RESUMO
ABSTRACT: Ruxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway. This phase 2 study evaluated dosing, efficacy, and safety of add-on PI3Kδ inhibitor parsaclisib for patients with primary or secondary myelofibrosis with suboptimal response to ruxolitinib. Eligible patients remained on a stable ruxolitinib dose and received add-on parsaclisib 10 or 20 mg, once daily for 8 weeks, and once weekly thereafter (daily-to-weekly dosing; n = 32); or parsaclisib 5 or 20 mg, once daily for 8 weeks, then 5 mg once daily thereafter (all-daily dosing; n = 42). Proportion of patients achieving a ≥10% decrease in spleen volume at 12 weeks was 28% for daily-to-weekly dosing and 59.5% for all-daily dosing. Proportions of patients achieving ≥50% decrease at week 12 in Myelofibrosis Symptom Assessment Form and Myeloproliferative Neoplasms Symptom Assessment Form symptom scores were 14% and 18% for daily-to-weekly dosing, and 28% and 32% for all-daily dosing, respectively. Most common nonhematologic treatment-emergent adverse events were nausea (23%), diarrhea (22%), abdominal pain and fatigue (each 19%), and cough and dyspnea (each 18%). New-onset grade 3 and 4 thrombocytopenia were observed in 19% of patients, each dosed daily-to-weekly, and in 26% and 7% of patients dosed all-daily, respectively, managed with dose interruptions. Hemoglobin levels remained steady. The addition of parsaclisib to stable-dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib. This trial was registered at www.clinicaltrials.gov as #NCT02718300.
Assuntos
Nitrilas , Mielofibrose Primária , Pirimidinas , Pirrolidinas , Humanos , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/induzido quimicamente , Fosfatidilinositol 3-Quinases , Pirazóis/efeitos adversosRESUMO
BACKGROUND: Ruxolitinib improves splenomegaly and symptoms in patients with intermediate-2 or high-risk myelofibrosis; however, nearly half develop grade 3/4 anemia and/or thrombocytopenia, necessitating dose reductions and/or transfusions. We report findings from an open-label phase 2 study exploring a dose-escalation strategy aimed at preserving clinical benefit while reducing hematological adverse events early in ruxolitinib treatment. METHODS: Patients with myelofibrosis received ruxolitinib 10 mg twice daily (BID), with incremental increases of 5 mg BID at weeks 12 and 18 for lack of efficacy (maximum, 20 mg BID). Symptom severity was measured using the Myelofibrosis Symptom Assessment Form Total Symptom Score (MFSAF TSS). RESULTS: Forty-five patients were enrolled, 68.9% of whom had a Dynamic International Prognostic Scoring System score of 1 to 2 (i.e., intermediate-1 disease risk). Median percentage change in spleen volume from baseline to week 24 was - 17.3% (≥ 10% reduction achieved by 26 patients [57.8%]), with a clear dose response. Median percentage change in MFSAF TSS from baseline at week 24 was - 45.6%, also with a dose response. The most frequent treatment-emergent adverse events were anemia (26.7%), fatigue (22.2%), and arthralgias (20.0%). Grade 3/4 anemia (20.0%) and dose decreases due to anemia (11.1%) or thrombocytopenia (6.7%) were infrequent. CONCLUSIONS: A dose-escalation approach may mitigate worsening anemia during early ruxolitinib therapy in some patients with myelofibrosis. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01445769 . Registered September 23, 2011.
