RESUMO
BACKGROUND: Patients with hidradenitis suppurativa have substantial unmet clinical needs and scarce therapeutic options. We aimed to assess the efficacy and safety of bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F and IL-17A, in patients with moderate-to-severe hidradenitis suppurativa. METHODS: BE HEARD I and II were two identically designed, 48-week randomised, double-blind, placebo-controlled, multicentre phase 3 trials. Patients aged 18 years or older with moderate-to-severe hidradenitis suppurativa were randomly assigned 2:2:2:1 using interactive response technology (stratified by worst Hurley Stage at baseline and baseline systemic antibiotic use) to receive subcutaneous bimekizumab 320 mg every 2 weeks; bimekizumab 320 mg every 2 weeks to week 16, then every 4 weeks to week 48; bimekizumab 320 mg every 4 weeks to week 48; or placebo to week 16, then bimekizumab 320 mg every 2 weeks. The primary outcome was an hidradenitis suppurativa clinical response of at least 50%, defined as a reduction in total abscess and inflammatory nodule count of at least 50% from baseline with no increase from baseline in abscess or draining tunnel count (HiSCR50) at week 16. Efficacy analyses included all randomly assigned study patients (intention-to-treat population). Safety analyses included all patients who received at least one full or partial dose of study treatment in the safety set, and of bimekizumab in the active-medication set. These trials are registered at ClinicalTrials.gov, NCT04242446 and NCT04242498, and both are completed. FINDINGS: Patients for BE HEARD I were recruited from Feb 19, 2020, to Oct 27, 2021, and 505 patients were enrolled and randomly assigned. Patients for BE HEARD II were recruited from March 2, 2020, to July 28, 2021, and 509 patients were enrolled and randomly assigned. The primary outcome at week 16 was met in the group who received bimekizumab every 2 weeks using modified non-responder imputation; higher responder rates were observed with bimekizumab versus placebo in both trials: 138 (48%) of 289 patients versus 21 (29%) of 72 patients in BE HEARD I (odds ratio [OR] 2·23 [97·5% CI 1·16-4·31]; p=0·0060) and 151 (52%) of 291 patients versus 24 (32%) of 74 patients in BE HEARD II (2·29 [1·22-4·29]; p=0·0032). In BE HEARD II, HiSCR50 was also met in the group who were administered bimekizumab every 4 weeks (77 [54%] of 144 vs 24 [32%] of 74 with placebo; 2·42 [1·22-4·80]; p=0·0038). Responses were maintained or increased to week 48. Serious treatment-emergent adverse events were reported in 40 (8%) patients in BE HEARD I and in 24 (5%) patients in BE HEARD II treated with bimekizumab over 48 weeks. The most frequently reported treatment-emergent adverse events to week 48 were hidradenitis in both trials, in addition to coronavirus infection and diarrhoea in BE HEARD I, and oral candidiasis and headache in BE HEARD II. One death was reported across the two trials, and was due to congestive heart failure in a patient with substantial cardiovascular history treated with bimekizumab every 2 weeks in BE HEARD I (considered unrelated to bimekizumab treatment by the investigator). No new safety signals were observed. INTERPRETATION: Bimekizumab was well tolerated by patients with hidradenitis suppurativa and produced rapid and deep clinically meaningful responses that were maintained up to 48 weeks. Data from these two trials support the use of bimekizumab for the treatment of patients with moderate-to-severe hidradenitis suppurativa. FUNDING: UCB Pharma.
