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1.
Br J Hosp Med (Lond) ; 80(7): 391-398, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31283393

RESUMO

Hereditary angioedema is a rare genetic disorder caused by deficiency of C1 esterase inhibitor (C1-INH) and characterized by recurrent episodes of severe swelling that affect the limbs, face, intestinal tract and airway. Since laryngeal oedema can be life-threatening as a result of asphyxiation, correct diagnosis and management of hereditary angioedema is vital. Hereditary angioedema attacks are mediated by bradykinin, the production of which is regulated by C1-INH. Hereditary angioedema therapy relies on treatment of acute attacks, and short- and long-term prophylaxis. Acute treatment options include C1-INH concentrate, icatibant and ecallantide. Self-administration of treatment is recommended and is associated with increased quality of life of patients with hereditary angioedema. Advances in diagnosis and management have improved the outcomes and quality of life of patients with hereditary angioedema.

2.
J Allergy Clin Immunol Pract ; 7(6): 1793-1802.e2, 2019 Jul - Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30772477

RESUMO

BACKGROUND: For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT). OBJECTIVE: To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC). METHODS: Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353). RESULTS: A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment. CONCLUSIONS: In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms.

4.
BioDrugs ; 33(1): 33-43, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30539362

RESUMO

Hereditary angioedema (HAE) with C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disease characterized by diminished levels or dysfunctional activity of C1-INH, leading to dysregulated plasma kallikrein activity within the kallikrein-kinin pathway. Symptoms manifest as painful, potentially life-threatening swelling of subcutaneous tissues throughout the body and/or submucosal edema in the upper airway or gastrointestinal tract. Attacks recur with unpredictable frequency, intensity, and duration, placing a heavy burden on patients' daily lives. Despite improved availability of medications for on-demand treatment during attacks and prophylaxis of future attacks, unmet needs remain. Lanadelumab, a fully human monoclonal antibody, may help address some of the limitations of existing prophylactic options (e.g., the need for intravenous administration or frequent dosing). Preclinical studies demonstrate that it is highly potent and specifically inhibits plasma kallikrein, and findings from phase Ia and Ib studies suggest this agent is well tolerated and provides sustained inhibition of plasma kallikrein, allowing for less frequent dosing. The phase III HELP Study (NCT02586805) evaluating the efficacy and safety of lanadelumab in preventing HAE attacks has been completed, and its open-label extension (NCT02741596) is ongoing. Lanadelumab is now approved in the USA and Canada for prophylaxis to prevent attacks of HAE in patients aged ≥ 12 years. This review provides an overview of the discovery and clinical development of lanadelumab, from preclinical through phase Ib studies, characterizing its safety/tolerability, efficacy, and pharmacokinetic and pharmacodynamic profiles. It also highlights how this agent may positively impact clinical care of patients with C1-INH-HAE.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/prevenção & controle , Anticorpos Monoclonais Humanizados/uso terapêutico , Calicreína Plasmática/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Angioedemas Hereditários/patologia , Angioedemas Hereditários/fisiopatologia , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/farmacologia , Ensaios Clínicos Fase I como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Pessoa de Meia-Idade , Calicreína Plasmática/efeitos dos fármacos , Adulto Jovem
5.
JAMA ; 320(20): 2108-2121, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30480729

RESUMO

Importance: Current treatments for long-term prophylaxis in hereditary angioedema have limitations. Objective: To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks. Design, Setting, and Participants: Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized. Interventions: Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments. Main Outcome and Measures: Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period. Results: Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P < .001); -1.44 (95% CI, -1.84 to -1.04; P < .001); and -1.71 (95% CI, -2.09 to -1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab). Conclusions and Relevance: Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy. Trial Registration: EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805.

7.
Clin Transl Allergy ; 8: 42, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30338053

RESUMO

The objective of this analysis was to evaluate the change over time in age at first symptoms, age at diagnosis, and delay in diagnosis using data from the Icatibant Outcome Survey (IOS). Patients with a diagnosis of C1-INH-HAE who were born before the year 1990 and who were diagnosed before they reached 25 years of age were included in the analysis. Both age at diagnosis and delay in diagnosis of C1-INH-HAE appear to decline with later decade of birth, despite wide variation across the countries assessed, suggesting that improved disease awareness causes increased rates of earlier diagnosis over time. Our findings demonstrate that some patients are still experiencing long delays to diagnosis, indicating an ongoing need for improved disease awareness.

