The primary purpose of this study is to evaluate the effectiveness and safety of ustekinumab (CNTO 1275) in the treatment of patients with moderate to severe plaque psoriasis.
ANTECEDENTES: Las interleucinas 12 y 23 tienen un papel importante en la fisiopatología de la psoriasis. Se evaluó ustekinumab, un anticuerpo monoclonal humano dirigido contra estas citoquinas, para el tratamiento de la psoriasis.
MÉTODOS: En esta fase III, doble ciego, estudio, paralelo, controlado con placebo, 766 pacientes con moderada a severa psoriasis fueron asignados al azar para recibir ustekinumab 45 mg (n = 255) o 90 mg (n = 256) en las semanas 0 y 4, y después cada 12 semanas; o placebo (n = 255) en las semanas 0 y 4, con la posterior cruce de ustekinumab en la semana 12. Los pacientes que fueron asignados al azar inicialmente para recibir ustekinumab en la semana 0, que logra la respuesta a largo plazo (mejora al menos el 75% en el área de la psoriasis y el índice de gravedad [PASI 75] en las semanas 28 y 40) fueron re-aleatorizados en la semana del 40 al ustekinumab mantenimiento o la retirada del tratamiento hasta la pérdida de respuesta. Ambos aleatorizaciones se realizaron con un método de minimización a través de un sistema de respuesta interactiva de voz centralizado. El criterio principal de valoración fue la proporción de pacientes que alcanzaron PASI 75 en la semana 12. Los análisis fueron por intención de tratar. Este estudio se ha registrado en ClinicalTrials.gov, número NCT00267969.
RESULTADOS: Todos los pacientes asignados al azar se incluyeron en el análisis de eficacia. 171 (67,1%) pacientes que recibieron ustekinumab 45 mg, 170 (66,4%) que recibieron ustekinumab 90 mg y ocho (3,1%) que recibieron placebo logrado PASI 75 en la semana 12 (diferencia en la tasa de respuesta frente a placebo 63,9%; IC del 95%: 57.8- 70,1, p <0,0001 para 45 mg y 63,3%, 57,1 a 69,4, p <0,0001 para 90 mg). En la semana 40, la respuesta a largo plazo había sido alcanzado por 150 pacientes en el grupo de 45 mg y 172 pacientes en el grupo de 90 mg. De estos, 162 pacientes fueron asignados aleatoriamente a ustekinumab mantenimiento y 160 a la retirada. Respuesta PASI 75 se mantiene mejor a por lo menos 1 año en los que recibieron ustekinumab mantenimiento que en los retirado de tratamiento en la semana 40 (p <0.0001 por la prueba de log-rank). Durante la fase controlada con placebo, los eventos adversos ocurrieron en 278 (54,5%) de los 510 pacientes que recibieron ustekinumab y 123 (48,2%) de los 255 que recibieron placebo. Los acontecimientos adversos graves se produjeron en seis (1.2%) de 510 pacientes que recibieron ustekinumab y en dos (0,8%) de 255 que recibieron placebo en esta fase. El patrón de acontecimientos adversos fue mucho los mismos en el cruce placebo y aleatorizados fases de abstinencia como lo fue en la fase controlada con placebo.
Interpretación: ustekinumab parece ser eficaz para el tratamiento de la psoriasis moderada a severa; la dosificación cada 12 semanas mantiene eficacia durante al menos un año en la mayoría de los pacientes.
The population pharmacokinetics of ustekinumab are characterized in patients with moderate to severe plaque psoriasis in 2 Phase 3 studies (PHOENIX 1 and PHOENIX 2). Serum concentration data from 1937 patients are analyzed to determine pharmacokinetic characteristics of ustekinumab and to assess factors that may contribute to their variability. The population typical mean (percentage relative standard error) values for apparent clearance, apparent volume of distribution, and absorption rate constant from the final covariate model are 0.465 L.day(-1) (2.0%), 15.7 L (2.0%), and 0.354 day(-1) (16.2%), respectively. The interindividual variabilities for apparent clearance and apparent volume of distribution are 41.0% and 33.2%, respectively. Of the factors evaluated in this analysis, body weight, diabetes, and positive immune response (antibodies to ustekinumab) are important covariates affecting the apparent clearance and/or apparent volume of distribution of ustekinumab. To fully understand the clinical relevance of these results, the covariate findings need to be evaluated concurrently with the efficacy and safety data.