Assuntos
Janus Quinases/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Pirazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Janus Quinases/farmacologia , Masculino , Pessoa de Meia-Idade , Nitrilas , Pirazóis/farmacologia , PirimidinasRESUMO
BACKGROUND: Dysregulation of the Janus kinase (JAK)/signal transducers and activators of transcription pathway contributes to abnormal inflammatory responses and poor prognosis in non-small-cell lung cancer (NSCLC). We evaluated the JAK1/JAK2 inhibitor ruxolitinib plus pemetrexed/cisplatin first-line in patients with stage IIIB/IV or recurrent nonsquamous NSCLC with systemic inflammation (modified Glasgow prognostic score [mGPS] 1/2). PATIENTS AND METHODS: Part 1 was an open-label, safety run-in, in which we assessed ruxolitinib (15 mg twice daily [b.i.d.]) plus pemetrexed (500 mg/m2 intravenous, day 1) and cisplatin (75 mg/m2 intravenous, day 1). Ruxolitinib dose selection for part 2 required <3 dose-limiting toxicities (DLTs) for 9 evaluable patients. In part 2 patients were randomized to ruxolitinib or placebo (each plus pemetrexed/cisplatin). The trial terminated early for reasons unrelated to this trial. RESULTS: Fifteen patients enrolled in part 1 (median age, 64 years; 80% male, 80% mGPS 1) received ruxolitinib 15 mg b.i.d. plus pemetrexed/cisplatin. Median treatment duration was 140 days and no DLTs occurred in 11 evaluable patients. No new safety concerns arose when ruxolitinib was combined with pemetrexed/cisplatin. At study termination, 39 patients were randomized to ruxolitinib and 37 to placebo in part 2. Median treatment duration was 43 days. Response rate was 31% (12 of 39) with ruxolitinib and 35% (13 of 37) with placebo (all partial responses). CONCLUSION: Ruxolitinib 15 mg b.i.d. had an acceptable safety profile in combination with pemetrexed/cisplatin asfirst-line treatment of patients with stage IIIB/IV or recurrent nonsquamous NSCLC and systemic inflammation. Early study termination limited the interpretation of efficacy data in the randomized phase II part of the study.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inflamação/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/administração & dosagem , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Quimioterapia de Indução , Inflamação/imunologia , Inflamação/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Nitrilas , Pemetrexede/administração & dosagem , Prognóstico , Pirazóis/administração & dosagem , Pirimidinas , Taxa de SobrevidaRESUMO
BACKGROUND: Ruxolitinib, a Janus kinase 1 and 2 inhibitor, demonstrated improvements in spleen volume, symptoms, and survival over placebo and best available therapy in intermediate-2 or high-risk myelofibrosis patients with baseline platelet counts ≥100 × 109/L in phase III studies. The most common adverse events were dose-dependent anemia and thrombocytopenia, which were anticipated because thrombopoietin and erythropoietin signal through JAK2. These events were manageable, rarely leading to treatment discontinuation. Because approximately one-quarter of MF patients have platelet counts <100 × 109/L consequent to their disease, ruxolitinib was evaluated in this subset of patients using lower initial doses. Interim results of a phase II study of ruxolitinib in myelofibrosis patients with baseline platelet counts of 50-100 × 109/L are reported. METHODS: Ruxolitinib was initiated at a dose of 5 mg twice daily (BID), and doses could be increased by 5 mg once daily every 4 weeks to 10 mg BID if platelet counts remained adequate. Additional dosage increases required evidence of suboptimal efficacy. Assessments included measurement of spleen volume by MRI, MF symptoms by MF Symptom Assessment Form v2.0 Total Symptom Score [TSS]), Patient Global Impression of Change (PGIC); EORTC QLQ-C30, and safety/tolerability. RESULTS: By week 24, 62% of patients achieved stable doses ≥10 mg BID. Median reductions in spleen volume and TSS were 24.2% and 43.8%, respectively. Thrombocytopenia necessitating dose reductions and dose interruptions occurred in 12 and 8 patients, respectively, and occurred mainly in patients with baseline platelet counts ≤75 × 109/L. Seven patients experienced platelet count increases ≥15 × 109/L. Mean hemoglobin levels remained stable over the treatment period. Two patients discontinued for adverse events: 1 for grade 4 retroperitoneal hemorrhage secondary to multiple and suspected pre-existing renal artery aneurysms and 1 for grade 4 thrombocytopenia. CONCLUSIONS: Results suggest that a low starting dose of ruxolitinib with escalation to 10 mg BID may be appropriate in myelofibrosis patients with low platelet counts.
