RESUMO
BACKGROUND: Iberdomide, a cereblon modulator promoting degradation of the transcription factors Ikaros and Aiolos, which affect leukocyte development and autoimmunity, is being evaluated for the treatment of systemic lupus erythematosus (SLE). METHODS: In this phase 2 trial, we randomly assigned patients in a 2:2:1:2 ratio to receive oral iberdomide (at a dose of 0.45, 0.30, or 0.15 mg) or placebo once daily for 24 weeks, in addition to standard medications. The primary end point at week 24 was a response on the SLE Responder Index (SRI-4), which was defined as a reduction of at least 4 points in the Systemic Lupus Erythematosus Disease Activity Index 2000 score (a 24-item weighted score of lupus activity that ranges from 0 to 105, with higher scores indicating greater disease activity), no new disease activity as measured on the British Isles Lupus Assessment Group 2004 index, and no increase of 0.3 points or more in the Physician's Global Assessment score (on a visual-analogue scale ranging from 0 [no disease activity] to 3 [maximal disease]). RESULTS: A total of 288 patients received the assigned intervention: 81 received iberdomide at a dose of 0.45 mg, 82 received iberdomide at a dose of 0.30 mg, 42 received iberdomide at a dose of 0.15 mg, and 83 received placebo. At week 24, the percentages of patients with an SRI-4 response were 54% in the iberdomide 0.45-mg group, 40% in the iberdomide 0.30-mg group, 48% in the iberdomide 0.15-mg group, and 35% in the placebo group (adjusted difference between the iberdomide 0.45-mg group and the placebo group, 19.4 percentage points; 95% confidence interval, 4.1 to 33.4; P = 0.01), with no significant differences between the groups that received the lower doses of iberdomide and the group that received placebo. Iberdomide-associated adverse events included urinary tract and upper respiratory tract infections and neutropenia. CONCLUSIONS: In this 24-week, phase 2 trial involving patients with SLE, iberdomide at a dose of 0.45 mg resulted in a higher percentage of patients with an SRI-4 response than did placebo. Data from larger, longer trials are needed to determine the efficacy and safety of iberdomide in SLE. (Funded by Bristol Myers Squibb; ClinicalTrials.gov number, NCT03161483; EudraCT number, 2016-004574-17.).
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/agonistas , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Morfolinas/uso terapêutico , Ftalimidas/uso terapêutico , Piperidonas/uso terapêutico , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Fator de Transcrição Ikaros/metabolismo , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/farmacologia , Ftalimidas/administração & dosagem , Ftalimidas/farmacologia , Piperidonas/administração & dosagem , Piperidonas/farmacologia , Índice de Gravidade de Doença , Ubiquitina-Proteína Ligases/metabolismoRESUMO
4ß-Hydroxycholesterol (4ß-HC) in plasma has been used as a biomarker to assess CYP3A drug-drug interaction (DDI) potential during drug development. However, due to the long half-life and narrow dynamic range of 4ß-HC, its use has been limited to the identification of CYP3A inducers, but not CYP3A inhibitors. The formation of 1ß-hydroxydeoxycholic acid (1ß-OH DCA) from deoxycholic acid (DCA) is mediated by CYP3A, thus 1ß-OH DCA can potentially serve as an alternative to 4ß-HC for assessment of CYP3A DDI potential. To study this feasibility, we developed a sensitive liquid chromatography-tandem mass spectrometry method for the simultaneous quantitation of 1ß-OH DCA and its glycine and taurine conjugates in human plasma with the lower limit of quantitation of 50 pg/ml, which enabled the quantitation of basal levels and further reduction. The method was applied to a DDI study to assess how 1ß-OH DCA and its glycine and taurine conjugates would respond to CYP3A induction or inhibition. Rifampin induction resulted in an increase of 1ß-OH DCA and its conjugates in plasma, with 6.8-, 7.8-, 8.3-, and 10.3-fold increases of area under the curve from the time of dosing to the last measurable concentration (AUCLST), area under the curve from the time of dosing to 24 hours (AUC24h), C max, and mean concentrations for total 1ß-OH DCA (total of all three forms), respectively. Importantly, inhibition with itraconazole resulted in notable reduction of these biomarkers, with 84%, 85%, 82%, and 81% reductions of AUCLST, AUC24h, C max, and mean concentrations for total 1ß-OH DCA, respectively. These preliminary data demonstrate for the first time that total 1ß-OH DCA in plasma has the potential to serve as a biomarker for CYP3A DDI assessment in early clinical development and may provide key advantages over 4ß-HC. SIGNIFICANCE STATEMENT: The authors have reported the use of total 1ß-hydroxydeoxycholic acid (1ß-OH DCA) (sum of 1ß-OH DCA and its glycine and taurine conjugates) plasma exposure as a biomarker for CYP3A activity. Itraconazole inhibition led to an 81%-85% decrease of total 1ß-OH DCA plasma exposures, whereas rifampin induction led to a 6.8- to 10.3-fold increase of total 1ß-OH DCA plasma exposures. Using 1ß-OH DCA exposures in plasma also provides the benefit of allowing pharmacokinetic and biomarker assessment using the same matrix.