PHOENIX Antecedentes 1 fue una fase III, doble ciego, aleatorizado, controlado con placebo que demostró la eficacia a largo plazo y la seguridad de ustekinumab en pacientes con psoriasis moderada a severa. Objetivos Evaluar el efecto de la terapia de mantenimiento con ustekinumab en la calidad relacionada con la salud de la vida (CVRS) en PHOENIX 1 pacientes. Pacientes y métodos Pacientes (n = 766) fueron asignados al azar para recibir ustekinumab 45 mg (n = 255) o 90 mg (n = 256) en las semanas 0 y 4, y cada 12 semanas o placebo (n = 255) en las semanas 0 y 4 con cruce de ustekinumab en la semana 12. Pacientes con ustekinumab aleatorizado, logrando un mejoramiento al menos el 75% en Psoriasis Area and Severity Index (PASI) 75 en la semana 28 y 40 fueron re-aleatorizados en la semana 40 para continuar ustekinumab o ser retirada hasta que la pérdida del efecto terapéutico. CVRS se evaluó mediante el SF-36 y el Índice de Calidad de Vida en Dermatología (DLQI). Resultados Al inicio del estudio, más del 97% tenían una DLQI> 1 y el DLQI promedio fue de> 10, lo que indica un impacto significativo en la CVRS de los pacientes. Una proporción significativamente mayor de pacientes tratados con ustekinumab 45 mg y 90 lograron una puntuación normalizada DLQI (<o = 1) en comparación con placebo (53,2%, 52,4% y 6,0%, respectivamente, ambos p <0,001) en la semana 12 y lograron una clínicamente significativa mejora (aumento de al menos cinco puntos) en SF-36 (23,1%, 33,7% y 15,6%) y mental (25,5%, 31,3% y 14,8%) puntuación de los componentes físicos. En la semana 12, los cambios en DLQI individual y SF-36 dominios fueron significativamente mejores en cada grupo de ustekinumab frente a placebo (p <0,001). La magnitud de la mejora a través de escalas SF-36 fue mayor para el dolor corporal y dominios funcionamiento social. Las mejoras en la CVRS se mantuvieron con la terapia de mantenimiento con ustekinumab a través de al menos 1 año. El análisis de regresión mostró que, después del ajuste para la mejora en PASI o Evaluación Global del Médico (PGA), los pacientes tratados con ustekinumab demostraron mejoras significativas en DLQI. Conclusiones El ustekinumab mejora la CVRS en pacientes con psoriasis moderada a severa. Resultados Paciente informó midieron un efecto del tratamiento más allá de lo indicado por las medidas clínicas.
