid distribution phase followed by a slower elimination phase when administered alone or in combination with atezolizumab. In phase 1a, across doses of tiragolumab ranging from 2 to 1200 mg (cycle 1), the geometric mean (GM), coefficient of variation (CV%), serum tiragolumab Cmax ranged from 0.682 to 270 µg/mL (18.6% to 36.5%) and Cmin ranged from 0.0125 to 75.3 µg/mL (0.0% to 24.2%). The GM systemic exposure (area under the plasma drug concentration-time curve, AUC0-21) ranged from 310 to 2670 µg day/mL (20.5% to 27.0%); interindividual variability in AUC0-21 ranged from 20.5% to 43.9%. Tiragolumab exposure increased in an approximately dose-proportional manner when administered alone or with atezolizumab at doses ≥100 mg. Postbaseline, 4/207 patients (1.9%) were positive for treatment-emergent antidrug antibodies (ADA) against tiragolumab, each at a single time point. Tiragolumab combined with atezolizumab demonstrated desirable PK properties, with no drug-drug interactions or immunogenicity liability. There were no meaningful differences in tiragolumab or atezolizumab exposure between the Q4W co-infusion and sequential dosing cohorts. ClinicalTrials.gov: NCT02794571 (date of registration June 6, 2016).

Factors contributing to the nonlinear pharmacokinetics of astegolimab: a close examination of potential causes.

Aim: This paper describes a case study of an antibody therapeutic targeting a membrane-bound receptor, also present in systemic circulation, as a soluble receptor. During phase I studies of astegolimab, nonlinear pharmacokinetics (PKs) were observed. We investigated the potential contribution of antidrug antibodies, target-mediated drug disposition and assay format. Materials & methods: A more target-tolerant assay was developed, and a subset of phase I samples were evaluated in both free and total PK assay formats. Results & conclusion: Our results demonstrate that there were two main contributors to PK nonlinearity: soluble target interference in the free PK assay, in addition to target-mediated drug disposition. Antidrug antibody status did not significantly impact PK.

Safety, tolerability, pharmacokinetics and efficacy of HB0017, a humanized monoclonal antibody that targets interleukin-17A, in healthy participants and patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Several interleukin (IL)-17 inhibitors have been approved for the treatment of moderate-to-severe plaque psoriasis (PsO). There is still scope for the development of affordable treatments for PsO. OBJECTIVES: To assess, in a phase Ia study, the safety, tolerability and pharmacokinetics (PK) of HB0017, a humanized monoclonal antibody that targets IL-17A, in healthy participants and patients with moderate-to-severe plaque PsO; and, in a phase Ib study, to assess the efficacy of HB0017 in patients with moderate-to-severe plaque PsO. METHODS: The phase Ia study (NCT04505033) was a randomized double-blind placebo-controlled dose-escalation study in healthy participants. Each cohort of 10 volunteers was randomly assigned to receive either a single dose of HB0017 (50 mg, 150 mg, 300 mg or 450 mg) or the matching placebo at a ratio of 4 : 1. The phase Ib study (NCT05442788) was a randomized double-blind placebo-controlled dose-escalation study in enrolled patients with moderate-to-severe plaque PsO. Each cohort of 10 patients was randomly assigned to receive either multiple doses of HB0017 (150 mg, 300 mg or 450 mg) or the matching placebo at a ratio of 4 : 1. RESULTS: HB0017 demonstrated dose-proportional linear PK and was tolerated across the dose range assessed. In the phase Ia and Ib studies, participants in both the HB0017 and placebo groups experienced treatment-emergent adverse events (69% vs. 87%, 96% vs. 100%, respectively). HB0017 demonstrated clinically meaningful effects in patients with moderate-to-severe plaque PsO. PASI 75 [≥ 75% improvement in Psoriasis Area and Severity Index (PASI)], PASI 90 (≥ 90% improvement in PASI) and static Physician Global Assessment (sPGA) 0/1 (i.e. 'clear' or 'almost clear') responses were 100% for the HB0017 300-mg group, with maximal improvements (100% or near 100% reductions from baseline) in PASI score observed at week 12, while the duration of effect was evident up to week 20. There was no clinical response in any participant in the placebo group in the phase Ib study. CONCLUSIONS: Overall, HB0017 showed acceptable safety and tolerability in both healthy participants and patients with moderate-to-severe plaque PsO. An encouraging signal of efficacy with a longer half-life provides HB0017 with the potential to be added to the currently available range of biologics targeting IL-17A.

A first-in-human phase I study of SHR-1906, a humanized monoclonal antibody against connective tissue growth factor, in healthy participants.