Assuntos
Plaquetas/patologia , Mielofibrose Primária/sangue , Mielofibrose Primária/tratamento farmacológico , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Idoso , Relação Dose-Resposta a Droga , Feminino , Humanos , Janus Quinases/antagonistas & inibidores , Masculino , Nitrilas , Contagem de Plaquetas , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas , Resultado do TratamentoRESUMO
COMFORT-I is a randomized, double-blind, placebo-controlled trial of the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib in 309 patients with intermediate-2 or high-risk myelofibrosis. This analysis of COMFORT-I describes the long-term efficacy and safety of ruxolitinib (median follow-up, 2 years). Spleen volume was measured by magnetic resonance imaging, and quality of life was evaluated using the EORTC QLQ-C30. Overall survival was determined according to randomized treatment group. At the time of this analysis, 100 of 155 patients randomized to ruxolitinib were still receiving treatment. All patients randomized to placebo crossed over to ruxolitinib or discontinued within 3 months of the primary analysis (median time to crossover, 41 weeks). Mean spleen volume reductions in the ruxolitinib group were 31.6% at week 24 and 34.9% at week 96; improvements in quality of life measures were also maintained. Improved survival was observed for ruxolitinib (n=27 deaths) versus placebo (n=41 deaths) (hazard ratio=0.58; 95% confidence interval: 0.36, 0.95; P=0.03). The incidence of new-onset grade 3 or 4 anemia and thrombocytopenia decreased over time to levels observed in patients receiving placebo. These data indicate that ruxolitinib treatment provides durable reductions in spleen volume and improvements in quality of life and suggest a continued survival advantage for ruxolitinib over placebo.
Assuntos
Janus Quinases/antagonistas & inibidores , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/mortalidade , Pirazóis/uso terapêutico , Idoso , Estudos Cross-Over , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Mielofibrose Primária/diagnóstico , Pirazóis/farmacologia , Pirimidinas , Taxa de Sobrevida/tendências , Resultado do TratamentoRESUMO
Patient-reported outcomes (PROs) and spleen size in patients not receiving therapy (N=154) in COMFORT-I, a randomized, double-blind study of the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis were evaluated. Baseline PROs indicated considerable disease burden. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scores, modified Myelofibrosis Symptom Assessment Form v2.0 Total Symptom Score, and Patient Reported Outcome Measurement Information System Fatigue scores worsened from baseline through week 24. At weeks 4 and 24, 18.3 and 40.2% of patients evaluated their condition as having worsened from baseline on the Patient Global Impression of Change questionnaire. Spleen volume and palpable length increased in most patients. These results demonstrate the progressive and debilitating effects of myelofibrosis. The consequences of delayed intervention should be assessed in the management of patients with myelofibrosis and treatment should be considered as clinically indicated for symptomatic relief or splenomegaly control.