OBJECTIVES: Ustekinumab(UST) has been shown to improve psoriasis(PsO) and health-related quality of life (HRQoL) in patients(pts) with moderate-to-severe PsO∗. This analysis examines the effects of UST on overall skin response and the impact on HRQoL in a subset of PsO pts with psoriatic arthritis(PsA). METHODS: In PHOENIX 1 and 2, pts with moderate-to-severe PsO(n = 1996) were randomized to UST45mg or 90 mg at wks 0, 4, and q12 wk thereafter, or placebo(PBO) at wks 0 and 4 with crossover to UST at wk12. PsA was identified in pts by medical history. PsO severity was assessed using the Psoriasis Area and Severity Index(PASI) and HRQoL with the Dermatology Life Quality Index (DLQI). RESULTS: At baseline, 563(28.2%) pts had PsA. The mean PASI was 20.7(SD = 8.4) and mean DLQI was 12.6(SD = 7.2) indicating significant poor HRQoL. At wk12, UST-treated pts had a significantly greater percent improvement in mean PASI score than PBO-treated pts(45 mg: 73.7%, 90 mg: 75.3%, PBO: 2.4%; p < 0.001). A significantly greater portion of UST-treated pts achieved PASI75 compared to PBO-treated pts(45 mg: 63.0%, 90 mg: 61.5%, PBO: 3.6%; p < 0.001). UST-treated pts had a significantly greater decrease (improvement) in DLQI score at wk12 than PBO-treated pts(45 mg: -9.2 [SD = 7.1], 90 mg: -9.7[SD = 6.6], PBO: -0.01[SD = 5.0]; p < 0.001). At wk12, 70.2% in the UST 45 mg group and 75.0% in the UST 90 mg group respectively, experienced ≥ 5 point improvement in DLQI compared to 15.6 % for the PBO group (p < 0.001). UST-treated pts (50.0% and 57.1% in the 45 mg and 90 mg groups, respectively) had a DLQI score of 0 or 1, indicating no impact of the disease or treatment on HRQoL compared with 1.0% of PBO-treated pts (p < 0.001). CONCLUSIONS: UST improved overall skin response and HRQoL in a subset of moderate-to-severe PsO pts with PsA.
The physician's global assessment (PGA) score is a 6-point measure of psoriasis severity that is widely used in clinical trials to assess response to psoriasis treatment. The objective of this study was to perform exposure-response modeling using the PGA score as a pharmacodynamic endpoint following treatment with ustekinumab in patients with moderate-to-severe psoriasis who participated in two Phase 3 studies (PHOENIX 1 and PHOENIX 2). Patients were randomly assigned to receive ustekinumab 45 or 90 mg or placebo, followed by active treatment or placebo crossover to ustekinumab, dose intensification or randomized withdrawal and long-term extension periods. A novel joint longitudinal-dropout model was developed from serum ustekinumab concentrations, PGA scores, and patient dropout information. The exposure-response component employed a semi-mechanistic drug model, integrated with disease progression and placebo effect under the mixed-effect logistic regression framework. This allowed potential tolerance to be investigated with a mechanistic approach. The dropout component of the joint model allowed the examination of its potential influence on the exposure-response relationship. The flexible Weibull dropout hazard function was used. Visual predictive check of the joint longitudinal-dropout model required special handling, and a conditional approach was proposed. The conditional approach was extended to external model validation. Finally, appropriate interpretation of model validation is discussed. This longitudinal-dropout model can serve as a basis to support future alternative dosing regimens for ustekinumab in patients with moderate-to-severe plaque psoriasis.
ANTECEDENTES: El ustekinumab, un anticuerpo monoclonal anti-interleukin-12/23 humana, se ha demostrado que efectivamente tratar la psoriasis moderada a severa que afecta significativamente la calidad relacionada con la salud de la vida (CVRS), incluyendo la vida sexual de los pacientes.
OBJETIVOS: El objetivo de este estudio fue determinar si las dificultades sexuales asociadas a la psoriasis están relacionados con la gravedad de la enfermedad y de si las dificultades sexuales mejoran con enfermedad de la piel durante el tratamiento con ustekinumab.
MÉTODOS: En la fase III PHOENIX 1 y 2 ensayos, los pacientes con psoriasis se asignaron al azar a ustekinumab (n = 1334) en las semanas 0 y 4 y a partir de entonces cada 12 semanas o placebo (n = 662) en las semanas 0 y 4 con cruce a ustekinumab en la semana 12 . Psoriasis Area and Severity Index (PASI) y el Índice de Calidad de Vida en Dermatología (DLQI) se utilizaron para evaluar la gravedad de la psoriasis y la CVRS informada por el paciente, respectivamente. Basado en DLQI pregunta # 9, la función sexual alterada se definió como 'muy' o 'mucho' de las dificultades sexuales.