8.
Angiogenesis ; 2018 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-30168024

RESUMO

Vascular complications such as bleeding due to gastrointestinal telangiectatic anomalies, pulmonary arteriovenous malformations, hepatopulmonary syndrome, and retinal vessel abnormalities are being reported in patients with telomere biology disorders (TBDs) more frequently than previously described. The international clinical care consortium of telomere-associated ailments and family support group Dyskeratosis Congenita Outreach, Inc. held a workshop on vascular abnormalities in the TBDs at the National Cancer Institute in October 2017. Clinicians and basic scientists reviewed current data on vascular complications, hypotheses for the underlying biology and developed new collaborations to address the etiology and clinical management of vascular complications in TBDs.

10.
Artigo em Inglês | MEDLINE | ID: mdl-30127805

RESUMO

Background: Hereditary angioedema (HAE) is a potentially life-threatening, bradykinin-mediated disease, often misdiagnosed and under-treated, with long diagnostic delays. There are limited real-world data on best-practice management of HAE in the UK. Objectives: To characterize the clinical profile, management and outcomes of patients with HAE type I and II from three specialist centres in the UK using data from the Icatibant Outcome Survey (IOS; Shire, Zug, Switzerland), an international observational study monitoring safety and effectiveness of icatibant, a selective bradykinin B2 receptor antagonist. Methods: We performed retrospective analyses of IOS data for patients with HAE type I and II from three centres in the UK and compared UK data with pooled IOS data from 10 countries (48 centres). Results: Analyses included 73 UK and 579 non-UK patients with HAE type I or II. Median diagnostic delay was 6.2 and 5.9 years, respectively. Analysis of data collected from February 2008 to July 2016 included 286 icatibant-treated attacks in 58 UK patients and 2553 icatibant-treated attacks in 436 non-UK patients (median of 3.0 attacks per patient in both groups). More attacks were treated by icatibant self-administration in UK patients (95.8%) than in non-UK patients (86.8%, p < 0.001). Time to icatibant treatment, time to resolution and attack duration were not significantly different in the UK versus non-UK patients. Conclusion: UK patients from the specialist centres studied report similar diagnostic delay and similar icatibant treatment outcomes to their non-UK counterparts. However, improvements in the timely diagnosis of HAE are still required.Trial registration ClinicalTrials.gov NCT01034969.

11.
N Engl J Med ; 379(4): 352-362, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-30044938

RESUMO

BACKGROUND: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks. METHODS: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life. RESULTS: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups. CONCLUSIONS: Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972 .).


Assuntos
Angioedemas Hereditários/prevenção & controle , Inibidores Enzimáticos/administração & dosagem , Calicreína Plasmática/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida
12.
Clin Exp Allergy ; 48(10): 1325-1332, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29998524

RESUMO

BACKGROUND: Long-term prophylaxis with subcutaneous (SC) administration of a highly concentrated plasma-derived C1-esterase inhibitor (C1-INH) formulation was recently approved by the Food and Drug Administration for hereditary angioedema (HAE) attack prevention. OBJECTIVE: To characterize the population pharmacokinetics of C1-INH (SC) (HAEGARDA® ; CSL Behring) in healthy volunteers and HAE patients, and assess the variability and influence of covariates on pharmacokinetics. METHODS: C1-INH functional activity data obtained after administration of various C1-INH (intravenous; IV) and C1-INH (SC) doses from 1 study in healthy volunteers (n = 16) and 2 studies in subjects with HAE (n = 108) were pooled to develop a population pharmacokinetic model (NONMEM v7.2). Pharmacokinetic parameters derived from steady-state simulations based on the final model were also evaluated. RESULTS: C1-INH functional activity following C1-INH (SC) administration was described by a linear one-compartment model with first-order absorption and elimination, with inter-individual variability in all parameters tested. The mean population bioavailability of C1-INH (SC), and pharmacokinetic parameters for clearance (CL), volume of distribution, and absorption rate were estimated to be ~43%, 1.03 mL/hour/kg, 0.05 L/kg and 0.0146 hour-1 , respectively. The effect of bodyweight on CL of C1-INH functional activity was included in the final model, estimated to be 0.74. Steady-state simulations of C1-INH functional activity vs time profiles in 1000 virtual HAE patients revealed higher minimum functional activity (Ctrough ) levels after twice-weekly dosing with 40 IU/kg (~40%) and 60 IU/kg (~48%) compared with 1000 IU IV (~30%). Based on the population pharmacokinetic model, the median time to peak concentration was ~59 hours and the median apparent plasma half-life was ~69 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Twice-weekly bodyweight-adjusted dosing of C1-INH (SC) exhibits linear pharmacokinetics and dose-dependent increases in Ctrough levels at each dosing interval. In this analysis, SC dosing led to maintenance of higher Ctrough levels than IV dosing.

