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1.
Blood ; 137(13): 1818-1827, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33150384

RESUMO

Rurioctocog alfa pegol prophylaxis targeting factor VIII (FVIII) troughs ≥1% has shown to be efficacious with an acceptable safety profile in people with hemophilia A (PwHA). The PROPEL trial compared safety and efficacy of 2 target FVIII troughs in PwHA aged 12 to 65 years, with severe disease, annualized bleeding rate ≥2, and previous FVIII treatment. PwHA were randomized to 12 months' pharmacokinetic (PK)-guided rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1% to 3% (reference arm) or 8% to 12% (elevated arm); first 6 months was treatment-adjustment period. The primary endpoint was absence of bleeds during the second 6 months, analyzed using multiple imputations (full analysis set [FAS]). In the 1% to 3% and 8% to 12% arms, respectively, point estimates (95% confidence interval) of proportions of PwHA with zero total bleeds were 42% (29% to 55%) and 62% (49% to 75%) in FAS (N = 115; P = .055) and 40% (27% to 55%) and 67% (52% to 81%) in per-protocol analysis set (N = 95; P = .015). Dosing frequency and consumption varied in each arm. Adverse events (AEs) occurred in 70/115 (60.9%) PwHA; serious AEs in 7/115 (6%) PwHA, including 1 treatment-related in 8% to 12% arm (transient anti-FVIII inhibitor). There were no deaths, serious thrombotic events, or AE-related discontinuations. PK-guided prophylaxis was achievable and efficacious in both arms. No new safety signals were observed in the 8% to 12% arm. These results demonstrate elevated FVIII troughs can increase the proportion of PwHA with zero bleeds and emphasize the importance of personalized treatment. This trial was registered at www.clinicaltrials.gov as #NCT02585960.


Assuntos
Coagulantes/uso terapêutico , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Adolescente , Adulto , Coagulantes/efeitos adversos , Coagulantes/farmacocinética , Fator VIII/efeitos adversos , Fator VIII/farmacocinética , Feminino , Hemofilia A/complicações , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
2.
J Clin Immunol ; 41(6): 1331-1338, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34036490

RESUMO

Patients with primary immunodeficiency diseases often require lifelong immunoglobulin (IG) therapy. Most clinical trials investigating IG therapies characterize serum immunoglobulin G (IgG) pharmacokinetic (PK) profiles by serially assessing serum IgG levels. This retrospective analysis evaluated whether steady-state serum IgG trough level measurement alone is adequate for PK assessment. Based on individual patient serum IgG trough levels from two pivotal trials (phase 2/3 European [NCT01412385] and North American [NCT01218438]) of weekly 20% subcutaneous IG (SCIG; Cuvitru, Ig20Gly), trough level-predicted IgG AUC (AUCτ,tp) were calculated and compared with the reported AUC calculated from serum IgG concentration-time profiles (AUCτ). In both studies, mean AUCτ,tp values for Ig20Gly were essentially equivalent to AUCτ with point estimates of geometric mean ratio (GMR) of AUCτ,tp/AUCτ near 1.0 and 90% CIs within 0.80-1.25. In contrast, for IVIG, 10%, mean AUCτ,tp values were lower than AUCτ by >20%, (GMR [90% CI]: 0.74 [0.70-0.78] and 0.77 [0.73-0.81] for the two studies, respectively). Mean AUCτ,tp values calculated for 4 other SCIG products (based on mean IgG trough levels reported in the literature/labels) were also essentially equivalent to the reported AUCτ (differences <10% for all except HyQvia, a facilitated SCIG product), while differences for IVIG products were >20%. In conclusion, steady-state serum IgG levels following weekly SCIG remain stable, allowing for reliable prediction of AUC over the dosing interval using trough IgG levels. These findings indicate that measuring steady-state serum IgG trough levels alone may be adequate for PK assessment of weekly SCIG.


Assuntos
Imunoglobulina G/sangue , Imunoglobulina G/uso terapêutico , Imunoglobulinas Intravenosas/farmacocinética , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Estudos Multicêntricos como Assunto , Doenças da Imunodeficiência Primária/sangue , Doenças da Imunodeficiência Primária/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos
3.
Haemophilia ; 27(3): e331-e339, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33772963