RESULTADOS: Al inicio del estudio, la media fue de 12,0 DLQI, lo que indica un gran efecto negativo en la vida de los pacientes. Deterioro de la función sexual se informó en un 22,6% (mujeres = 27.1%; hombres = 20.8%) y se asoció de forma significativa con una mayor gravedad de la psoriasis. En la semana 12, los pacientes tratados con ustekinumab tuvieron una mejoría media mayor en DLQI (-9,13 vs -0,53 con placebo, P <0,001) y la proporción de pacientes con deterioro de la función sexual disminuyó de 22,4% a 2,7% en comparación con ningún cambio con el placebo (P <0,001). Los pacientes con mayor mejoría PASI experimentaron una mayor reducción de las dificultades sexuales debido a la psoriasis. Se observó un patrón similar de la función sexual mejoró en las semanas 24 a 28 de los pacientes con placebo y cruzado.
Conclusiones: El tratamiento ustekinumab se asocia con una mejoría significativa en la CVRS y dificultades sexuales debido a la psoriasis.
ANTECEDENTES: los objetivos de ustekinumab interleuquina (IL) -12 y la IL-23 en el tratamiento de la psoriasis moderada a severa.
OBJETIVO: Se pretende evaluar el impacto de ustekinumab en infecciones y neoplasias, tanto los riesgos teóricos de bloqueo de la IL-12 e IL-23 en pacientes expuestos hasta 3 años.
MÉTODOS: Las tasas de infecciones y tumores malignos fueron evaluados en los datos de seguridad acumulativas de 3117 pacientes tratados con ustekinumab en 4 estudios.
RESULTADOS: (132.2) grupos de 90 mg Durante los períodos controlados con placebo, las tasas de infecciones generales por cada 100 pacientes-año fueron similares entre el placebo (121,0), ustekinumab 45 mg (145,7), y con ustekinumab, con intervalos de confianza superpuestos, y se mantuvo estable a lo largo de 3 años en grupos ustekinumab. Las tasas de infecciones graves durante los períodos controlados con placebo fueron similares entre el placebo (1.70) y 90 mg (1,97) grupos, sin embargo, menor en el grupo 45-mg (0,49). Tasas se mantuvieron estables (90 mg) o disminución (45 mg) con el tiempo, y fueron comparables con los de la población de Estados Unidos psoriasis basado en una base de datos de atención médica administrada. Las tasas de tumores malignos en los períodos controlados con placebo fueron comparables entre los grupos (placebo: 1,70; 45 mg: 0,99; 90 mg: 0,98) y se mantuvo estable en el tiempo en grupos ustekinumab. Las tasas de enfermedades malignas, excluyendo el cáncer de piel no melanoma, fueron comparables con las tasas esperadas en la población general de Estados Unidos en base a la Vigilancia, Epidemiología y Resultados Finales de base de datos.
LIMITACIONES: períodos controlados no se extienden más allá de 12 a 20 semanas. Sólo 1.247 pacientes fueron tratados durante al menos 2 años, hasta la fecha. poblaciones de base de datos de comparación no pueden representar plenamente la población del ensayo clínico.
CONCLUSIONES: El perfil de seguridad de ustekinumab emergentes sigue siendo favorable y no sugiere un aumento de las tasas de infección o tumor maligno a través de 3 años.
BACKGROUND: Ustekinumab targets interleukin (IL)-12 and IL-23 in the treatment of moderate-to-severe psoriasis.
OBJECTIVE: To evaluate overall pooled study data to assess the safety profile of ustekinumab through 3 years of treatment.
METHODS: Cumulative safety data were pooled from studies in 3117 ustekinumab-treated patients.
RESULTS: During the placebo-controlled periods (Phase 2, PHOENIX 1, PHOENIX 2), rates of adverse events (AEs) were comparable among patients treated with placebo (50.4%), with ustekinumab 45 mg (57.6%), or with ustekinumab 90 mg (51.6%); similar findings were observed during the controlled period of the ACCEPT trial (etanercept: 70.0%; ustekinumab 45 mg: 66.0%; and ustekinumab 90 mg: 69.2%). Rates of serious AEs (SAEs) through the controlled periods were low and comparable among all groups (1.2% to 1.9%). Through 3 years, rates of AEs per 100 patient-years of follow-up (/100 patient-yrs) (45 mg: 305.2/100 patient-yrs; 90 mg: 305.9/100 patient-yrs) and SAEs (45 mg: 6.8/100 patient-yrs; 90 mg: 8.2/100 patient-yrs) were comparable between ustekinumab doses. No cases of demyelination or tuberculosis were reported in these trials. No dose response in rates of AEs, overall infections, or SAEs was apparent through 3 years. Rates of AEs, infections, SAEs, and AEs leading to study agent discontinuation remained generally stable or decreased over time.