Assuntos
Biomarcadores , Indutores do Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Ácido Desoxicólico , Interações Medicamentosas , Hidroxicolesteróis , Humanos , Citocromo P-450 CYP3A/metabolismo , Biomarcadores/sangue , Ácido Desoxicólico/sangue , Indutores do Citocromo P-450 CYP3A/farmacologia , Hidroxicolesteróis/sangue , Espectrometria de Massas em Tandem/métodos , Masculino , Adulto , Rifampina/farmacologia , Rifampina/sangue , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Cromatografia Líquida/métodos , Taurina/sangue , Taurina/análogos & derivadosRESUMO
Here we report efficacy, pharmacokinetics, and safety data obtained in treatment-naive, pediatric patients with newly diagnosed advanced MDS receiving azacitidine in the AZA-JMML-001 study. The primary endpoint was response rate (proportion of patients with complete response [CR], partial response [PR], or marrow CR, sustained for ≥4 weeks). Of the 10 patients enrolled, one had an unconfirmed marrow CR and none had confirmed responses after three cycles; the study was therefore closed after stage 1. Azacitidine was well tolerated. The lack of efficacy of azacitidine in pediatric patients with newly diagnosed advanced MDS highlights the need for effective new treatments in these patients.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Criança , Azacitidina/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/diagnóstico , Resultado do Tratamento , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
OBJECTIVES: Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Pharmacodynamics and pharmacokinetics of oral iberdomide were evaluated in a phase 2b study of patients with active systemic lupus erythematosus (SLE). METHODS: Adults with autoantibody-positive SLE were randomised to placebo (n=83) or once daily iberdomide 0.15 mg (n=42), 0.3 mg (n=82) or 0.45 mg (n=81). Pharmacodynamic changes in whole blood leucocytes were measured by flow cytometry, regulatory T cells (Tregs) by epigenetic assay, plasma cytokines by ultrasensitive cytokine assay and gene expression by Modular Immune Profiling. RESULTS: Iberdomide exhibited linear pharmacokinetics and dose-dependently modulated leucocytes and cytokines. Compared with placebo at week 24, iberdomide 0.45 mg significantly (p<0.001) reduced B cells, including those expressing CD268 (TNFRSF13C) (-58.3%), and plasmacytoid dendritic cells (-73.9%), and increased Tregs (+104.9%) and interleukin 2 (IL-2) (+144.1%). Clinical efficacy was previously reported in patients with high IKZF3 expression and high type I interferon (IFN) signature at baseline and confirmed here in those with an especially high IFN signature. Iberdomide decreased the type I IFN gene signature only in patients with high expression at baseline (-81.5%; p<0.001) but decreased other gene signatures in all patients. CONCLUSION: Iberdomide significantly reduced activity of type I IFN and B cell pathways, and increased IL-2 and Tregs, suggesting a selective rebalancing of immune abnormalities in SLE. Clinical efficacy corresponded to reduction of the type I IFN gene signature. TRIAL REGISTRATION NUMBER: NCT03161483.