14.
J Neurol ; 265(5): 1199-1209, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29550884

RESUMO

BACKGROUND: The mechanism of action of oral cladribine, recently licensed for relapsing multiple sclerosis, is unknown. OBJECTIVE: To determine whether cladribine depletes memory B cells consistent with our recent hypothesis that effective, disease-modifying treatments act by physical/functional depletion of memory B cells. METHODS: A cross-sectional study examined 40 people with multiple sclerosis at the end of the first cycle of alemtuzumab or injectable cladribine. The relative proportions and absolute numbers of peripheral blood B lymphocyte subsets were measured using flow cytometry. Cell-subtype expression of genes involved in cladribine metabolism was examined from data in public repositories. RESULTS: Cladribine markedly depleted class-switched and unswitched memory B cells to levels comparable with alemtuzumab, but without the associated initial lymphopenia. CD3+ T cell depletion was modest. The mRNA expression of metabolism genes varied between lymphocyte subsets. A high ratio of deoxycytidine kinase to group I cytosolic 5' nucleotidase expression was present in B cells and was particularly high in mature, memory and notably germinal centre B cells, but not plasma cells. CONCLUSIONS: Selective B cell cytotoxicity coupled with slow repopulation kinetics results in long-term, memory B cell depletion by cladribine. These may offer a new target, possibly with potential biomarker activity, for future drug development.


Assuntos
Subpopulações de Linfócitos B/efeitos dos fármacos , Cladribina/efeitos adversos , Fatores Imunológicos/efeitos adversos , Esclerose Múltipla/sangue , Esclerose Múltipla/tratamento farmacológico , Administração Oral , Adulto , Alemtuzumab/efeitos adversos , Alemtuzumab/uso terapêutico , Apoptose/efeitos dos fármacos , Subpopulações de Linfócitos B/metabolismo , Cladribina/uso terapêutico , Estudos Transversais , Desoxicitidina Quinase/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfonodos/patologia , Linfopenia/sangue , Linfopenia/etiologia , Masculino , Esclerose Múltipla/patologia , RNA Mensageiro/metabolismo , Resultado do Tratamento
15.
Front Immunol ; 9: 543, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29599784

RESUMO

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2-3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.

16.
Clin Transl Allergy ; 8: 11, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29599966

RESUMO

Background: Icatibant is a bradykinin B2-receptor antagonist used for the treatment of hereditary angioedema attacks resulting from C1-inhibitor deficiency. Treatment is not adjusted by body weight however the impact of body mass index (BMI) on the effectiveness of icatibant is not documented in the literature. We examined disease characteristics and icatibant treatment effectiveness in patients stratified by BMI in the Icatibant Outcome Survey, an ongoing, international, observational study monitoring the real-world safety and effectiveness of icatibant. Methods: Attack and treatment characteristics as well as outcomes following treatment with icatibant were compared among patients with underweight, normal, overweight, and obese BMI. Results: Data from 2697 icatibant-treated attacks in 342 patients (3.5, 44.7, 34.8, and 17.0% patients of underweight, normal, overweight, and obese BMI, respectively) were analyzed. There was no significant difference in the frequency and severity of attacks across BMI groups, although obese patients tended to have more attacks of high severity. There was no impact of BMI on the frequency of laryngeal attacks, but patients with normal BMI had fewer cutaneous attacks and more abdominal attacks. Most attacks (71.9-83.8%) were treated with a single icatibant injection without the need for rescue with plasma-derived C1-inhibitor (pdC1-INH), regardless of BMI. Patients with obese BMI used pdC1-INH as rescue treatment more often (P < 0.0001; P = 0.0232 excluding 2 outliers) and treated attacks earlier than patients with normal BMI (P = 0.007). Furthermore, time to resolution and duration of attack were shorter for patients with high BMI (P < 0.001 for overweight and P < 0.05 for obese versus normal). Conclusion: Overall, icatibant was comparatively effective in treating attacks in patients across all BMI groups.Trial registration NCT01034969.

17.
J Allergy Clin Immunol ; 142(4): 1285-1296, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29477724

RESUMO

BACKGROUND: The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses. RESULTS: Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases. CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

18.
J Allergy Clin Immunol Pract ; 6(5): 1733-1741.e3, 2018 Sep - Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29391286