Assuntos
Anticorpos Monoclonais Humanizados , Hidradenite Supurativa , Humanos , Hidradenite Supurativa/tratamento farmacológico , Método Duplo-Cego , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Resultado do Tratamento , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Índice de Gravidade de Doença , Interleucina-17/antagonistas & inibidoresRESUMO
BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin-17A and interleukin-17F. The efficacy and safety of bimekizumab as compared with the tumor necrosis factor inhibitor adalimumab in patients with moderate-to-severe plaque psoriasis have not been extensively examined. METHODS: We randomly assigned patients with moderate-to-severe plaque psoriasis in a 1:1:1 ratio to receive subcutaneous bimekizumab at a dose of 320 mg every 4 weeks for 56 weeks; bimekizumab at a dose of 320 mg every 4 weeks for 16 weeks, then every 8 weeks for weeks 16 to 56; or subcutaneous adalimumab at a dose of 40 mg every 2 weeks for 24 weeks, followed by bimekizumab at a dose of 320 mg every 4 weeks to week 56. The primary end points were a 90% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score (PASI 90 response; PASI scores range from 0 to 72, with higher scores indicating worse disease) and an Investigator's Global Assessment (IGA) score of 0 or 1, signifying clear or almost clear skin (scores range from 0 [clear skin] to 4 [severe disease]), at week 16. The analysis of the primary end points tested noninferiority at a margin of -10 percentage points and then tested for superiority. RESULTS: A total of 614 patients were screened, and 478 were enrolled; 158 patients were assigned to receive bimekizumab every 4 weeks, 161 to receive bimekizumab every 4 weeks and then every 8 weeks, and 159 to receive adalimumab. The mean age of the patients was 44.9 years; the mean PASI score at baseline was 19.8. At week 16, a total of 275 of 319 patients (86.2%) who received bimekizumab (both dose groups combined) and 75 of 159 (47.2%) who received adalimumab had a PASI 90 response (adjusted risk difference, 39.3 percentage points; 95% confidence interval [CI], 30.9 to 47.7; P<0.001 for noninferiority and superiority). A total of 272 of 319 patients (85.3%) who received bimekizumab and 91 of 159 (57.2%) who received adalimumab had an IGA score of 0 or 1 (adjusted risk difference, 28.2 percentage points; 95% CI, 19.7 to 36.7; P<0.001 for noninferiority and superiority). The most common adverse events with bimekizumab were upper respiratory tract infections, oral candidiasis (predominantly mild or moderate as recorded by the investigator), hypertension, and diarrhea. CONCLUSIONS: In this 56-week trial, bimekizumab was noninferior and superior to adalimumab through 16 weeks in reducing symptoms and signs of plaque psoriasis but was associated with a higher frequency of oral candidiasis and diarrhea. Longer and larger trials are required to determine the efficacy and safety of bimekizumab as compared with other agents in the treatment of plaque psoriasis. (Funded by UCB Pharma; BE SURE ClinicalTrials.gov number, NCT03412747.).
Assuntos
Adalimumab/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Interleucina-17/antagonistas & inibidores , Psoríase/tratamento farmacológico , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Candidíase Bucal/etiologia , Diarreia/induzido quimicamente , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits both interleukin-17A and interleukin-17F. The efficacy and safety of bimekizumab as compared with secukinumab, which selectively inhibits interleukin-17A alone, in patients with moderate-to-severe plaque psoriasis have not been extensively examined. METHODS: In this phase 3b trial, we randomly assigned patients with moderate-to-severe plaque psoriasis, in a 1:1 ratio, to receive bimekizumab subcutaneously at a dose of 320 mg every 4 weeks or secukinumab subcutaneously at a dose of 300 mg weekly to week 4, followed by every 4 weeks to week 48. At week 16, patients receiving bimekizumab underwent rerandomization, in a 1:2 ratio, to receive maintenance dosing every 4 weeks or every 8 weeks to week 48. The primary end point was 100% reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 16. The primary analysis was first tested for the noninferiority of bimekizumab to secukinumab at a margin of -10 percentage points and then tested for superiority. RESULTS: A total of 1005 patients were screened and 743 were enrolled; 373 patients were assigned to receive bimekizumab and 370 to receive secukinumab. At week 16, a total of 230 patients (61.7%) in the bimekizumab group and 181 (48.9%) in the secukinumab group had a 100% reduction from baseline in the PASI score (PASI 100) (adjusted risk difference, 12.7 percentage points; 95% confidence interval [CI], 5.8 to 19.6); bimekizumab was shown to be noninferior and superior to secukinumab (P<0.001 for noninferiority and superiority). At week 48, a total of 250 patients (67.0%) treated with bimekizumab had a PASI 100 response, as compared with 171 patients (46.2%) treated with secukinumab (adjusted risk difference, 20.9 percentage points; 95% CI, 14.1 to 27.7; P<0.001). At the week 4 time point, 265 patients (71.0%) in the bimekizumab group had 75% or greater reduction from baseline in the PASI score, as compared with 175 patients (47.3%) in the secukinumab group (adjusted risk difference, 23.7; 95% CI, 17.0 to 30.4; P<0.001). Oral candidiasis occurred more often with bimekizumab (72 patients, 19.3%) than with secukinumab (11 patients, 3.0%). CONCLUSIONS: In patients with moderate-to-severe psoriasis, treatment with bimekizumab resulted in greater skin clearance than treatment with secukinumab over 16 and 48 weeks but was associated with oral candidiasis (predominantly mild or moderate as recorded by the investigator). Longer and larger trials are required to determine the comparative effect and risks of interleukin-17 inhibitors in psoriasis. (Funded by UCB Pharma; BE RADIANT ClinicalTrials.gov number, NCT03536884.).