RESUMO
PURPOSE: Iberdomide is a cereblon E3 ligase modulator capable of redirecting the protein degradation machinery of the cell towards the elimination of target proteins potentially driving therapeutic effects. In vitro studies demonstrated that iberdomide predominantly undergoes oxidative metabolism mediated by cytochrome P450 (CYP) 3A4/5 but had no notable inhibition or induction of CYP enzymes. Consequently, the potential of iberdomide as a victim of drug-drug interactions (DDI) was evaluated in a clinical study with healthy subjects. METHODS: A total of 33 males and 5 females with 19 subjects per part were enrolled. Part 1 evaluated the pharmacokinetics (PK) of iberdomide alone (0.6 mg) and when administered with the CYP3A and P-gp inhibitor itraconazole (200 mg twice daily on day 1 and 200 once daily on days 2 through 9). Part 2 evaluated the PK of iberdomide alone (0.6 mg) and with CYP3A4 inducer rifampin (600 mg QD days 1 through 13). Plasma concentrations of iberdomide and the active metabolite M12 were determined by validated liquid chromatography-tandem mass spectrometry assay. RESULTS: Coadministration of iberdomide with itraconazole increased iberdomide peak plasma concentration (Cmax) 17% and area under the concentration curve (AUC) approximately 2.4-fold relative to administration of iberdomide alone. The Cmax and AUC of iberdomide were reduced by approximately 70% and 82%, respectively, when iberdomide was administered with rifampin compared with iberdomide administered alone. Exploratory assessment of metabolite M12 concentrations demonstrated that CYP3A is responsible for M12 formation. CONCLUSIONS: Caution should be taken when coadministering iberdomide with strong CYP3A inhibitors. Coadministration of iberdomide with strong CYP3A inducers is not advised. CLINICAL TRIAL REGISTRATION: Clinical trial identification number is NCT02820935 and was registered in July 2016.
Assuntos
Indutores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Fatores Imunológicos/farmacocinética , Adulto , Área Sob a Curva , Citocromo P-450 CYP3A/metabolismo , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Humanos , Fatores Imunológicos/administração & dosagem , Itraconazol/administração & dosagem , Itraconazol/farmacocinética , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Microssomos Hepáticos , Pessoa de Meia-Idade , Morfolinas , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Ftalimidas , Piperidonas , Rifampina/administração & dosagem , Rifampina/farmacocinética , Adulto JovemRESUMO
CC-90001 is predominantly metabolised via glucuronidation, while oxidative metabolism is a minor pathway in human hepatocytes and liver microsomes. In vitro, CC-90001 glucuronidation was catalysed by UGT1A9, UGT1A4, and UGT1A1, while oxidative metabolism was primarily mediated by CYP3A4/5 with minor contributions from CYP1A2, CYP2C9, CYP2B6, and CYP2D6.CC-90001 in vitro inhibits CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 ≤ 55% at 100 µM, and the inhibition was negligible at ≤30 µM. CC-90001 is not a time-dependent CYP inhibitor.In human hepatocytes CC-90001 is an inducer of CYP2B6 and CYP3A, with mRNA levels increased 34.4% to 52.8% relative to positive controls.In vitro CC-90001 is a substrate of P-gp, and an inhibitor of P-gp, BCRP, OAT3, OATP1B1, OATP1B3, OCT2, MATE1, and MATE2k with IC50 values of 30.3, 25.8, 17.7, 0.417, 19.9, 0.605, 4.17, and 20 µM, respectively.A clinical study demonstrated that CC-90001 has no or little impact on the exposure of warfarin (CYP2C9), omeprazole (CYP2C19), midazolam (CYP3A) or metformin (OCT2, MATE1/2k). CC-90001 co-administration increases the AUCt and Cmax 176% and 339% for rosuvastatin (BCRP/OATP1B1/3), 116% and 171% for digoxin (P-gp), and 266% and 321% for nintedanib (CYP3A & P-gp), respectively.In conclusion, CC-90001 in unlikely to be a victim or perpetrator of clinically relevant interactions involving CYPs or UGTs. Weak to moderate interactions are expected in clinic with substrates of P-gp and OATP1B1 due to CC-90001 inhibition of these transporters.
Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno , Preparações Farmacêuticas , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Interações Medicamentosas , Humanos , Microssomos Hepáticos , Proteínas de NeoplasiasRESUMO
Alnuctamab, a B-cell maturation antigen (BCMA)-targeting T-cell engager, has demonstrated encouraging antitumor activity in the phase I study CC-93269-MM-001 treating patients with relapsed or refractory multiple myeloma. Identification of a recommended Phase III dose (RP3D) was a key objective, as such population pharmacokinetic (PopPK) and exposure-response analysis was critical. Intravenous (IV) alnuctamab was administered in fixed doses (0.15-10 mg) or in step-up doses to a maximum 10-mg target dose. Subcutaneous (SC) step-up doses of 3 and 6 mg were followed by a target dose range of 10-60 mg. Concentration data from IV and SC alnuctamab administration was pooled and was well described by a two-compartment PopPK model with first-order absorption and elimination. Covariate analysis determined that the inclusion of baseline soluble BCMA (sBCMA) on clearance significantly improved model fitting. Individual exposure parameters were estimated from the final model to characterize exposure-response relationships. Switching from IV to SC administration improved the safety profile of alnuctamab by limiting the frequency of grade ≥2 CRS events. A significant exposure-CRS relationship was observed after the first SC dose, but not subsequent dose administrations. Exposure-safety analysis did not find a statistically significant relationship between increasing exposure and the probability of key safety events of interest. Logistic regression analysis for patients administered SC alnuctamab identified that increased exposure significantly increased the probability of response, although the additional benefit was minimal at exposures above 30 mg target dose. Considering the totality of exposure-response data, the clinical pharmacology assessment supported a SC RP3D of 3/6/30 mg.