Assuntos
Avaliação de Resultados em Cuidados de Saúde/métodos , Mielofibrose Primária/tratamento farmacológico , Pirazóis/uso terapêutico , Inquéritos e Questionários , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos Fase III como Assunto , Progressão da Doença , Método Duplo-Cego , Humanos , Janus Quinases/antagonistas & inibidores , Pessoa de Meia-Idade , Nitrilas , Placebos , Mielofibrose Primária/patologia , Pirimidinas , Ensaios Clínicos Controlados Aleatórios como Assunto , Baço/efeitos dos fármacos , Baço/patologia , Fatores de TempoRESUMO
Myelofibrosis (MF) patients can present with a wide spectrum of disease characteristics. We analysed the consistency of ruxolitinib efficacy across patient subgroups in the COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment (COMFORT-I,) a double-blind trial, where patients with intermediate-2 or high-risk MF were randomized to twice-daily oral ruxolitinib (n = 155) or placebo (n = 154). Subgroups analysed included MF subtype (primary, post-polycythaemia vera, post-essential thrombocythaemia), age (≤65, > 65 years), International Prognostic Scoring System risk group, baseline Eastern Cooperative Oncology Group performance status (0, 1, ≥2), JAK2 V617F mutation (positive, negative), baseline haemoglobin level (≥100, <100 g/l), baseline platelet count (100-200 × 10(9)/l, >200 × 10(9)/l), baseline palpable spleen size (≤10, >10 cm), and baseline quartile of spleen volume and Total Symptom Score (TSS; Q1 = lowest, Q4 = highest). Mean percentage change from baseline to week 24 in spleen volume and TSS were calculated for ruxolitinib and placebo in each subgroup. Overall survival was estimated by Kaplan-Meier method according to original randomization group. In ruxolitinib-treated patients, reductions in spleen volume and TSS and evidence of improved survival relative to placebo across subgroups were consistent with those seen in the COMFORT-I population, confirming that ruxolitinib is an effective therapy for the spectrum of MF patients studied in COMFORT-I.
Assuntos
Antineoplásicos/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Humanos , Pessoa de Meia-Idade , Nitrilas , Tamanho do Órgão , Mielofibrose Primária/mortalidade , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas , Baço/efeitos dos fármacos , Baço/patologia , Resultado do TratamentoRESUMO
PURPOSE: To assess the effects of ruxolitinib on symptom burden and quality of life (QoL) and to evaluate the ability of the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 to measure meaningful changes in myelofibrosis-related symptoms in patients with myelofibrosis. PATIENTS AND METHODS: COMFORT-I (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment-I) is a double-blind, placebo-controlled phase III study evaluating ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Exploratory analyses were conducted on the following patient-reported outcomes (PROs) assessments: modified MFSAF v2.0 (individual symptoms and Total Symptom Score [TSS]), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and Patient Global Impression of Change (PGIC). RESULTS: Patients receiving ruxolitinib experienced improvements in individual myelofibrosis-related symptoms, although patients receiving placebo experienced worsening (P < .001). The majority (91%) of ruxolitinib-treated patients designated as ≥ 50% TSS responders (≥ 50% TSS improvement) self-reported their condition as either "Much improved" or "Very much improved" on the PGIC. These patients achieved significant improvements in the EORTC QLQ-C30 functional domains and Global Health Status/QoL versus patients receiving placebo, who experienced worsening on these measures (P ≤ .0135). Ruxolitinib-treated patients with a lesser degree of symptom improvement (< 50% TSS responders) also achieved improvements over placebo on these measures. The degree of spleen volume reduction with ruxolitinib correlated with improvements in TSS, PGIC, PROMIS Fatigue Scale, and EORTC Global Health Status/QoL. Ruxolitinib-treated patients who achieved a ≥ 35% reduction in spleen volume experienced the greatest improvements in these PROs. CONCLUSION: Ruxolitinib-treated patients achieved clinically meaningful improvements in myelofibrosis-related symptoms and QoL, but patients receiving placebo reported worsening of symptoms and other PROs.
Assuntos
Janus Quinases/antagonistas & inibidores , Pirazóis/uso terapêutico , Baço/efeitos dos fármacos , Anemia/induzido quimicamente , Relação Dose-Resposta a Droga , Método Duplo-Cego , Fadiga/induzido quimicamente , Humanos , Nitrilas , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/enzimologia , Mielofibrose Primária/patologia , Pirazóis/efeitos adversos , Pirimidinas , Qualidade de Vida , Baço/patologia , Inquéritos e Questionários , Trombocitopenia/induzido quimicamente , Resultado do TratamentoRESUMO
BACKGROUND: Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis. METHODS: In this double-blind trial, we randomly assigned patients with intermediate-2 or high-risk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival. RESULTS: The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P=0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group. CONCLUSIONS: Ruxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.).