LIMITATIONS: Controlled periods did not extend beyond 12 to 20 weeks. Only 1247 of the 3117 ustekinumab-treated patients were treated for 2 or more years.
CONCLUSIONS: The safety profile of continued ustekinumab exposure through up to 3 years is favorable and consistent with previous short-term reports.
BACKGROUND: The efficacy and safety profile of ustekinumab with up to three years of exposure suggested a favorable benefit-risk profile in patients with moderate to severe psoriasis.
OBJECTIVE: To evaluate the safety of ustekinumab in patients with moderate to severe psoriasis treated for up to four years.
METHODS: Safety data were pooled across four Phase II/III randomized controlled trials. Rates over time and cumulative rates of adverse events (AEs), AEs leading to treatment discontinuation, serious adverse events (SAEs), serious infections, malignancies, and major adverse cardiovascular events (MACE) (i.e., cardiovascular death, myocardial infarction [MI], or stroke as adjudicated by an independent panel of academic cardiologists) were evaluated. Observed rates of AEs of interest were compared with those expected in the general (malignancies, MI, and stroke) and psoriasis (serious infections, MI, and stroke) populations.
RESULTS: Overall, 3,117 patients were followed for up to four years (6,791 patient-years). Rates of AEs, AEs leading to treatment discontinuation, and SAEs remained stable over time, whereas cumulative rates were generally comparable between patients who received 45 mg and 90 mg of ustekinumab. The rates of AEs of interest also remained stable over time, and cumulative rates per 100 patient-years were 0.80 and 1.32 (serious infections), 0.70 and 0.53 (nonmelanoma skin cancer), 0.63 and 0.61 (other malignancies), and 0.56 and 0.46 (MACE) in patients treated with 45 mg and 90 mg, respectively. Rates of AEs of interest were consistent with those in the general and psoriasis populations.
CONCLUSION: The safety profile of long-term ustekinumab treatment with up to four years of continuous use remains consistent with previous reports, with no evidence of cumulative toxicity.
BACKGROUND: An unmet need remains for safe and effective long-term treatments of psoriasis.
OBJECTIVES: To evaluate ustekinumab efficacy and safety for up to 3 years in the PHOENIX 1 trial.
METHODS: Patients (n = 766) with moderate-to-severe psoriasis were randomized to ustekinumab 45 mg or 90 mg at weeks 0 and 4, and then every 12 weeks, or placebo at weeks 0 and 4, with crossover to ustekinumab at week 12. Ustekinumab responders [≥ 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at weeks 28 and 40] were re-randomized at week 40 to continue or withdraw from treatment until psoriasis recurrence. Partial responders (week 28: PASI 50-74; week 40: < PASI 75) switched to dosing every 8 weeks. Clinical efficacy was assessed by PASI, the Physician's Global Assessment (PGA), and the Dermatology Life Quality Index (DLQI) measures.
RESULTS: Overall, 79·8% of the ustekinumab-treated patients remained in the study for 3 years. PASI 75 response rates (45 mg: 61·2%; 90 mg: 72·4%) at week 76 were maintained through year 3 (45 mg: 62·7%; 90 mg: 72·2%); PGA response was similarly durable. At year 3, 80·9% (45 mg) and 82·7% (90 mg) of week 40 responders continuing treatment every 12 weeks achieved a PASI 75 response, while 42·6% (45 mg) and 58·0% (90 mg) achieved a PASI 90 response. Among partial responders adjusted to dosing every 8 weeks, 50·9% (45 mg) and 52·0% (90 mg) had a PASI 75 response at year 3. DLQI responses paralleled the PASI responses. Through year 3, no dose response was observed in rates of adverse events (AEs), overall infections, serious AEs, or AEs leading to discontinuation; nor was there evidence of cumulative organ toxicity. CONCLUSIONS; Continuous, stable, maintenance dosing with ustekinumab was generally well tolerated and sustained durable efficacy for up to 3 years of treatment.