Assuntos
Antígeno de Maturação de Linfócitos B , Relação Dose-Resposta a Droga , Mieloma Múltiplo , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Mieloma Múltiplo/tratamento farmacológico , Complexo CD3/imunologia , Injeções Subcutâneas , Adulto , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Modelos Biológicos , Idoso de 80 Anos ou mais , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversosRESUMO
Bispecific T-cell Engagers (TCEs) are promising anti-cancer treatments that bind to both the CD3 receptors on T cells and an antigen on the surface of tumor cells, creating an immune synapse, leading to killing of malignant tumor cells. These novel therapies have unique development challenges, with specific safety risks of cytokine release syndrome. These on-target adverse events fortunately can be mitigated and deconvoluted from efficacy via innovative dosing strategies, making clinical pharmacology key in the development of these therapies. This review assesses dose selection and the role of quantitative clinical pharmacology in the development of the first eight approved TCEs. Model informed drug development (MIDD) strategies can be used at every stage to guide TCE development. Mechanistic modeling approaches allow for (1) efficacious yet safe first-in-human dose selection as compared with in vitro minimum anticipated biological effect level (MABEL) approach; (2) rapid escalation and reducing number of patients with subtherapeutic doses through model-based adaptive design; (3) virtual testing of different step-up dosing regimens that may not be feasible to be evaluated in the clinic; and (4) selection and justification of the optimal clinical step-up and full treatment doses. As the knowledge base around TCEs continues to grow, the relevance and utilization of MIDD strategies for supporting the development and dose optimization of these molecules are expected to advance, optimizing the benefit-risk profile for cancer patients.
Assuntos
Anticorpos Biespecíficos , Neoplasias , Linfócitos T , Humanos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Neoplasias/tratamento farmacológico , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Desenvolvimento de Medicamentos/métodos , Relação Dose-Resposta a Droga , Animais , Farmacologia Clínica/métodosRESUMO
Introduction: Iberdomide, a novel cereblon modulator (CELMoD®), is currently under clinical investigation for hematology indications. To evaluate the influence of hepatic impairment on the pharmacokinetics (PK) of iberdomide and its major active metabolite M12, a phase 1, multicenter, open-label study was conducted in healthy subjects and subjects with mild, moderate, and severe hepatic impairment. Methods: Forty subjects were enrolled in the study and divided into five groups based on hepatic function. 1 mg iberdomide was administered and plasma samples were collected to evaluate the pharmacokinetics of iberdomide and M12. Results: After a single dose of iberdomide (1 mg), mean iberdomide Cmax (maximum observed concentration) and AUC (area under the concentration-time curve) exposure were generally comparable between hepatic impairment (HI) subjects (severe, moderate and mild) and their respective matched normal controls. Mean Cmax and AUC exposure of the metabolite M12 were generally comparable between mild HI and matched normal subjects. However, mean Cmax of the M12 was 30% and 65% lower and AUC was 57% and 63% lower in moderate and severe HI subjects as compared to their respective matched normal controls. However, given the relatively low M12 exposure as compared to its parent drug, the observed differences were not considered clinically meaningful. Conclusion: In summary, 1 mg single oral dose of iberdomide was generally well-tolerated. HI (mild, moderate or severe) had no clinically relevant impact on iberdomide PK and therefore, no dose adjustment is warranted.