New therapeutic targets and drugs are urgently needed to halt the fibrosing process in idiopathic pulmonary fibrosis (IPF). SHR-1906 is a novel fully humanized monoclonal antibody against the connective tissue growth factor, which plays an essential role in the genesis of IPF. We assessed the safety, tolerability, pharmacokinetics (PKs), and immunogenicity of single dose SHR-1906 in healthy participants. This was a randomized, double-blind, placebo-controlled, dose-escalation, phase I study. Twelve healthy participants for each dose level were enrolled to receive single ascending doses of SHR-1906 intravenously (1.5, 6, 12, 20, 30, and 45 mg/kg) or placebo and followed for 71 days. The primary end points were safety and tolerability. Treatment-related treatment-emergent adverse events occurred in 25 participants (46.3%) in the SHR-1906 group and 11 (61.1%) in the placebo group. No serious adverse events occurred. Over the dose range investigated, the geometric mean clearance was 0.14-0.63 mL/h/kg, the geometric mean volume of distribution at steady-state was 47.4-75.5 mL/kg, and the terminal elimination half-life was 51.9-349 h. SHR-1906 showed nonlinear PKs. The peak concentration increased in a dose-proportional manner, whereas the area under the concentration-time curve showed a greater than dose-proportional increase. Anti-drug antibodies of SHR-1906 were detected in nine of 54 participants (16.7%). A single dose of SHR-1906 up to 45 mg/kg demonstrated a favorable tolerability profile in healthy participants. The PKs and immunogenicity of SHR-1906 were evaluated, supporting further clinical development.

Mirikizumab Pharmacokinetics in Patients with Moderately to Severely Active Ulcerative Colitis: Results from Phase III LUCENT Studies.

BACKGROUND AND OBJECTIVE: Mirikizumab is a humanized anti-interleukin-23-p19 monoclonal antibody being developed for ulcerative colitis and Crohn's disease. This analysis characterized mirikizumab pharmacokinetics using phase II and III trial data from patients with moderately to severely active ulcerative colitis. METHODS: Serum pharmacokinetic data in patients receiving mirikizumab 50-1000 mg intravenously every 4 weeks as induction treatment and mirikizumab 200 mg subcutaneously every 4 or 12 weeks as maintenance treatment across three trials (N = 1362) were analyzed using non-linear mixed-effects modeling. Covariate effects on mirikizumab exposure were evaluated using simulation-based estimations. RESULTS: Mirikizumab pharmacokinetics was best described by a linear two-compartment model with first-order absorption. Clearance, volume of distribution for central and peripheral compartments, and half-life were estimated at approximately 0.022 L/h (linear), 3.11 L and 1.69 L, and 9.5 days, respectively. Statistically significant effects of body weight and serum albumin levels on clearance, body weight on central and peripheral volumes of distribution, and body mass index on bioavailability were observed but effects were small relative to random inter-individual variability (% coefficient of variation: 18-64%). The subcutaneous bioavailability of mirikizumab was 48%. CONCLUSIONS: Mirikizumab displayed pharmacokinetic characteristics typical of a monoclonal antibody where clearance increased with body weight and decreased with the albumin level, and bioavailability decreased with body mass index. These effects were small relative to random variability, indicating that a dose adjustment for patient factors is not required. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02589665 (28 October, 2015), NCT03518086 (8 May, 2018), NCT03524092 (14 May, 2018).

Relationship Between Cetuximab Target-Mediated Pharmacokinetics and Progression-Free Survival in Metastatic Colorectal Cancer Patients.

BACKGROUND AND OBJECTIVE: Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal immunoglobulin (Ig)G1 antibody, has been approved for the treatment of metastatic colorectal cancer (mCRC). The influence of target-antigen on cetuximab pharmacokinetics has never been investigated using target-mediated drug disposition (TMDD) modelling. This study aimed to investigate the relationship between cetuximab concentrations, target kinetics and progression-free survival (PFS). METHODS: In this ancillary study (NCT00559741), 91 patients with mCRC treated with cetuximab were assessed. Influence of target levels on cetuximab pharmacokinetics was described using TMDD modelling. The relationship between cetuximab concentrations, target kinetics and time-to-progression (TTP) was described using a joint pharmacokinetic-TTP model, where unbound target levels were assumed to influence hazard of progression by an Emax model. Mitigation strategies of concentration-response relationship, i.e., time-varying endogenous clearance and mutual influences of clearance and time-to-progression were investigated. RESULTS: Cetuximab concentration-time data were satisfactorily described using the TMDD model with quasi-steady-state approximation and time-varying endogenous clearance. Estimated target parameters were baseline target levels (R0 = 43 nM), and complex elimination rate constant (kint = 0.95 day-1). Estimated time-varying clearance parameters were time-invariant component of CL (CL0= 0.38 L/day-1), time-variant component of CL (CL1= 0.058 L/day-1) and first-order rate of CL1 decreasing over time (kdes = 0.049 day-1). Part of concentration-TTP was TTP-driven, where clearance and TTP were inversely correlated. In addition, increased target occupancy was associated with increased TTP. CONCLUSION: This is the first study describing the complex relationship between cetuximab target-mediated pharmacokinetics and PFS in mCRC patients using a joint PK-time-to-progression model. Further studies are needed to provide a more in-depth description of this relationship.