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Interleucina-17/antagonistas & inibidores , Psoríase/tratamento farmacológico , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Candidíase Bucal/etiologia , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Patients with psoriasis require long-term management; therefore, understanding the long-term safety of new treatments, such as bimekizumab (BKZ), is crucial. OBJECTIVES: To evaluate BKZ's 3-year safety profile in patients with moderate-to-severe plaque psoriasis. METHODS: Three years of safety data were pooled from three phase III trials (BE VIVID, BE READY and BE SURE) and their ongoing open-label extension (BE BRIGHT). Treatment-emergent adverse events (TEAEs) are reported using exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY). RESULTS: In total, 1495 patients received at least one BKZ dose; total BKZ exposure was 3876.4 PY. The overall EAIR of TEAEs was 175.5/100 PY and decreased with longer exposure to BKZ. The most commonly reported TEAEs were nasopharyngitis, oral candidiasis and upper respiratory tract infection (EAIRs of 15.0/100 PY, 10.1/100 PY and 6.5/100 PY, respectively); 99.3% of oral candidiasis events were mild or moderate in severity, none were serious and few led to discontinuation. EAIRs of other TEAEs of interest were low, including serious infections (1.2/100 PY), adjudicated inflammatory bowel disease (0.2/100 PY) and laboratory elevations in aspartate aminotransferase or alanine aminotransferase (> 5 × upper limit of normal: 0.6/100 PY). CONCLUSIONS: In these analyses pooled across 3â years, no new safety signals were observed with longer exposure to BKZ. The vast majority of oral candidiasis events were mild or moderate in severity, as reported previously.
Assuntos
Candidíase Bucal , Doenças Inflamatórias Intestinais , Psoríase , Humanos , Anticorpos Monoclonais Humanizados/efeitos adversos , Candidíase Bucal/induzido quimicamente , Candidíase Bucal/tratamento farmacológico , Método Duplo-Cego , Doenças Inflamatórias Intestinais/epidemiologia , Psoríase/tratamento farmacológico , Psoríase/induzido quimicamente , Índice de Gravidade de Doença , Resultado do Tratamento , Ensaios Clínicos Fase III como AssuntoRESUMO
BACKGROUND: Patients with psoriasis have increased risk of suicidal ideation and behavior (SIB) and depression. Bimekizumab, a biologic that inhibits interleukin (IL)-17A and IL-17F, received Food and Drug Administration approval in 2023 for moderate to severe plaque psoriasis, following 2021 European Medicines Agency approval. OBJECTIVE: To report SIB and depression in patients with moderate to severe psoriasis treated in bimekizumab clinical trials. METHODS: Mental health changes, including neuropsychiatric events, were actively monitored across 9 bimekizumab clinical trials in psoriasis phase 2/3 trials. The patient-reported electronic Columbia-Suicide Severity Rating Scale (measuring SIB) and Patient Health Questionnaire-9 (measuring depression) were administered, monitored by an independent Neuropsychiatric Adjudication Committee. RESULTS: Throughout 7166 patient-years (PY) of bimekizumab exposure, the adjudicated SIB rate was 0.13/100PY; SIB ranges for the general psoriasis population and patients receiving anti-IL-17A/anti-IL-23 therapies are 0.09 to 0.54/100PY and 0.09 to 0.19/100PY, respectively. At week 16, 92.9% vs 81.1% of bimekizumab- vs placebo-treated patients had no/minimal depression. Newonset positive electronic Columbia-Suicide Severity Rating Scale responses and mean Patient Health Questionnaire-9 scores were low for bimekizumab-treated patients. LIMITATIONS: Patient exclusion for significant/severe prespecified SIB/depression history. CONCLUSION: The long-term adjudicated SIB rate with bimekizumab was low and within ranges reported in the general psoriasis patient population and psoriasis patients treated with anti-IL-17A/anti-IL-23 biologics. Screening/monitoring questionnaires reported low SIB and depression levels.
Assuntos
Anticorpos Monoclonais Humanizados , Depressão , Psoríase , Índice de Gravidade de Doença , Ideação Suicida , Humanos , Psoríase/tratamento farmacológico , Psoríase/psicologia , Masculino , Feminino , Depressão/epidemiologia , Pessoa de Meia-Idade , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Interleucina-17/antagonistas & inibidores , Ensaios Clínicos Fase II como Assunto , Saúde Mental , Resultado do TratamentoRESUMO
BACKGROUND: Patients with psoriasis are at increased risk of liver function abnormalities. OBJECTIVE: Explore rates of hepatic treatment-emergent adverse events (TEAEs) and changes in liver parameters in bimekizumab-treated patients with psoriasis. METHODS: Data are reported from 5 phase 3/3b trials over 2 years. Hepatic TEAEs, laboratory elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST), and changes in clinical markers of liver fibrosis (Fibrosis-4 [FIB-4] Index and AST to Platelet Ratio Index [APRI]) are reported. TEAEs are presented using exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY). RESULTS: 2186 patients received ≥1 bimekizumab dose. Over 2 years, the EAIR of hepatic TEAEs was 3.5/100 PY and did not increase from first to second year. 2-year EAIRs of ALT/AST elevations >3x and >5x the upper limit of normal were 2.3 and 0.6/100 PY; rates were similar to placebo, adalimumab, secukinumab, and ustekinumab during controlled study periods. FIB-4 and APRI scores did not increase through 2 years, regardless of fibrosis risk at baseline. LIMITATIONS: Obesity, diabetes, dyslipidemia, chronic alcohol consumption, and medication changes are confounding factors for hepatic dysfunction. CONCLUSION: Rates of hepatic adverse events (AEs) with bimekizumab were consistent through 2 years; incidences of transaminase elevations were similar to comparators during phase 3/3b controlled study periods.