RESUMO

BACKGROUND: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) impairs health-related quality of life (HRQoL). OBJECTIVE: The objective of this study was to assess HRQoL outcomes in patients self-administering subcutaneous C1-INH (C1-INH[SC]; HAEGARDA) for routine prevention of HAE attacks. METHODS: Post hoc analysis of data from the placebo-controlled, crossover phase III COMPACT study (Clinical Studies for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy). Ninety patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH(SC) 40 or 60 IU/kg twice weekly for 16 weeks, preceded or followed by 16 weeks of twice weekly placebo injections. All HAE attacks were treated with open-label on-demand treatment as necessary. HRQoL assessments at week 14 (last visit) included the European Quality of Life-5 Dimensions Questionnaire (EQ-5D-3L), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication (TSQM). RESULTS: Compared with placebo (on-demand treatment alone), treatment with twice weekly C1-INH(SC) (both doses combined) was associated with better EQ-5D visual analog scale general health, less HADS anxiety, less WPAI presenteeism, work productivity loss, and activity impairment, and greater TSQM effectiveness and overall treatment satisfaction. More patients self-reported a "good/excellent" response during routine prevention with C1-INH(SC) compared with on-demand only (placebo prophylaxis) management. For each HRQoL measure, a greater proportion of patients had a clinically meaningful improvement during C1-INH(SC) treatment compared with placebo. CONCLUSIONS: In patients with frequent HAE attacks, a treatment strategy of routine prevention with self-administered twice weekly C1-INH(SC) had a greater impact on improving multiple HAE-related HRQoL impairments, most notably anxiety and work productivity, compared with on-demand treatment alone (placebo prophylaxis).

19.
CPT Pharmacometrics Syst Pharmacol ; 7(3): 158-165, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29316335

RESUMO

Subcutaneous C1-inhibitor (HAEGARDA, CSL Behring), is a US Food and Drug Administration (FDA)-approved, highly concentrated formulation of a plasma-derived C1-esterase inhibitor (C1-INH), which, in the phase III Clinical Studies for Optimal Management in Preventing Angioedema with Low-Volume Subcutaneous C1-inhibitor Replacement Therapy (COMPACT) trial, reduced the incidence of hereditary angioedema (HAE) attacks when given prophylactically. Data from the COMPACT trial were used to develop a repeated time-to-event model to characterize the timing and frequency of HAE attacks as a function of C1-INH activity, and then develop an exposure-response model to assess the relationship between C1-INH functional activity levels (C1-INH(f)) and the risk of an attack. The C1-INH(f) values of 33.1%, 40.3%, and 63.1% were predicted to correspond with 50%, 70%, and 90% reductions in the HAE attack risk, respectively, relative to no therapy. Based on trough C1-INH(f) values for the 40 IU/kg (40.2%) and 60 IU/kg (48.0%) C1-INH (SC) doses, the model predicted that 50% and 67% of the population, respectively, would see at least a 70% decrease in the risk of an attack.

20.
Circ Res ; 122(4): 555-559, 2018 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-29298774

RESUMO

RATIONALE: The balance between vascular prostacyclin, which is antithrombotic, and platelet thromboxane A2, which is prothrombotic, is fundamental to cardiovascular health. Prostacyclin and thromboxane A2 are formed after the concerted actions of cPLA2α (cytosolic phospholipase A2) and COX (cyclooxygenase). Urinary 2,3-dinor-6-keto-PGF1α (PGI-M) and 11-dehydro-TXB2 (TX-M) have been taken as biomarkers of prostacyclin and thromboxane A2 formation within the circulation and used to explain COX biology and patient phenotypes, despite concerns that urinary PGI-M and TX-M originate in the kidney. OBJECTIVE: We report data from a remarkable patient carrying an extremely rare genetic mutation in cPLA2α, causing almost complete loss of prostacyclin and thromboxane A2, who was transplanted with a normal kidney resulting in an experimental scenario of whole-body cPLA2α knockout, kidney-specific knockin. By studying this patient, we can determine definitively the contribution of the kidney to the productions of PGI-M and TX-M and test their validity as markers of prostacyclin and thromboxane A2 in the circulation. METHODS AND RESULTS: Metabolites were measured using liquid chromatography-tandem mass spectrometry. Endothelial cells were grown from blood progenitors. Before kidney transplantation, the patient's endothelial cells and platelets released negligible levels of prostacyclin (measured as 6-keto-prostaglandin F1α) and thromboxane A2 (measured as TXB2), respectively. Likewise, the urinary levels of PGI-M and TX-M were very low. After transplantation and the establishment of normal renal function, the levels of PGI-M and TX-M in the patient's urine rose to within normal ranges, whereas endothelial production of prostacyclin and platelet production of thromboxane A2 remained negligible. CONCLUSIONS: These data show that PGI-M and TX-M can be derived exclusively from the kidney without contribution from prostacyclin made by endothelial cells or thromboxane A2 by platelets in the general circulation. Previous work relying on urinary metabolites of prostacyclin and thromboxane A2 as markers of whole-body endothelial and platelet function now requires reevaluation.

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