BACKGROUND: Long-term safety evaluations of biologics are needed to inform patient management decisions.
OBJECTIVES: To evaluate the safety of ustekinumab in patients with moderate-to-severe psoriasis treated for up to 5 years.
METHODS: Safety data were pooled from four studies of ustekinumab for psoriasis. Rates of adverse events (AEs), serious AEs (SAEs) and AEs of interest [infections, nonmelanoma skin cancers (NMSCs), other malignancies and major adverse cardiovascular events (MACE)] per 100 patient-years (PY) of follow-up were analysed by ustekinumab dose (45 or 90 mg) and by year of follow-up (years 1-5) to evaluate the dose response and impact of cumulative exposure. Observed rates of overall mortality and other malignancies were compared with those expected in the general U.S. population.
RESULTS: Analyses included 3117 patients (8998 PY) who received one or more doses of ustekinumab, with 1482 patients treated for ≥4 years (including 838 patients ≥5 years). At year 5, event rates (45 mg, 90 mg, respectively) for overall AEs (242·6, 225·3), SAEs (7·0, 7·2), serious infections (0·98, 1·19), NMSCs (0·64, 0·44), other malignancies (0·59, 0·61) and MACE (0·56, 0·36) were comparable between dose groups. Year-to-year variability was observed, but no increasing trend was evident. Rates of overall mortality and other malignancies were comparable with those expected in the general U.S. population.
CONCLUSIONS: No dose-related or cumulative toxicity was observed with increasing duration of ustekinumab exposure for up to 5 years. Rates of AEs reported in ustekinumab psoriasis trials are generally comparable with those reported for other biologics approved for the treatment of moderate-to-severe psoriasis.
BACKGROUND: Ongoing evaluation of biological agents in patients with moderate-to-severe psoriasis is needed to support their long-term use.
OBJECTIVE: To evaluate long-term efficacy and safety of ustekinumab through 5 years in the PHOENIX 1 study.
METHODS: Patients were randomized to placebo or ustekinumab (45 mg or 90 mg) at Weeks 0, 4 and every-12-weeks thereafter; placebo patients crossed-over to ustekinumab at Week 12. Clinical response through Week 244 was evaluated using the Psoriasis Area and Severity Index (PASI) in the Overall Population (i.e. patients receiving ≥ 1 dose of ustekinumab), Initial Responders (i.e. PASI 75 responders [Weeks 28/40] re-randomized at Week 40 to continue every-12-week maintenance) and Partial Responders (i.e. <PASI 75 responders adjusted to every-8-week maintenance at Weeks 28 or 40). Safety endpoints were evaluated through Week 264 for the Overall Population.
RESULTS: Overall, 68.7% (517/753) of ustekinumab-treated patients completed treatment through Week 244. Initial clinical responses were generally maintained through Week 244 (PASI 75: 63.4% and 72.0%; PASI 90: 39.7% and 49.0%; PASI 100: 21.6% and 26.4%) for patients receiving 45 mg and 90 mg, respectively. Similarly, PASI 75 responses were generally maintained among Initial Responders [79.1% (45 mg) and 80.8% (90 mg)] and Partial Responders [57.6% (45 mg) and 55.1% (90 mg)]. With 3104 patient-years of follow-up, rates of overall adverse events (AEs), serious AEs, serious infections, malignancies and major adverse cardiovascular events were generally consistent over time and comparable between doses.
CONCLUSIONS: Through 5 years of continuous treatment, ustekinumab demonstrated stable clinical response and a safety profile consistent with previous reports.
BACKGROUND: Most patients with psoriasis have nail changes, and treating nail psoriasis is challenging.