RESUMO
Iberdomide is an orally available cereblon-modulating agent being developed for the treatment of hematologic malignancies and autoimmune-mediated diseases. To assess the potential concentration-QTc relationship in humans and to ascertain or exclude a potential QT effect by iberdomide, a plasma concentration and ΔQTcF (change from baseline of corrected QT interval using the Fridericia formula) model of iberdomide was developed. Iberdomide concentration and paired high-quality, intensive electrocardiogram signal from a single-ascending-dose study in healthy subjects (N = 56) were included in the analysis. The primary analysis was based on a linear mixed-effect model with ΔQTcF as the dependent variable; iberdomide plasma concentration and baseline QTcF as continuous covariates; treatment (active or placebo) and time as a categorical factor; and a random intercept per subject. The predicted change from baseline and placebo corrected (ΔΔQTcF) at the observed geometric mean maximum plasma concentration and 2-sided 90% confidence intervals at different dose levels were calculated. The upper bound of the 90% confidence interval of the model-predicted ΔΔQTcF effect at maximum concentration from the supratherapeutic dose of 6 mg (2.54 milliseconds) is <10-millisecond threshold, suggesting that iberdomide does not have a clinically relevant QT prolongation liability.
Assuntos
Fluoroquinolonas , Humanos , Moxifloxacina/farmacologia , Fluoroquinolonas/farmacologia , Método Duplo-Cego , Frequência Cardíaca , Relação Dose-Resposta a DrogaRESUMO
Mezigdomide is a novel cereblon E3 ligase modulator (CELMoD) agent with enhanced autonomous cell-killing activity in multiple myeloma (MM) cells, and promising immunomodulatory and antitumor activity in patients with MM. We developed a population pharmacokinetics (PKs) model for mezigdomide in healthy subjects (HSs), and quantified effects of high-fat meal and proton pump inhibitor (PPI) on human disposition parameters. Plasma concentrations from 64 HS in two phase I clinical studies (NCT03803644 and NCT04211545) were used to develop a population PK model. The HSs received single oral doses of 0.4-3.2 mg mezigdomide with full PK profiles collected. A two-compartment linear PK model with first-order absorption and lag time best described mezigdomide PK profiles in HSs. The population PK parameters of absorption rate constant, lag time, central volume of distribution, clearance, peripheral volume of distribution, and intercompartmental clearance were estimated to be 1.18 h-1 (interoccasion variability [IOV]: 65%), 0.423 h (IOV: 31%), 440 L (interindividual variability [IIV]: 63%), 35.1 L/h (IIV: 40%), 243 L (IIV: 26%), and 36.8 L/h (IIV: 26%), respectively. High-fat meal increased oral bioavailability by ~30% and PPI co-administration decreased oral bioavailability by ~64%. Mezigdomide demonstrated a linear dose-exposure relationship in HSs. The PK model suggests a modest effect of high-fat meal, and a substantial effect of PPIs on mezigdomide oral bioavailability. This population PK model enables data integration across studies to identify important covariate effects and is being used to guide dose selection in clinical study designs for mezigdomide in patients with MM.
Assuntos
Imunossupressores , Substâncias Redutoras , Humanos , Administração OralRESUMO
Oral azacitidine (oral-AZA) maintenance is approved for adults with acute myeloid leukemia (AML) in remission post-intensive chemotherapy, not proceeding to hematopoietic stem cell transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model to characterize oral-AZA concentration-time profiles in patients with AML, myelodysplastic syndrome, or chronic myelomonocytic leukemia. PopPK-estimated exposure parameters were used to evaluate exposure-response relationships in the phase III QUAZAR AML-001 study. The PopPK dataset comprised 286 patients with 1,933 evaluable oral-AZA concentration records. The final PopPK model was a one-compartment model with first-order absorption incorporating an absorption lag time and first-order elimination. Regression analyses identified two oral-AZA exposure parameters (area under the plasma concentration-time curve at steady state (AUCss ); maximum plasma concentration (Cmax )) as statistically significant predictors for relapse-free survival (hazard ratio (HR) = 0.521, P < 0.001; HR = 0.630, P = 0.013; respectively), and AUCss as a significant predictor for overall survival (HR = 0.673, P = 0.042). The probability of grade ≥ 3 neutropenia was significantly increased with increases in AUCss (odds ratio (OR) = 5.71, 95% confidence interval (CI) = 2.73-12.62, P < 0.001), cumulative AUC through cycles 1 to 6 (OR = 2.71, 95% CI = 1.76-4.44, P < 0.001), and Cmax at steady-state (OR = 2.38, 95% CI = 1.23-4.76, P = 0.012). A decreasing trend was identified between AUCss and relapse-related schedule extensions, vs. an increasing trend between AUCss and event-related dose reductions. As the majority (56.8%) of patients required no dose modifications, and the proportions requiring schedule extension (19.4%) or dose reduction (22.9%) were almost equal, oral-AZA 300 mg once daily for 14 days is the optimal dosing schedule balancing survival benefit and safety risk.