Phase I, Randomized, Placebo-Controlled, Dose-Escalation Study of GB223, a Fully-Humanized Monoclonal Antibody to RANKL, in Healthy Chinese Adults.

BACKGROUND: GB223 is a novel, fully-humanized monoclonal antibody against the receptor activator of nuclear factor-kappa B ligand (RANKL). In this phase I study, the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of GB223 were investigated. PATIENTS AND METHODS: This was a randomized, double-blinded, placebo-controlled, single-dose escalation study conducted in 44 healthy Chinese adults. Participants were randomly assigned to receive a single subcutaneous injection dose of 7, 21, 63, 119, or 140 mg of GB223 (n = 34) or placebo (n = 10) and were followed up for 140-252 days. RESULTS: The results of noncompartmental analysis showed that GB223 was slowly absorbed after dosing, with a time to reach maximum concentration (Tmax) ranging from 5 to 11 days. Serum GB223 concentrations decreased slowly, with a long half-life ranging from 7.91 to 19.60 days. A two-compartment Michaelis-Menten model was found to best describe the pharmacokinetics of GB223, and the absorption rate of GB223 differed between males (0.0146 h-1) and females (0.0081 h-1). Serum C-terminal telopeptide of type I collagen decreased significantly postdose, and the inhibition lasted 42-168 days. No deaths or drug-related serious adverse events occurred. The most frequent adverse events were blood parathyroid hormone increased (94.1%), blood phosphorus decreased (67.6%) and blood calcium decreased (58.8%). In the GB223 group, 44.1% (15/34) of subjects were antidrug antibody positive after dosing. CONCLUSION: In this study, we demonstrated for the first time that a single subcutaneous injection of GB223, from 7 to 140 mg, is safe and well tolerated in healthy Chinese subjects. GB223 has a nonlinear pharmacokinetic profile, and sex was a potential covariate that may affect the absorption rate of GB223. CLINICAL TRIAL REGISTRATION: NCT04178044 and ChiCTR1800020338.

Population Pharmacokinetics of Ranibizumab Delivered via the Port Delivery System Implanted in the Eye in Patients with Neovascular Age-Related Macular Degeneration.

The port delivery system with ranibizumab (PDS) is designed to continuously deliver ranibizumab to maintain therapeutic drug concentrations in the vitreous of the eye for an extended duration. The PDS has been evaluated for the treatment of neovascular age-related macular degeneration in the Ladder (PDS 10, 40, and 100 mg/mL, with refill exchanges as needed, versus monthly intravitreal ranibizumab 0.5 mg), Archway (PDS 100 mg/mL with 24-week refill exchanges, versus monthly intravitreal ranibizumab 0.5 mg), and ongoing Portal (PDS 100 mg/mL with 24-week refill exchanges) clinical trials. Data from Ladder, Archway, and Portal were used to develop a population pharmacokinetics (PK) model to estimate the ranibizumab release rate from the PDS implant, describe ranibizumab PK in serum and aqueous humor, and predict the concentration in vitreous humor. A model was developed to adequately describe the serum and aqueous humor PK data, as suggested by goodness-of-fit plots as well as visual predictive checks. In the final model, the first-order implant release rate was estimated to be 0.00654 (1/day), corresponding to a half-life of 106 days, consistent with the implant release rate determined in vitro. The model-predicted vitreous concentrations achieved with PDS 100 mg/mL given every 24 weeks were below the intravitreal peak concentration and above the intravitreal trough concentration of ranibizumab over the entire 24-week refill interval. The results demonstrate a durable release of ranibizumab from the PDS with a half-life of 106 days, providing vitreous exposure to ranibizumab for at least 24 weeks that is within the range of exposure for monthly intravitreal treatment.

Nivolumab + relatlimab for the treatment of unresectable or metastatic melanoma.

