RESUMEN
BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks. OBJECTIVE: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial). METHODS: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period. RESULTS: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred. CONCLUSION: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.
Asunto(s)
Angioedemas Hereditarios/tratamiento farmacológico , Pirazoles/administración & dosificación , Administración Oral , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Calicreína Plasmática/administración & dosificación , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1-INH-HAE) usually begin during childhood or adolescence. However, limited data are available regarding indications and modalities of treatment of children. This study evaluated recombinant human C1-INH (rhC1-INH) for HAE attacks in children. METHODS: This open-label, phase 2 study included children aged 2-13 years with C1-INH-HAE. Eligible HAE attacks were treated intravenously with rhC1-INH 50 IU/kg body weight (maximum, 4200 IU). The primary end-point was time to beginning of symptom relief (TOSR; ≥20 mm decrease from baseline in visual analog scale [VAS] score, persisting for two consecutive assessments); secondary end-point was time to minimal symptoms (TTMS; <20 mm VAS score for all anatomic locations). RESULTS: Twenty children (aged 5-14 years; 73 HAE attacks) were treated with rhC1-INH. Seventy (95.9%) of the attacks were treated with a single dose of rhC1-INH. Seven (35.0%) children were treated for four or more attacks. Overall, median TOSR was 60.0 minutes (95% confidence interval [CI], 60.0-65.0); data were consistent across attacks. Median TTMS was 122.5 minutes (95% CI, 120.0-126.0); data were consistent across attacks. No children withdrew from the study due to adverse events. No treatment-related serious adverse events or hypersensitivity reactions were reported; no neutralizing antibodies were detected. CONCLUSIONS: Recombinant human C1-INH was efficacious, safe, and well tolerated in children. Data support use of the same dosing regimen for HAE attacks in children (50 IU/kg; up to 4200 IU, followed by an additional dose, if needed) as is currently recommended for adolescents and adults.
Asunto(s)
Angioedemas Hereditarios/tratamiento farmacológico , Proteína Inhibidora del Complemento C1/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Administración Intravenosa , Adolescente , Peso Corporal , Niño , Preescolar , Protocolos Clínicos , Cálculo de Dosificación de Drogas , Femenino , Humanos , Masculino , Resultado del TratamientoRESUMEN
BACKGROUND: The randomized, controlled PALISADE trial demonstrated the benefit of daily oral immunotherapy with Peanut (Arachis Hypogaea) allergen powder-dnfp (PTAH, formerly AR101) in peanut-allergic children and adolescents. OBJECTIVE: ARC004, the open-label follow-on study to PALISADE, used 5 dosing cohorts to explore PTAH treatment beyond 1 year and alternative dosing regimens in peanut-allergic individuals. METHODS: Active arm (PTAH-continuing) PALISADE participants who tolerated 300-mg peanut protein at the exit double-blind placebo-controlled food challenge and placebo arm (PTAH-naive) participants could enter ARC004. PTAH-continuing participants were assigned to receive daily (cohorts 1 and 3A) or non-daily (cohorts 2, 3B, and 3C) dosing regimens; PTAH-naive participants were built up to 300 mg/d PTAH, followed by maintenance dosing. At study completion, participants underwent an exit double-blind placebo-controlled food challenge with doses up to 2000 mg peanut protein. Data were assessed using descriptive statistics. RESULTS: Overall, 358 (87.5%) eligible participants (4-17 years) entered ARC004 (PTAH-continuing, n = 256; PTAH-naive, n = 102). Among PTAH-continuing participants, exposure-adjusted adverse event rates were 12.94 to 17.54/participant-year and 25.95 to 42.49/participant-year in daily and non-daily dosing cohorts, respectively; most participants (83%) experienced mild or moderate adverse events. Daily dosing cohorts appeared to have higher desensitization rates than non-daily dosing cohorts. Of all PTAH-continuing cohorts, cohort 3A had the longest daily dosing duration and the highest desensitization rates. Changes in immune markers with PTAH continuation demonstrated ongoing immunomodulation. Outcomes in PTAH-naive participants mirrored those of the PALISADE active arm. CONCLUSIONS: Continued daily PTAH treatment beyond 1 year showed sustained safety and efficacy. Ongoing immunomodulation was observed during the second year of treatment.