Assuntos
Leucemia Mieloide Aguda , Leucemia Mielomonocítica Crônica , Síndromes Mielodisplásicas , Adulto , Humanos , Antimetabólitos , Antimetabólitos Antineoplásicos , Azacitidina/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mielomonocítica Crônica/induzido quimicamente , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/induzido quimicamente , Ensaios Clínicos Fase III como AssuntoRESUMO
Approved treatments for idiopathic pulmonary fibrosis have tolerability concerns and limited efficacy. CC-90001, a c-Jun N-terminal kinase inhibitor, is under investigation as a therapy for fibrotic diseases. A Phase 1b safety, pharmacokinetics, and pharmacodynamics study of oral CC-90001 (100, 200, or 400 mg) administered once daily for 12 weeks was conducted in patients with pulmonary fibrosis (NCT02510937). Sixteen patients with a mean age of 68 years were studied. The most common treatment-emergent adverse events were nausea and headache; all events were of mild or moderate intensity. Pharmacokinetic profiles were similar between the patients in this trial and healthy adults in previous studies. Forced vital capacity increased in the 200- and 400-mg cohorts from baseline to Week 12, and dose-dependent reductions in fibrosis biomarkers were observed. Antifibrotic activity of CC-90001 was also evaluated in vitro in transforming growth factor beta 1 (TGF-ß1)-stimulated cells. CC-90001 reduced in vitro profibrotic gene expression in both lung epithelial cells and fibroblasts, supporting a potential direct antifibrotic action of c-Jun N-terminal kinase inhibition in either or both cell types. Overall, CC-90001 was generally safe and well tolerated, and treatment was associated with forced vital capacity improvement and reductions in profibrotic biomarkers.
RESUMO
CC-90001 selectively inhibits c-Jun N-terminal kinase (JNK), a stress-activated protein implicated in fibrosis. In 3 phase 1 trials evaluating CC-90001 pharmacokinetics, pharmacodynamics, and safety, healthy adults (N = 184) received oral CC-90001 in a single dose (10-720 mg) or multiple doses (30-480 mg once daily for 7-18 days) or placebo. CC-90001 was rapidly absorbed (median time to maximum concentration, 1-4 hours) and eliminated with a mean terminal elimination half-life of 12-28 hours. Steady state was reached on day 5, with a mean accumulation ratio of 1.5- to 2-fold following daily dosing. Exposure was similar in fed versus fasted participants and in Japanese versus non-Japanese participants. CC-90001 demonstrated dose- and exposure-dependent inhibition of JNK as determined by histopathological analysis of c-Jun phosphorylation in ultraviolet-irradiated skin. The most common treatment-emergent adverse events were nausea and headache; all were mild or moderate in intensity. Based on exposure-response analysis using high-quality electrocardiogram data, no clinically relevant QT prolongation liability for CC-90001 was observed. Overall, single- and multiple-dose CC-90001 were generally safe and well tolerated at the tested doses and demonstrated JNK pathway engagement. These results support further clinical evaluation of CC-90001.
Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno , Adulto , Humanos , Voluntários Saudáveis , Meia-Vida , Relação Dose-Resposta a Droga , Método Duplo-CegoRESUMO
OBJECTIVE: To evaluate safety, pharmacokinetics, pharmacodynamics and efficacy of iberdomide in patients with SLE. Iberdomide is a high-affinity cereblon ligand that targets the hematopoietic transcription factors Ikaros and Aiolos for proteasomal degradation. METHODS: A 12-week, multicentre, double-blind, placebo-controlled, dose-escalation study in active SLE was followed by a 2-year, open-label active treatment extension phase (ATEP) (NCT02185040). In the dose-escalation phase, adults with active SLE were randomised to oral placebo or iberdomide (0.3 mg every other day, 0.3 mg once daily, 0.6 mg and 0.3 mg alternating once daily, or 0.6 mg once daily). Primary endpoints were safety and tolerability. RESULTS: The dose-escalation phase enrolled 42 patients, with 33 completing this phase and 17 patients enrolling into the ATEP. In the dose-escalation phase, the most common treatment-emergent adverse events (TEAEs; iberdomide/placebo groups) were nausea (20.6%/12.5%), diarrhoea (17.6%/12.5%) and upper respiratory tract infection (11.8%/12.5%). Most TEAEs were mild or moderate in severity and more common in the highest dose groups in both study phases. In the dose-escalation phase, Physician's Global Assessment and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity scores improved relative to baseline and placebo in all iberdomide groups, with a trend toward continued score improvements in the ATEP. In the dose-escalation phase, iberdomide treatment resulted in dose-dependent reductions in total B cells and plasmacytoid dendritic cells in blood. Improvements in CLASI activity scores correlated with plasmacytoid dendritic cell depletion. CONCLUSIONS: These proof-of-concept findings suggest a favourable benefit/risk ratio in SLE for iberdomide, a drug with a novel immunomodulatory mechanism of action, supporting further clinical investigation.