Assuntos
Alanina Transaminase , Anticorpos Monoclonais Humanizados , Aspartato Aminotransferases , Doença Hepática Induzida por Substâncias e Drogas , Psoríase , Índice de Gravidade de Doença , Humanos , Psoríase/tratamento farmacológico , Feminino , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/efeitos adversos , Aspartato Aminotransferases/sangue , Alanina Transaminase/sangue , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Adulto , Cirrose Hepática/epidemiologia , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , IncidênciaRESUMO
Expression of the cell cycle regulatory gene CDK6 is required for Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) cell growth, whereas expression of the closely related CDK4 protein is dispensable. Moreover, CDK6 silencing is more effective than treatment with the dual CDK4/6 inhibitor palbociclib in suppressing Ph+ ALL in mice, suggesting that the growth-promoting effects of CDK6 are, in part, kinase-independent in Ph+ ALL. Accordingly, we developed CDK4/6-targeted proteolysis-targeting chimeras (PROTACs) that inhibit CDK6 enzymatic activity in vitro, promote the rapid and preferential degradation of CDK6 over CDK4 in Ph+ ALL cells, and markedly suppress S-phase cells concomitant with inhibition of CDK6-regulated phospho-RB and FOXM1 expression. No such effects were observed in CD34+ normal hematopoietic progenitors, although CDK6 was efficiently degraded. Treatment with the CDK6-degrading PROTAC YX-2-107 markedly suppressed leukemia burden in mice injected with de novo or tyrosine kinase inhibitor-resistant primary Ph+ ALL cells, and this effect was comparable or superior to that of the CDK4/6 enzymatic inhibitor palbociclib. These studies provide "proof of principle" that targeting CDK6 with PROTACs that inhibit its enzymatic activity and promote its degradation represents an effective strategy to exploit the "CDK6 dependence" of Ph+ ALL and, perhaps, of other hematologic malignancies. Moreover, they suggest that treatment of Ph+ ALL with CDK6-selective PROTACs would spare a high proportion of normal hematopoietic progenitors, preventing the neutropenia induced by treatment with dual CDK4/6 inhibitors.
Assuntos
Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 6 Dependente de Ciclina/metabolismo , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Perfilação da Expressão Gênica , Genes cdc , Humanos , Camundongos , Estrutura Molecular , Fosforilação , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/uso terapêutico , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A. OBJECTIVES: To assess patients' ability to self-inject bimekizumab subcutaneously using a 1 mL safety syringe or auto-injector. METHODS: DV0002 and DV0006 were sub-studies of BE BRIGHT, a multicenter, phase 3 open-label extension study. Patients with moderate to severe plaque psoriasis received bimekizumab 320 mg (2x160 mg injections) every 4 or 8 weeks and were randomized 1:1 to the safety syringe or the auto-injector. The ability of patients to safely and effectively self-inject bimekizumab was assessed at 8 weeks (primary endpoint) and immediately after self-injection training at Baseline (secondary endpoint). Patient experience was evaluated using the pain visual analog scale (VAS; 0–100 mm; 100 being worst pain), and the Self-Injection Assessment Questionnaire (SIAQ; 0–10; 10 being most positive experience). RESULTS: All evaluable patients in DV0002 (n=125) and DV0006 (n=86) safely and effectively self-injected bimekizumab at Week 8. All evaluable patients in DV0002 who used the safety syringe (n=64) and 97.1% (n=66/68) who used the auto-injector, as well as all evaluable DV0006 patients (n=88) also self-injected bimekizumab safely and effectively at Baseline. Median VAS scores were low (range: 7.0–20.0), and median pre-injection and post-injection SIAQ scores were high (range: 5.8–10.0 and 7.1–10.0, respectively) across both devices, sub-studies, and timepoints. CONCLUSIONS: Both devices provide a safe and effective option for patients to self-administer bimekizumab. Furthermore, patients reported a positive self-injection experience. TRIAL REGISTRATION: NCT03766685 J Drugs Dermatol. 2022;21(2):162-171. doi:10.36849/JDD.6274THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.