Asunto(s)
Hipersensibilidad al Cacahuete , Administración Oral , Adolescente , Alérgenos , Arachis , Niño , Desensibilización Inmunológica , Método Doble Ciego , Humanos , Hipersensibilidad al Cacahuete/terapiaRESUMEN
BACKGROUND: Immunoglobulin (Ig)E-mediated hypersensitivity is a mechanism suggested to explain adverse reactions to buckwheat. This is the first reported case in the United States of a person who developed asthma and worsening allergic rhinitis after exposure to a buckwheat pillow. OBJECTIVE: To describe a patient who developed asthma and worsening allergic rhinitis after exposure to a buckwheat pillow and to provide evidence that the adverse reaction was IgE-mediated. METHODS: The patient underwent skin prick and ImmunoCAP testing (Pharmacia Diagnostics, Kalamazoo, MI) to buckwheat as well as skin prick testing to several environmental allergens. RESULTS: The patient showed a 4+ skin prick test response to buckwheat. He also showed 4+ positive skin prick responses to multiple trees, grasses, and weeds, Alternaria, Helminthosporium, dog, and histamine control and was 3+ positive to house-dust mites, Penicillium, Aspergillus, cat, and feather mix. His negative control was negative. His ImmunoCAP test for buckwheat-specific IgE was class 4, or strongly positive. He had normal spirometry values. Performance of house-dust mite avoidance measures did not result in improvement of the patient's symptoms. Removal of the patient's two buckwheat pillows resulted in resolution of his asthma and improvement of rhinitis symptoms. CONCLUSIONS: The positive skin prick and ImmunoCAP test to buckwheat along with the positive clinical response to buckwheat pillow elimination support an IgE-mediated mechanism in explaining our patient's buckwheat pillow-induced asthma and allergic rhinitis.
Asunto(s)
Asma/etiología , Ropa de Cama y Ropa Blanca , Fagopyrum/efectos adversos , Rinitis Alérgica Perenne/etiología , Adulto , Asma/diagnóstico , Humanos , Masculino , Rinitis Alérgica Perenne/diagnósticoRESUMEN
It has become clear in recent months that the threat of bioterrorism is very real. All physicians need to be aware of the presenting signs and symptoms of the most likely agents. Allergists and immunologists care for a unique population of patients with several alterations of their immune system that might change the expected course of illnesses from biologic terror agents. In this review, we discuss specific bioterrorism agents, focusing on their presentation, pathogenesis, and immunology. In addition, we describe how these illnesses might differ in the population of patients followed by allergists and immunologists.
Asunto(s)
Alergia e Inmunología , Infecciones Bacterianas , Bioterrorismo , Virosis , Adulto , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/fisiopatología , Infecciones Bacterianas/prevención & control , Bioterrorismo/prevención & control , Niño , Femenino , Humanos , Hipersensibilidad/complicaciones , Hipersensibilidad/inmunología , Hipersensibilidad/fisiopatología , Huésped Inmunocomprometido , Síndromes de Inmunodeficiencia/complicaciones , Masculino , Vacunas/administración & dosificación , Virosis/inmunología , Virosis/fisiopatología , Virosis/prevención & control , Virosis/virologíaRESUMEN
BACKGROUND: Nasal polyps are a common problem that is difficult to diagnose and treat, in part because the cause of nasal polyposis is unknown. Although information on the pathogenesis of polyposis is lacking, there are reports suggesting that a genetic predisposition underlies this disorder. OBJECTIVE: We sought to better understand the basis of nasal polyposis associated with allergic rhinitis. We hypothesize that the expression of unique genes is associated with the nasal polyposis phenotype. METHODS: We examined 12000 human genes transcribed in the nasal mucosa of patients with allergic rhinitis with and without nasal polyps. Biopsy specimens of the mucosa of patients with and without polyps were obtained after the patients refrained from the use of topical or systemic steroid therapy for 2 weeks. RESULTS: Thirty-four genes were differentially expressed between the patient groups, including those for inflammatory molecules and putative growth factors. The greatest differential expression identified by the array analysis was for a group of genes associated with neoplasia, including mammaglobin, a gene transcribed 12-fold higher in patients with polyps compared with control patients with rhinitis alone. Quantitative RT-PCR confirmed this differential expression and documented that the number of mammaglobin mRNA copies is actually 64-fold greater in tissues of patients with polyps versus control patients. The specificity of mammaglobin protein expression was evaluated by means of immunohistochemistry, which showed specific staining in nasal polyp mucosal goblet cells only in patients with polyps. CONCLUSION: These data suggest that nasal polyposis involves deregulated cell growth, using gene activation in some ways similar to a neoplasm. In addition, mammaglobin, a gene of unknown function associated with breast neoplasia, might be related to polyp growth.