Assuntos
Lúpus Eritematoso Sistêmico , Piperidonas , Relação Dose-Resposta a Droga , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Morfolinas/uso terapêutico , Ftalimidas , Piperidonas/uso terapêuticoRESUMO
SOCS3 is a cytokine-inducible negative regulator of cytokine receptor signaling. Recently, SOCS3 was shown to be induced by a cAMP-dependent pathway involving exchange protein directly activated by cAMP (Epac). We observed in livers of fasted mice that Socs3 mRNA was increased 4-fold compared with refed mice, suggesting a physiologic role for SOCS3 in the fasted state that may involve glucagon and Epac. Treating primary hepatocytes with glucagon resulted in a 4-fold increase in Socs3 mRNA levels. The Epac-selective cAMP analog 8-4-(chlorophenylthio)-2'-O-methyladenosine-3',5'-monophosphate, acetoxymethyl ester (cpTOME) increased Socs3 expression comparably. In gain-of-function studies, adenoviral expression of SOCS3 in primary hepatocytes caused a 50% decrease in 8-br-cAMP-dependent PKA phosphorylation of the transcription factor CREB. Induction of the gluconeogenic genes Ppargc1a, Pck1, and G6pc by glucagon or 8-br-cAMP was suppressed nearly 50%. In loss-of-function studies, hepatocytes from liver-specific SOCS3 knock-out mice responded to 8-br-cAMP with a 200% greater increase in Ppargc1a and Pck1 expression, and a 30% increase in G6pc expression, relative to wild-type cells. Suppression of SOCS3 by shRNA in hepatocytes resulted in a 60% increase in cAMP-dependent G6pc and Pck1 expression relative to control cells. SOCS3 expression also inhibited cAMP-dependent phosphorylation of the IP3 receptor but did not inhibit nuclear localization of the catalytic subunit of PKA. Using an in vitro kinase assay, cAMP-dependent PKA activity was reduced by 80% in hepatocytes expressing ectopic SOCS3. These data indicate that cAMP activates both the PKA and Epac pathways with induction of SOCS3 by the Epac pathway negatively regulating the PKA pathway.
Assuntos
AMP Cíclico/análogos & derivados , Ésteres/química , Glucagon/metabolismo , Hepatócitos/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , 8-Bromo Monofosfato de Adenosina Cíclica/metabolismo , Animais , Células Cultivadas , AMP Cíclico/química , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Gluconeogênese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína 3 Supressora da Sinalização de CitocinasRESUMO
Pharmacokinetics, pharmacodynamics, and safety/tolerability of iberdomide (CC-220), a highly potent oral cereblon E3 ligase modulator (CELMoD), were evaluated in escalating single-dose (0.03, 0.1, 0.3, 1, 2, 4, 6 mg) and multiple-dose (0.3 mg once daily for 14 days, 1 mg once daily for 28 days, 0.3 mg once daily for 28 days, or 1 mg once daily for 7 days with a 7-day washout, then once daily for 7 more days) studies in healthy subjects (n = 99). Iberdomide exposure increased in a dose-proportional manner. Terminal half-life was 9-13 hours after a single dose. Iberdomide decreased peripheral CD19+ B lymphocytes (Emax , 92.4%; EC50 , 0.718 ng/mL), with modest reductions in CD3+ T lymphocytes (Emax , 34.8%; EC50 , 0.932 ng/mL). Lipopolysaccharide-stimulated proinflammatory cytokines (IL-1α, IL-1ß) were reduced, but anti-CD3-stimulated IL-2 and interferon-γ were increased. Iberdomide 1 mg once daily partially decreased T-cell-independent antibody responses to PPV23 but did not change tetanus toxoid recall response. Pharmacodynamic data suggest dose-dependent, differential immunomodulatory effects on B and T lymphocytes. Iberdomide was tolerated up to 6 mg as a single dose and at 0.3 mg once daily for 4 weeks. Grade 3 asymptomatic neutropenia was observed following 1 mg once daily for 21 days; a 7-day drug holiday alleviated neutropenia. Further investigation of iberdomide in autoimmune and hematological diseases is warranted.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/efeitos dos fármacos , Morfolinas/administração & dosagem , Ftalimidas/administração & dosagem , Piperidonas/administração & dosagem , Ubiquitina-Proteína Ligases/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Linfócitos B/imunologia , Estudos Cross-Over , Citocinas/imunologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Morfolinas/farmacocinética , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Ftalimidas/efeitos adversos , Ftalimidas/farmacocinética , Piperidonas/efeitos adversos , Piperidonas/farmacocinética , Linfócitos T/imunologia , Ubiquitina-Proteína Ligases/metabolismo , Adulto JovemRESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration--time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Juvenil , Adulto , Azacitidina/efeitos adversos , Criança , Metilação de DNA , Humanos , Leucemia Mielomonocítica Juvenil/tratamento farmacológico , Leucemia Mielomonocítica Juvenil/genética , MutaçãoRESUMO