Assuntos
Anticorpos Monoclonais Humanizados , Psoríase , Autoadministração/instrumentação , Anticorpos Monoclonais Humanizados/administração & dosagem , Método Duplo-Cego , Humanos , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Epigenetic regulators play a critical role in normal and malignant hematopoiesis. Deregulation, including epigenetic deregulation, of the HOXA gene cluster drives transformation of about 50% of acute myeloid leukemia. We recently showed that the Histone 3 Lysine 9 methyltransferase SETDB1 negatively regulates the expression of the pro-leukemic genes Hoxa9 and its cofactor Meis1 through deposition of promoter H3K9 trimethylation in MLL-AF9 leukemia cells. Here, we investigated the biological impact of altered SETDB1 expression and changes in H3K9 methylation on acute myeloid leukemia. We demonstrate that SETDB1 expression is correlated to disease status and overall survival in acute myeloid leukemia patients. We recapitulated these findings in mice, where high expression of SETDB1 delayed MLL-AF9 mediated disease progression by promoting differentiation of leukemia cells. We also explored the biological impact of treating normal and malignant hematopoietic cells with an H3K9 methyltransferase inhibitor, UNC0638. While myeloid leukemia cells demonstrate cytotoxicity to UNC0638 treatment, normal bone marrow cells exhibit an expansion of cKit+ hematopoietic stem and progenitor cells. Consistent with these data, we show that bone marrow treated with UNC0638 is more amenable to transformation by MLL-AF9. Next generation sequencing of leukemia cells shows that high expression of SETDB1 induces repressive changes to the promoter epigenome and downregulation of genes linked with acute myeloid leukemia, including Dock1 and the MLL-AF9 target genes Hoxa9, Six1, and others. These data reveal novel targets of SETDB1 in leukemia that point to a role for SETDB1 in negatively regulating pro-leukemic target genes and suppressing acute myeloid leukemia.
Assuntos
Leucemia Mieloide Aguda , Proteína de Leucina Linfoide-Mieloide , Animais , Histona-Lisina N-Metiltransferase/genética , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Lisina , Metilação , Camundongos , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Fusão Oncogênica/metabolismoRESUMO
BACKGROUND: Certolizumab pegol, the only Fc-free, PEGylated anti-tumor necrosis factor biologic, demonstrated clinically meaningful improvements suggestive of a positive risk-benefit balance in phase 2 studies in adults with moderate-to-severe chronic plaque psoriasis. OBJECTIVE: Assess certolizumab efficacy and safety versus placebo in phase 3 studies. METHODS: Patients with moderate-to-severe chronic plaque psoriasis were randomized 2:2:1 to certolizumab 400 mg, certolizumab 200 mg, or placebo every 2 weeks. At week 16, certolizumab-treated patients achieving a 50% reduction in Psoriasis Area and Severity Index continued treatment through week 48. Coprimary endpoints were week 16 responder rates, defined as a 75% reduction in Psoriasis Area and Severity Index and Physician's Global Assessment 0/1 (clear/almost clear) and ≥2-point improvement. Safety was assessed by treatment-emergent adverse events. RESULTS: Week-16 endpoints were significantly greater for both doses of certolizumab versus placebo, and the responses were maintained through week 48. For most measures, improvement was numerically greater for certolizumab 400 mg. No unexpected safety signals were identified. LIMITATION: There was no active comparator. CONCLUSION: Treatment with either certolizumab 400 mg or 200 mg every 2 weeks was associated with significant and clinically meaningful improvements in moderate-to-severe psoriasis. The 400-mg dose could provide additional clinical benefit. The safety profile was consistent with the therapeutic class.
Assuntos
Produtos Biológicos/efeitos adversos , Produtos Biológicos/uso terapêutico , Certolizumab Pegol/efeitos adversos , Certolizumab Pegol/uso terapêutico , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Psoríase/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Doença Crônica , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Phase 2 psoriasis studies with the Fc-free, PEGylated, anti-tumor necrosis factor biologic certolizumab pegol demonstrated meaningful clinical activity. OBJECTIVE: Assess safety and efficacy of certolizumab in adults with moderate-to-severe chronic plaque psoriasis. METHODS: Patients were randomized 3:3:1:3 to certolizumab 400 mg, certolizumab 200 mg, or placebo every 2 weeks for 16 weeks or etanercept 50 mg twice weekly for 12 weeks. Certolizumab-treated patients achieving a ≥75% reduction in Psoriasis Area and Severity Index (PASI) at week 16 from baseline PASI were rerandomized to certolizumab or placebo for 32 weeks. The primary endpoint was responder rate (≥75% reduction in PASI from baseline PASI) versus placebo (primary analysis) and etanercept (secondary analysis) at week 12; secondary endpoints included responder rates on various measures versus placebo at weeks 12, 16, and 48. Safety was assessed by treatment-emergent adverse events. RESULTS: All endpoints were significantly greater for certolizumab versus placebo with the greatest response seen with 400 mg. Certolizumab 400 mg was superior to and 200 mg was noninferior to etanercept. Adverse events were consistent with the anti-tumor necrosis factor class of drugs. LIMITATIONS: Etanercept was administered by unblinded study staff or self-administered, but efficacy assessments were performed by a blinded assessor. CONCLUSION: Both certolizumab regimens improved psoriasis symptoms, with a greater response seen with the higher dose. No new safety signals were observed.