Assuntos
Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Mielofibrose Primária/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Esplenomegalia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Nitrilas , Tamanho do Órgão , Mielofibrose Primária/mortalidade , Mielofibrose Primária/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas , Qualidade de Vida , Baço/efeitos dos fármacos , Baço/patologiaRESUMO
BACKGROUND: Symptomatic burden from constitutional symptoms, anemia, and splenomegaly-related symptoms are common and morbidity inducing in patients with myelofibrosis (MF). The authors previously developed a MF-specific instrument for capturing the burden of MF-associated disease-related symptoms, the Myelofibrosis Symptom Assessment Form. METHODS: The authors evaluated the usefulness of serial administration of the Myelofibrosis Symptom Assessment Form as an instrument for the assessment of symptomatic burden and improvement in conjunction with the therapeutic clinical trial of the open label phase 2 trial of the JAK1 and JAK2 inhibitor INCB018424 in patients with MF. RESULTS: The analysis cohort of 87 patients treated in this trial demonstrated that the instrument was comprehensive and sensitive to symptoms present at trial enrollment. In addition, baseline Myelofibrosis Symptom Assessment Form symptom scores correlated well with objective parameters such as splenomegaly and impaired performance status assessed by the 6-minute walk test. Serial administration while on therapy with INCB018424 demonstrated the instrument to be sensitive to symptomatic change, and that improvements in symptoms correlated well with objective improvements in both weight loss and performance status (6-minute walk test). CONCLUSIONS: The use of the Myelofibrosis Symptom Assessment Form in this phase 2 trial helped characterize the symptomatic improvements observed with use of INCB018424 in MF patients. In an era of many targeted therapies undergoing testing for MF with potential symptomatic benefit, the Myelofibrosis Symptom Assessment Form may provide a useful tool for objective symptomatic assessment and potentially allow some nonrandomized comparison between therapeutic agents.
Assuntos
Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Mielofibrose Primária/tratamento farmacológico , Pirazóis/uso terapêutico , Inquéritos e Questionários , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Masculino , Nitrilas , Mielofibrose Primária/diagnóstico , Pirimidinas , Esplenomegalia/diagnósticoRESUMO
C-C chemokine receptor 5 (CCR5) is a clinically proven target for inhibition of HIV-1 infection and a potential target for various inflammatory diseases. In this article, we describe 5-[(4-{(3S)-4-[(1R,2R)-2-ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine dihydrochloride (INCB9471), a potent and specific inhibitor of human CCR5 that has been proven to be safe and efficacious in viral load reduction in phase I and II human clinical trails. INCB9471 was identified using a primary human monocyte-based radioligand competition binding assay. It potently inhibited macrophage inflammatory protein-1ß-induced monocyte migration and infection of peripheral blood mononuclear cells by a panel of R5-HIV-1 strains. The results from binding and signaling studies using incremental amounts of INCB9471 demonstrated INCB9471 as a noncompetitive CCR5 inhibitor. The CCR5 residues that are essential for interaction with INCB9471 were identified by site-specific mutagenesis studies. INCB9471 rapidly associates with but slowly dissociates from CCR5. When INCB9471 was compared with three CCR5 antagonists that had been tested in clinical trials, the potency of INCB9471 in blocking CCR5 ligand binding was similar to those of 4,6-dimethyl-5-{[4-methyl-4-((3S)-3-methyl-4-{(1R0-2-(methyloxy)-1-[4-(trifluoromethyl) phenyl]ethyl}-1-piperazingyl)-1-piperidinyl]carbonyl}pyrimidine (SCH-D; vicriviroc), 4-{[4-({(3R)-1-butyl-3-[(R)-cyclohexyl(hydroxyl)methyl]-2, 5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenyl]oxy}benzoic acid hydrochloride (873140; aplaviroc), and 4,4-difluoro-N-((1S)-3-{(3-endo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropyl)cyclohexanecarboxamide (UK427857; maraviroc). Its inhibitory activity against CCR5-mediated Ca(2+) mobilization was also similar to those of SCH-D and 873140. Further analysis suggested that INCB9471 and UK427857 may have different binding sites on CCR5. The significance of two CCR5 antagonists with different binding sites is discussed in the context of potentially overcoming drug-resistant HIV-1 strains.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Movimento Celular/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Sítio Alostérico/fisiologia , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/uso terapêutico , Movimento Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Células HEK293 , Infecções por HIV/imunologia , Infecções por HIV/patologia , Humanos , Macaca fascicularis , Monócitos/patologia , Piperazinas/química , Ligação Proteica/fisiologia , Pirimidinas/química , Receptores CCR5/fisiologiaRESUMO
BACKGROUND: Myelofibrosis is a Philadelphia chromosomenegative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor. METHODS: We conducted a phase 1−2 trial of INCB018424 in patients with JAK2 V617F−positive or JAK2 V617F−negative primary myelofibrosis, postessential thrombocythemia myelofibrosis, or postpolycythemia vera myelofibrosis. RESULTS: A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis. CONCLUSIONS: INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed. (Funded by Incyte; ClinicalTrials.gov number, NCT00509899.)