While adipose tissue-associated macrophages contribute to development of chronic inflammation and insulin resistance of obesity, little is known about the role of hepatic Kupffer cells in this environment. Here we address the impact of Kupffer cell ablation using clodronate-encapsulated liposome depletion in a diet-induced obese (DIO) and insulin resistant mouse model. Hepatic expression of macrophage markers measured by realtime RT-PCR remained unaltered in DIO mice despite characteristic expansion of adipose tissue-associated macrophages. DIO mouse livers displayed increased expression of alternative activation markers but unaltered proinflammatory cytokine expression when compared to lean mice. Kupffer cell ablation reduced hepatic anti-inflammatory cytokine IL-10 mRNA expression in lean and DIO mice by 95% and 84%, respectively. Despite decreased hepatic IL-6 gene expression after ablation in lean and DIO mice, hepatic STAT3 phosphorylation, Socs3 and acute phase protein mRNA expression increased. Kupffer cell ablation in DIO mice resulted in additional hepatic triglyceride accumulation and a 30-40% reduction in hepatic insulin receptor autophosphorylation and Akt activation. Implicating systemic loss of IL-10, high-fat-fed IL-10 knockout mice also displayed increased hepatic STAT3 signaling and hepatic triglyceride accumulation. Insulin signaling was not altered, however. In conclusion, Kupffer cells are a major source of hepatic IL-10 expression, the loss of which is associated with increased STAT3-dependent signaling and steatosis. One or more additional factors appear to be required, however, for the Kupffer cell-dependent protective effect on insulin receptor signaling in DIO mice.
Assuntos
Dieta/efeitos adversos , Fígado Gorduroso/metabolismo , Insulina/metabolismo , Células de Kupffer/metabolismo , Obesidade/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/farmacologia , Ácido Clodrônico/efeitos adversos , Ácido Clodrônico/farmacologia , Modelos Animais de Doenças , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Resistência à Insulina , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Células de Kupffer/patologia , Lipossomos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Obesidade/induzido quimicamente , Obesidade/patologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro , Receptor de Insulina/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Triglicerídeos/metabolismoRESUMO
A population pharmacokinetic (PPK) model to describe the pharmacokinetics of thalidomide in different patient populations was developed using data pooled from healthy subjects and patients with Hansen's disease, human immunodeficiency virus (HIV), and multiple myeloma (MM). The analysis data set had a total of 164 evaluable subjects who received various doses (50 to 400 mg) of oral thalidomide in single- and/or multiple-dose regimens. The plasma thalidomide concentrations were adequately described by a linear 1-compartment PPK model with first-order absorption and first-order elimination. Inclusion of MM as a covariate on apparent clearance (CL/F) accounted for 4.4% of the interindividual variability (IIV) of CL/F. Body weight as a covariate on CL/F and apparent volume of distribution (V/F) also improved model fitting slightly, accounting for 7.2% and 20% of IIV, respectively. Although inclusion of body weight and MM as covariates of CL/F and body weight on V/F improved the goodness of fit of the model in a statistically significant manner, the impact of this difference in CL/F is not considered clinically relevant. Other factors such as age, sex, race, creatinine clearance, and alanine transaminase had no effect on thalidomide pharmacokinetics. MM, HIV, and Hansen's disease have no clinically relevant effect on thalidomide disposition relative to healthy volunteers.