INTRODUCTION: Though melanoma is one of the less common skin malignancies, it accounts for the majority of deaths due to cutaneous cancers. The recent progress and drug approvals in targeted treatment and immunotherapy revolutionized the outcome of patients with metastatic disease, and now is also changing the landscape of adjuvant treatment in melanoma. AREA COVERED: A combination of anti-PD-1 and anti-CTLA-4 (nivolumab with ipilimumab) has demonstrated superior outcomes in terms of progression-free survival (PFS) and overall survival with recent data confirming median survival exceeding six years. However, the use of this immunotherapy combination is limited in routine practice to approximately half of the patients due to high toxicity with the majority of patients at risk of severe adverse events. The current efforts are to determine how best to integrate combination immunotherapy in different clinical scenarios and limit these drugs' toxicity. That is why novel strategies in immunotherapy are needed and one of the examples of such novelty are anti-LAG-3 antibodies (lymphocyte-activation gene 3). LAG-3 inhibitor (relatlimab) in combination with nivolumab significantly improved PFS as compared to anti-PD-1 monotherapy in patients with previously untreated metastatic or unresectable melanoma. We describe the current status of combination of nivolumab+ relatlimab in the treatment of advanced melanoma patients based on the available data coming from pivotal clinical trials. EXPERT OPINION: The most important question to be answered is what would be the place of this novel combination in the treatment planning strategy.

Model-Based Investigation of Inadequate Efficacy of Tesnatilimab, an Anti-Natural Killer Group 2 Member D Monoclonal Antibody, in Moderately to Severely Active Crohn Disease.

Tesnatilimab is a human immunoglobulin G4 isotype monoclonal antibody that blocks the natural killer group 2 member D (NKG2D) receptor and prevents the downstream signaling of proinflammatory cytokines and cytotoxic mediators. Subcutaneous tesnatilimab was investigated in a phase 2 randomized, double-blind, placebo-controlled trial in patients with moderately to severely active Crohn disease (CD). While the proof-of-concept part I of the study demonstrated significant treatment effects, part II (dose-ranging) revealed an unexpected lack of dose-response and a modest degree of clinical benefit for treatment groups. To inform further drug development, population pharmacokinetic (PopPK) modeling and exposure-response (E-R) analyses were planned and performed. A 1-compartment PopPK model with first-order absorption and parallel linear and nonlinear elimination pathways was established for tesnatilimab in patients with CD. No clinically significant covariates were identified, and overall consistent pharmacokinetics were observed between part I and part II patients. Receptor occupancy data suggested full occupancy of the peripheral blood natural killer group 2 member D receptors and target engagement at all tested dose levels. Pooled part I and part II data showed a positive efficacy E-R relationship; however, this was driven by data from part I. Part II-only analysis did not show an apparent efficacy E-R relationship. No important covariates were identified in efficacy E-R analyses, overall, and in various subpopulations. No apparent E-R relationships were observed for the investigated safety end points. The PopPK and E-R analyses indicated that the inadequate efficacy of tesnatilimab in CD was unlikely due to insufficient drug exposure and target engagement.

Pharmacokinetics, pharmacodynamics, safety and immunogenicity of recombinant, fully human anti-RANKL monoclonal antibody (MW031) versus denosumab in Chinese healthy subjects: a single-center, randomized, double-blind, single-dose, parallel-controlled trial.

BACKGROUND: MW031 is a biosimilar candidate of denosumab (Prolia®). This study aimed to compare the pharmacokinetics, pharmacodynamics, safety and immunogenicity of MW031 to denosumab in healthy Chinese participants. RESEARCH DESIGN AND METHODS: In this single-center, randomized, double-blind, parallel-controlled, single-dose trial, participants were given 60 mg MW031 (N = 58) or denosumab (N = 61) by subcutaneous injection and observed for 140 days. The primary endpoint was the bioequivalence of PK parameters (Cmax, AUC0-∞), and secondary endpoints including PD parameter, safety, and immunogenicity. RESULTS: A comparison of main PK parameters showed that the geometric mean ratios (GMR) (90% confidence intervals [CIs]) of AUC0-∞ and Cmax for MW031 over denosumab were 105.48% (98.96%, 112.43%) and 98.58% (92.78%, 104.75%), respectively. The inter-CV values of AUC0-∞ and Cmax for MW031 ranged from 19.9% to 23.1%. PD parameter (sCTX) in the MW031 and denosumab groups were similar, and the positivity rates of immunogenicity were 0% in both groups. This study also showed similar safety profiles in both groups, and there were no drug-related, high-incidence and previously unreported adverse reactions. CONCLUSION: This trial confirmed similar pharmacokinetic profiles of MW031 and denosumab in healthy male participants, and pharmacodynamic profile, immunogenicity and safety were comparable for both drugs. TRIAL REGISTRATION: NCT04798313; CTR20201149.