Assuntos
Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Mielofibrose Primária/tratamento farmacológico , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/tratamento farmacológico , Anemia/etiologia , Biomarcadores/sangue , Citocinas/sangue , Relação Dose-Resposta a Droga , Feminino , Hepatomegalia/tratamento farmacológico , Hepatomegalia/etiologia , Humanos , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Mutação , Nitrilas , Mielofibrose Primária/sangue , Mielofibrose Primária/complicações , Mielofibrose Primária/genética , Pirimidinas , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Baço/efeitos dos fármacos , Baço/patologiaRESUMO
A series of 2',3'-dideoxy (D2) and 2',3'-didehydro-2',3'-dideoxy (D4) 5-fluorocytosine nucleosides modified with substituted benzoyl, heteroaromatic carbonyl, cycloalkylcarbonyl and alkanoyl at the N4-position were synthesized and evaluated for anti-human immunodeficiency virus type 1 (HIV-1) and anti-hepatitis B virus (HBV) activity in vitro. For most D2-nucleosides, N4-substitutions improved the anti-HIV-1 activity markedly without increasing the cytotoxicity. In the D4-nucleosides series, some of the substituents at the N4-position enhanced the anti-HIV-1 activity with a modest increase in the cytotoxicity. The most potent and selective N4-modified nucleoside for the D2-series was N4-p-iodobenzoyl-D2FC, which had a 46-fold increase in anti-HIV-1 potency in MT-2 cells compared to the parent nucleoside D-D2FC. In the D4-series, N4-p-bromobenzoyl-D4FC was 12-fold more potent in MT-2 cells compared to the parent nucleoside D-D4FC. All eight N4-p-halobenzoyl-substituted D2- and D4-nucleosides evaluated against HBV in HepAD38 cells demonstrated equal or greater potency than the two parental compounds, D-D2FC and D-D4FC. The N4-modification especially in the D2-nucleoside series containing the N4-nicotinoyl, o-nitrobenzoyl and n-butyryl showed a significant reduction in mitochondrial toxicity relative to the parent nucleoside analogue. Although the 5'-triphosphate of the parent compound (D-D4FC-TP) was formed from the N4-acyl-D4FC analogues in different cells, the levels of the 5'-triphosphate nucleotide did not correlate with the cell-derived 90% effective antiviral concentrations (EC90), suggesting that a direct interaction of the triphosphates of these N4-acyl nucleosides was involved in the antiviral activity.