Assuntos
Produtos Biológicos/efeitos adversos , Produtos Biológicos/uso terapêutico , Certolizumab Pegol/efeitos adversos , Certolizumab Pegol/uso terapêutico , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Psoríase/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Doença Crônica , Método Duplo-Cego , Esquema de Medicação , Etanercepte/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Neutralizing interleukin (IL) 17F in addition to IL-17A might provide a more complete and specific approach to inhibiting inflammation. OBJECTIVE: Assess the efficacy and safety of bimekizumab, a monoclonal antibody that potently and selectively neutralizes IL-17A and IL-17F, in patients with moderate-to-severe plaque psoriasis. METHODS: Double-blinded, placebo-controlled phase 2b study (NCT02905006). Patients (randomized 1:1:1:1:1:1) received subcutaneous bimekizumab every 4 weeks at doses of 64 mg, 160 mg, 160 mg with 320 mg loading dose, 320 mg, 480 mg, or placebo. Primary endpoint was ≥90% reduction in Psoriasis Area Severity Index (PASI90) at week 12. RESULTS: There was a significant (P < .0001) dose-dependent response for PASI90 (week 12); more patients achieved PASI90 in the bimekizumab groups (46.2%-79.1%) than patients in the placebo group (0%; P < .0001 all doses). Across all doses, there were significant improvements from baseline for all secondary endpoints (PASI90 week 8, PASI75 week 12, PASI100 week 12, and Investigators Global Assessment clear or almost clear weeks 8 and 12; P ≤ .0003) compared with placebo. More bimekizumab-treated patients than placebo-treated patients achieved PASI100 (week 12) (27.9%-60.0% vs 0%; P ≤ .0002 all doses). Treatment-emergent adverse events were reported by 126 of 208 (61%) bimekizumab-treated patients and 15 of 42 (36%) placebo-treated patients. LIMITATIONS: No active comparator. CONCLUSION: Dual neutralization of IL-17A and IL-17F with bimekizumab provided rapid and substantial clinical improvements in patients with psoriasis, with no unexpected or dose-related safety findings.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Interleucina-17/antagonistas & inibidores , Psoríase/tratamento farmacológico , Psoríase/imunologia , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Doença Crônica , Fármacos Dermatológicos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: To date, head-to-head trials comparing the efficacy and safety of biological disease-modifying antirheumatic drugs within the same class, including TNF inhibitors, in patients with active rheumatoid arthritis despite methotrexate therapy are lacking. We aimed to compare the efficacy and safety of two different TNF inhibitors and to assess the efficacy and safety of switching to the other TNF inhibitor without a washout period after insufficient primary response to the first TNF inhibitor at week 12. METHODS: In this 104-week, randomised, single-blind (double-blind until week 12 and investigator blind thereafter), parallel-group, head-to-head superiority study (EXXELERATE), eligible patients from 151 centres worldwide were aged 18 years or older with a diagnosis of rheumatoid arthritis at screening, as defined by the 2010 ACR/EULAR criteria, and had prognostic factors for severe disease progression, including a positive rheumatoid factor, or anti-cyclic citrullinated peptide antibody result, or both. Participants were randomly assigned (1:1) via an interactive voice and web response system with no stratification to receive certolizumab pegol plus methotrexate or adalimumab plus methotrexate. All study staff were kept masked throughout the study and participants were masked until week 12. At week 12, patients were classified as responders (by either achieving low disease activity [LDA] according to Disease Activity Score 28-erythrocyte sedimentation rate [DAS28-ESR] ≤3·2 or DAS28-ESR reduction ≥1·2 from baseline) or as non-responders. Non-responders to the first TNF inhibitor to which they were randomised were switched to the other TNF inhibitor with no washout period. Primary endpoints were the percentage of patients achieving a 20% improvement according to the American College of Rheumatology criteria (ACR20) at week 12 and LDA at week 104 (week 12 non-responders were considered LDA non-responders). This study is registered with ClinicalTrials.gov, number NCT01500278. FINDINGS: Between Dec 14, 2011, and Nov 11, 2013, 1488 patients were screened of whom 915 were randomly assigned; 457 to certolizumab pegol plus methotrexate and 458 to adalimumab plus methotrexate. No statistically significant difference was observed in ACR20 response at week 12 (314 [69%] of 454 patients and 324 [71%] of 454 patients; odds ratio [OR] 0·90 [95% CI 0·67-1·20]; p=0·467) or DAS28-ESR LDA at week 104 (161 [35%] of 454 patients and 152 [33%] of 454 patients; OR 1·09 [0·82-1·45]; p=0·532) between certolizumab pegol plus methotrexate and adalimumab plus methotrexate, respectively. At week 12, 65 non-responders to certolizumab pegol were switched to adalimumab and 57 non-responders to adalimumab were switched to certolizumab pegol; 33 (58%) of 57 patients switching to certolizumab pegol and 40 (62%) of 65 patients switching to adalimumab responded 12 weeks later by achieving LDA or a DAS28-ESR reduction 1·2 or greater. 389 [75%] of 516 patients who received certolizumab pegol plus methotrexate and 386 [74%] of 523 patients who received adalimumab plus methotrexate reported treatment-emergent adverse events. Three deaths (1%) occurred in each group. No serious infection events were reported in the 70-day period after treatment switch. INTERPRETATION: These results show that certolizumab pegol plus methotrexate is not superior to adalimumab plus methotrexate. The data also show the clinical benefit and safety of switching to a second TNF inhibitor without a washout period after primary failure to a first TNF inhibitor. FUNDING: UCB Pharma.