OBJECTIVES: To assess improvement in fingernail psoriasis with ustekinumab treatment in the PHOENIX 1 trial.
METHODS: Patients received ustekinumab 45 mg or 90 mg, or placebo at weeks 0 and 4. Ustekinumab-randomized patients continued maintenance dosing every 12 weeks, while patients receiving placebo crossed over to receive ustekinumab 45 mg or 90 mg at weeks 12/16 followed by dosing every 12 weeks. At week 40, initial responders [those with ≥ 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75)] were rerandomized either to continue maintenance dosing or to withdraw from treatment. Nail involvement was evaluated using the Nail Psoriasis Severity Index (NAPSI) on a target fingernail, Nail Physician's Global Assessment (Nail PGA) and mean number of nails involved.
RESULTS: Of 766 randomized patients, 545 (71·1%) had nail psoriasis. At week 24, the percentage improvement from baseline NAPSI score was 46·5% (ustekinumab 45 mg) and 48·7% (ustekinumab 90 mg). Percentage improvements in NAPSI ranged from 29·7% (PASI < 50) to 57·3% (PASI ≥ 90). Mean NAPSI scores improved from 4·5 at baseline to 2·4 at week 24 (45 mg) and from 4·4 to 2·2 (90 mg). Nail PGA scores and the mean number of psoriatic nails improved by week 24. Further improvement was observed for all end points among initial responders continuing maintenance treatment through week 52.
CONCLUSIONS: Ustekinumab significantly improves nail psoriasis, and improvements continue over time until up to 1 year of treatment in those receiving maintenance treatment.
INTRODUCTION: Theoretical risks of biologic agents remain under study.
OBJECTIVE: The aim of this study was to integrate 1-year safety data from 12 ustekinumab registrational trials.
METHODS: Patients had moderate-to-severe plaque psoriasis, active psoriatic arthritis (PsA) (± methotrexate), or moderate-to-severe Crohn's disease (CD; failed/intolerant of immunomodulators/corticosteroids). Psoriatic patients received subcutaneous ustekinumab 45/90 mg or placebo, generally at week 0, week 4, then every 12 weeks thereafter, while those with CD received a single intravenous ustekinumab dose (130 mg or weight range-based dosing of approximately 6 mg/kg) or placebo induction dose at week 0, followed by subcutaneous ustekinumab 90 mg at week 8 and every 8/12 weeks thereafter. The incidence rates of a priori-defined safety events were integrated post hoc (adjusted for duration of follow-up, reported per 100 patient-years [PYs]).
RESULTS: Among 6280 enrolled patients, 5884 ustekinumab-treated patients (psoriasis: 3117; PsA: 1018; CD: 1749) contributed 4521 PYs versus 674 PYs in placebo-treated patients through year 1 (829 PYs and 385 PYs during 8- to 16-week controlled periods). Combined across diseases among ustekinumab- versus placebo-treated patients, respective incidences/100 PYs (95% confidence intervals) of infections were 125.4 (122.2-128.7) versus 129.4 (120.9-138.3) through year 1, and not meaningfully increased in patients who did versus those who did not receive methotrexate (92.5 [84.2-101.5] vs. 115.3 [109.9-121.0]), or significantly increased in patients who did versus those who did not receive corticosteroids (116.3 [107.3-125.9] vs. 107.3 [102.0-112.8]) at baseline. Major adverse cardiovascular events (0.5 [0.3-0.7] vs. 0.3 [0.0-1.1]), malignancies (0.4 [0.2-0.6] vs. 0.2 [0.0-0.8]), and deaths (0.1 [0.0-0.3] vs. 0.0 [0.0-0.4]) were rare across indications.
CONCLUSIONS: Ustekinumab demonstrated a favorable and consistent safety profile across registrational trials in approved indications.
TRIAL REGISTRATIONS: ClinicalTrials.gov identifier: NCT00320216, NCT00267969, NCT00307437, NCT00454584, NCT00267956, NCT01009086, NCT01077362, NCT00265122, NCT00771667, NCT01369329, NCT01369342, and NCT01369355.