Assuntos
Antivirais/farmacologia , Zalcitabina/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antivirais/síntese química , Antivirais/química , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Chlorocebus aethiops , Relação Dose-Resposta a Droga , HIV-1/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Células Vero , Zalcitabina/análogos & derivados , Zalcitabina/síntese química , Zalcitabina/químicaRESUMO
The backbone of effective highly active antiretroviral therapy regimens for the treatment of HIV infections currently contains at least two nucleosides. Among the features that influence the potency of each component of a regimen and the overall efficacy of the combination are the cellular uptake and bioconversion of nucleoside analogues to their active triphosphate form, and the extent of possible interactions in these steps that might occur when more than one nucleoside is used in a regimen. D-d4FC (Reverset), a new cytidine analogue with the ability to inhibit many nucleoside-resistant viral variants, was examined for these parameters. In phytohemaglutinin-stimulated human peripheral blood mononuclear cells, D-d4FC was taken up in a rapid (8 h to 50% maximal value), saturable (plateau above 10 microM parent nucleoside concentration) process, resulting in levels of D-d4FC triphosphate that should provide potent antiviral activity against a variety of virus genotypes. Based on measurement of antiviral effects in cell culture, additive and in some cases, synergistic interactions were observed with protease inhibitors, non-nucleoside reverse transcriptase inhibitors or other nucleosides, including cytidine analogues.
Assuntos
Fármacos Anti-HIV/farmacologia , Citidina Trifosfato/farmacologia , Farmacorresistência Viral , HIV-1/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Células Cultivadas , Citidina Trifosfato/análogos & derivados , Citidina Trifosfato/metabolismo , Interações Medicamentosas , Inibidores da Protease de HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/fisiologia , Humanos , Membranas Intracelulares/metabolismo , Leucócitos Mononucleares/metabolismo , Nucleosídeos/química , Nucleosídeos/farmacologia , Fosforilação/efeitos dos fármacos , Fito-Hemaglutininas , Zalcitabina/análogos & derivadosRESUMO
Nucleoside reverse transcriptase inhibitors (NRTIs) represent the cornerstone of highly active antiretroviral therapy when combined with non-nucleoside reverse transcriptase inhibitors (NNRTIs) or HIV-1 protease inhibitors (PIs). Unlike the NNRTIs and PIs, NRTIs must be successively phosphorylated by cellular kinases to a triphosphate form, which represents the active metabolite possessing antiviral activity. Emergence of viral resistance to NRTIs has severely hampered treatment options for persons infected with HIV-1. As such, there is an urgent need to develop NRTIs capable of suppressing NRTI-resistant strains of HIV-1. We have recently reported that the cytidine analogue D-d4FC (DPC817, Reverset) effectively inhibits clinically prevalent resistant strains of HIV-1. In this report, we have extended these findings and now describe a detailed resistance profile for this novel NRTI. By examining a panel of 50 viruses carrying RTs derived from HIV-1 clinical isolates displaying a wide range of NRTI resistance mutations, we report that the median fold increase in effective antiviral concentration for such a panel of viruses is 3.2, which is comparable to tenofovir (2.8-fold) and didanosine (2.4-fold). D-d4FC is highly effective at inhibiting subsets of lamivudine- and zidovudine-resistant variants but, like other NRTIs, seems less potent against multi-NRTI-resistant viruses, particularly those carrying the Q151M complex of mutations. Finally, in vitro selections for HIV-1 mutants capable of replicating in the presence of D-d4FC yielded a mutant carrying the RT K65R mutation. This mutation confers 5.3- to 8.7-fold resistance to D-d4FC in vitro. These findings suggest that D-d4FC may represent an alternative NRTI for the treatment of individuals infected with lamivudine- and zidovudine-resistant strains of HIV-1.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/farmacologia , Citidina Trifosfato/farmacologia , Farmacorresistência Viral Múltipla , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Organofosfonatos , Inibidores da Transcriptase Reversa/farmacologia , Adenina/farmacologia , Linhagem Celular , Citidina Trifosfato/análogos & derivados , Citidina Trifosfato/análise , Didanosina/farmacologia , Farmacorresistência Viral Múltipla/genética , Genótipo , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Lamivudina/farmacologia , Mutação , Compostos Organofosforados/farmacologia , Especificidade da Espécie , Tenofovir , Transfecção , Zalcitabina/análogos & derivados , Zidovudina/farmacologiaRESUMO
A series of P1/P1' substituted cyclic urea analogues were prepared in an attempt to increase the intra-cellular antiviral potency of the nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851. The effect of alkyl substitution of the P1/P1' residues on cellular antiviral potency, protein binding, resistance profile and pharmacokinetics are described.