Assuntos
Adalimumab/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Certolizumab Pegol/administração & dosagem , Adalimumab/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/uso terapêutico , Certolizumab Pegol/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Método Simples-CegoRESUMO
Objective: The aim was to assess the long-term safety and efficacy of certolizumab pegol over 4 years of continuous treatment in patients with axial spondyloarthritis (axSpA), including both AS and non-radiographic (nr-) axSpA. Methods: RAPID-axSpA was a phase 3 randomized trial, double blind and placebo controlled to week 24, dose blind to week 48 and open label to week 204. Patients had a clinical diagnosis of axSpA, meeting Assessment of SpondyloArthritis international Society (ASAS) criteria, and had active disease. The assessed outcomes included ASAS20, ASAS40, AS DAS (ASDAS), BASDAI, BASFI and BASMI scores, along with selected measures of remission. Further patient-reported outcomes, peripheral arthritis, enthesitis, uveitis and quality-of-life measures are also reported. Results: Two hundred and eighteen of 325 patients randomized (AS: 121; nr-axSpA: 97) received certolizumab pegol from week 0. Of these, 65% remained in the study at week 204 (AS: 67%; nr-axSpA: 63%). Across all outcomes, for AS and nr-axSpA, sustained improvements were observed to week 204 [week 204 overall axSpA: ASAS20: 54.1% (non-responder imputation); 83.7% (observed case, OC); ASAS40: 44.0% (non-responder imputation); 68.1% (OC); ASDAS inactive disease: 32.1% (last observation carried forward); 31.4% (OC)]. In the safety set (n = 315), there were 292.8 adverse events and 10.4 serious adverse events per 100 patient-years. No deaths were reported. Conclusion: In the first study to evaluate the efficacy of an anti-TNF across both axSpA subpopulations, improvements in clinical and patient-reported outcomes at 24 and 96 weeks were sustained through 4 years of treatment, with no new safety signals. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01087762.
Assuntos
Antirreumáticos/uso terapêutico , Certolizumab Pegol/uso terapêutico , Imunossupressores/uso terapêutico , Espondilartrite/tratamento farmacológico , Adulto , Antirreumáticos/efeitos adversos , Artrite/tratamento farmacológico , Certolizumab Pegol/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Indução de Remissão , Índice de Gravidade de Doença , Espondilite Anquilosante/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Uveíte/tratamento farmacológicoRESUMO
Usp9x was recently shown to be highly expressed in myeloma patients with short progression-free survival and is proposed to enhance stability of the survival protein Mcl-1. In this study, we found that the partially selective Usp9x deubiquitinase inhibitor WP1130 induced apoptosis and reduced Mcl-1 protein levels. However, short hairpin RNA-mediated knockdown (KD) of Usp9x in myeloma cells resulted in transient induction of apoptosis, followed by a sustained reduction in cell growth. A compensatory upregulation of Usp24, a deubiquitinase closely related to Usp9x, in Usp9x KD cells was noted. Direct Usp24 KD resulted in marked induction of myeloma cell death that was associated with a reduction of Mcl-1. Usp24 was found to sustain myeloma cell survival and Mcl-1 regulation in the absence of Usp9x. Both Usp9x and Usp24 were expressed and activated in primary myeloma cells whereas Usp24 protein overexpression was noted in some patients with drug-refractory myeloma and other B-cell malignancies. Furthermore, we improved the drug-like properties of WP1130 and demonstrated that the novel compound EOAI3402143 dose-dependently inhibited Usp9x and Usp24 activity, increased tumor cell apoptosis, and fully blocked or regressed myeloma tumors in mice. We conclude that small-molecule Usp9x/Usp24 inhibitors may have therapeutic activity in myeloma.