Assuntos
Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , Ureia/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Cães , Resistência a Medicamentos , HIV/efeitos dos fármacos , Inibidores da Protease de HIV/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
A series of peptide boronic acids containing extended, hydrophobic P1 residues was prepared to probe the shallow, hydrophobic S1 region of HCV NS3 protease. The p-trifluoromethylphenethyl P1 substituent was identified as optimal with respect to inhibitor potency for NS3 and selectivity against elastase and chymotrypsin.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Ácidos Borônicos/síntese química , Ácidos Borônicos/farmacologia , Hepacivirus/enzimologia , Peptídeos/síntese química , Peptídeos/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Quimotripsina/antagonistas & inibidores , Hepacivirus/efeitos dos fármacos , Humanos , Indicadores e Reagentes , Leucócitos/efeitos dos fármacos , Leucócitos/enzimologia , Pâncreas/enzimologia , Elastase Pancreática/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Efavirenz and a series of related quinazolinone nonnucleoside inhibitors of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) were evaluated in a series of two-drug combinations with several nucleoside RT inhibitors (NRTIs), nonnucleoside RT inhibitors (NNRTIs), and protease inhibitors (PIs). These combinations were tested in an established HIV-1 RT enzyme assay and a cell-based yield reduction assay with HIV-1 (replicative form [RF])-infected MT-2 cells. Synergy, additivity, and antagonism were determined in the two different assay systems by the method of Chou and Talalay (T.-C. Chou and P. Talalay, Adv. Enzyme Reg. 22:27-55, 1984). Efavirenz, DPC082, DPC083, DPC961, and DPC963 used in combination with the NRTIs zidovudine and lamivudine acted synergistically to inhibit RT activity in the HIV-1 RT enzyme assay and additively to slightly synergistically to inhibit HIV-1 (RF) replication in the yield reduction assay. The five NNRTIs in combination with the PI nelfinavir acted additively in the yield reduction assay to inhibit HIV-1 replication. Interestingly, efavirenz in combination with a second NNRTI acted additively to inhibit HIV-1 RT function in the enzyme assay, while it acted antagonistically to inhibit HIV-1 (RF) replication in the yield reduction assay. These data suggest that antiretroviral combination regimens containing multiple NNTRIs should be given thorough consideration before being used.
Assuntos
Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Alcinos , Benzoxazinas , Células Cultivadas , Ciclopropanos , Combinação de Medicamentos , Interações Medicamentosas , Transcriptase Reversa do HIV/biossíntese , HIV-1/enzimologia , Humanos , Nevirapina/farmacologia , Nucleosídeos/farmacologia , Oxazinas/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
Highly active antiretroviral therapy (HAART) is the standard treatment for infection with the human immunodeficiency virus (HIV). HAART regimens consist of protease inhibitors or nonnucleoside reverse transcriptase inhibitors combined with two or more nucleoside reverse transcriptase inhibitors (NRTIs). DPC 817, 2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (PSI 5582 D-D4FC) is a potent inhibitor of HIV type 1 replication in vitro. Importantly, DPC 817 retains activity against isolates harboring mutations in the reverse transcriptase gene that confer resistance to lamivudine (3TC) and zidovudine (AZT), which are frequent components of initial HAART regimens. DPC 817 combines this favorable resistance profile with rapid uptake and conversion to the active metabolite DPC 817-triphosphate, which has an intracellular half-life of 13 to 17 h. Pharmacokinetics in the rhesus monkey suggest low clearance of parent DPC 817 and a plasma half-life longer than that of either AZT or 3TC. Together, these properties suggest that DPC 817 may be useful as a component of HAART regimens in individuals with resistance to older NRTI agents.