Assuntos
Apoptose/efeitos dos fármacos , Cianoacrilatos/farmacologia , Inibidores Enzimáticos/farmacologia , Linfoma de Célula do Manto/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Piridinas/farmacologia , Ubiquitina Tiolesterase/antagonistas & inibidores , Animais , Apoptose/genética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma de Célula do Manto/enzimologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Masculino , Camundongos , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismoRESUMO
Modified reaction conditions that facilitate Pd-catalyzed alkene carboamination reactions of electron-deficient nitrogen nucleophiles are reported. Pent-4-enylamine derivatives bearing N-tosyl or N-trifluoroacetyl groups are coupled with aryl triflates to afford substituted pyrrolidines in good yield. These reactions proceed via a mechanism involving anti-aminopalladation of the alkene, which differs from previously reported analogous reactions of N-aryl and N-boc pentenylamines. The application of these conditions to a formal synthesis of (±)-aphanorphine is also described.
RESUMO
Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a). Approximately 30% of the identified common targets of microarray and ChIP-chip assays overlap with the human t(8;21)-gene expression molecular signature. CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced. Re-expression of CD45 suppresses JAK/STAT activation, delays leukemia development, and promotes apoptosis of t(8;21)-positive cells. This study demonstrates the benefit of combining gene expression and promoter occupancy profiling assays to identify molecular and potential therapeutic targets in human cancers and describes a previously unappreciated signaling pathway involving t(8;21) fusion proteins, CD45, and JAK/STAT, which could be a potential novel target for treating t(8;21) AML.
Assuntos
Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , DNA de Neoplasias/metabolismo , Perfilação da Expressão Gênica , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Translocação Genética , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Imunoprecipitação da Cromatina , Ativação Enzimática , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes/genética , Genes Neoplásicos/genética , Humanos , Janus Quinases/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas/genética , Reprodutibilidade dos Testes , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/genéticaRESUMO
PURPOSE: The emergence of large real-world clinical databases and tools to mine electronic medical records has allowed for an unprecedented look at large data sets with clinical and epidemiologic correlates. In clinical cancer genetics, real-world databases allow for the investigation of prevalence and effectiveness of prevention strategies and targeted treatments and for the identification of barriers to better outcomes. However, real-world data sets have inherent biases and problems (eg, selection bias, incomplete data, measurement error) that may hamper adequate analysis and affect statistical power. METHODS: Here, we leverage a real-world clinical data set from a large health network for patients with breast cancer tested for variants in BRCA1 and BRCA2 (N = 12,423). We conducted data cleaning and harmonization, cross-referenced with publicly available databases, performed variant reassessment and functional assays, and used functional data to inform a variant's clinical significance applying American College of Medical Geneticists and the Association of Molecular Pathology guidelines. RESULTS: In the cohort, White and Black patients were over-represented, whereas non-White Hispanic and Asian patients were under-represented. Incorrect or missing variant designations were the most significant contributor to data loss. While manual curation corrected many incorrect designations, a sizable fraction of patient carriers remained with incorrect or missing variant designations. Despite the large number of patients with clinical significance not reported, original reported clinical significance assessments were accurate. Reassessment of variants in which clinical significance was not reported led to a marked improvement in data quality. CONCLUSION: We identify the most common issues with BRCA1 and BRCA2 testing data entry and suggest approaches to minimize data loss and keep interpretation of clinical significance of variants up to date.
Assuntos
Proteína BRCA1 , Proteína BRCA2 , Neoplasias da Mama , Mutação em Linhagem Germinativa , Sistema de Registros , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/epidemiologia , Feminino , Proteína BRCA1/genética , Proteína BRCA2/genética , Pessoa de Meia-Idade , Predisposição Genética para Doença , Adulto , Registros Eletrônicos de Saúde , IdosoRESUMO
Microarray technology has contributed valuable information to gene expression signatures of leukemia and other types of cancers and helped to identify biological markers and potential therapeutic targets for treating these diseases. Acute myeloid leukemia (AML) is often caused by aberrant fusion transcription factors resulting from chromosomal translocations, and the dysregulated genes detected by microarray include both direct and indirect targets of the oncogenic transcription factors. The ChIP-chip technology enables the identification of direct targets of a transcription factor based on its promoter occupancy and cellular context. Using AML1-ETO9a-induced AML as a cancer model and using a combined gene expression and promoter occupancy profiling approach, we recently identified CD45 as a direct down-regulated target of t(8;21) fusion proteins. This finding subsequently led us to discover the enhanced Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, which is negatively regulated by CD45, in t(8;21) AML. This review summarizes the background of t(8;21) leukemia, structural features of the translocation fusion proteins, and the merits of combining gene discovery technologies for the identification of therapeutic targets in t(8;21) leukemia.