RESUMO

INTRODUCTION: In patients with haemophilia A undergoing surgery, factor VIII (FVIII) replacement therapy by continuous infusion (CI) may offer an alternative to bolus infusion (BI). AIM: To compare the perioperative haemostatic efficacy and safety of antihaemophilic factor (recombinant) (ADVATE® ; Baxalta US Inc., a Takeda company, Lexington, MA, USA) CI or BI administration. METHODS: In this multicentre, phase III/IV, controlled study (NCT00357656), 60 previously treated adult patients with severe or moderately severe disease undergoing elective unilateral major orthopaedic surgery (knee replacement, n = 48; hip surgery, n = 4; other, n = 8) requiring drain placement were randomized to receive antihaemophilic factor (recombinant) CI (n = 29) or BI (n = 31) through postoperative day 7. Primary outcome measure was cumulative packed red blood cell (PRBC)/blood volume in the drainage fluid within 24 h after surgery, used to establish non-inferiority of CI to BI. RESULTS: CI:BI ratio of cumulative PRBC volume in the 24-h drainage fluid was 0.92 (p-value <.001 for non-inferiority; 95% confidence interval, 0.82-1.05). Total antihaemophilic factor (recombinant) dose per kg body weight received in the combined trans- and postoperative periods was similar with CI and BI to maintain targeted FVIII levels during/after surgery. Treatment-related adverse events (AEs) were reported in five patients treated by CI (eight events) and five treated by BI (six events), including two serious AEs in each arm. CONCLUSION: CI administration of antihaemophilic factor (recombinant) is a viable alternative to BI in patients with haemophilia A undergoing major orthopaedic surgery, providing comparable efficacy and safety.


Assuntos
Hemofilia A , Procedimentos Ortopédicos , Adulto , Testes de Coagulação Sanguínea , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia A/cirurgia , Hemostasia , Humanos , Proteínas Recombinantes
4.
Pharm Stat ; 20(2): 272-281, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33063443

RESUMO

For the clinical development of a new drug, the determination of dose-proportionality is an essential part of the pharmacokinetic evaluations, which may provide early indications of non-linear pharmacokinetics and may help to identify sub-populations with divergent clearances. Prior to making any conclusions regarding dose-proportionality, the goodness-of-fit of the model must be assessed to evaluate the model performance. We propose the use of simulation-based visual predictive checks to improve the validity of dose-proportionality conclusions for complex designs. We provide an illustrative example and include a table to facilitate review by regulatory authorities.


Assuntos
Relação Dose-Resposta a Droga , Simulação por Computador , Humanos
5.
Haemophilia ; 26(4): e168-e178, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32597029

RESUMO

INTRODUCTION: Previous studies reported the efficacy and safety profile of extended half-life PEGylated recombinant factor VIII (FVIII) rurioctocog alfa pegol (TAK-660, SHP660, BAX 855) in preventing bleeding in haemophilia A patients. AIM: This study evaluated long-term safety and efficacy of rurioctocog alfa pegol for prophylaxis and treatment of bleeding in previously treated children and adults. METHODS: In this phase 3b, prospective, open-label, multicentre study (NCT01945593), eligible patients ≤ 75 years with severe haemophilia A (FVIII < 1%) received prophylactic rurioctocog alfa pegol in a fixed dose (FD, twice-weekly or less frequent) or pharmacokinetic (PK)-tailored dose regimen. Co-primary endpoints were incidence of confirmed FVIII inhibitory antibody development and spontaneous annualized bleed rate (ABR), analysed using a generalised linear model. Secondary endpoints included overall haemostatic efficacy, occurrence of adverse events and health-related quality of life (HRQoL). RESULTS: Overall, 216 patients were included; mean (SD) age at enrolment was 22.8 (15.7) years. No patients developed confirmed FVIII inhibitors. The point estimate (95% CI) of mean spontaneous ABR was 1.20 (0.92-1.56) among 186 patients receiving twice-weekly FD prophylaxis and 0.96 (0.54-1.71) among 25 patients receiving PK-tailored prophylaxis. Overall haemostatic efficacy was rated good or excellent in 88.6% of all bleeds. No new safety signals were observed. Patients reported improvements in HRQoL measures of pain, and physical and mental well-being. CONCLUSION: These results highlight the long-term safety and efficacy of rurioctocog alfa pegol prophylaxis in previously treated children and adults with severe haemophilia A, with a safety profile similar to previous studies and continuing ABR reduction.


Assuntos
Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemorragia/prevenção & controle , Hemostasia/efeitos dos fármacos , Adolescente , Adulto , Criança , Fator VIII/administração & dosagem , Fator VIII/efeitos adversos , Fator VIII/farmacocinética , Feminino , Hemofilia A/sangue , Hemofilia A/etnologia , Humanos , Masculino , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Qualidade de Vida , Proteínas Recombinantes , Segurança , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
6.
Haemophilia ; 26(3): 478-486, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32338433

RESUMO

INTRODUCTION: Antihaemophilic factor (recombinant) (rAHF; ADVATE® ) is approved for prophylaxis and treatment of bleeding in children and adults with haemophilia A. Reconstitution in 2 mL sterile water for injection instead of 5 mL allows for a 60% reduction in infusion volume and administration time, but could increase the likelihood of hypersensitivity and infusion-related reactions, especially in children. AIM: To assess local tolerability, safety and effectiveness of rAHF 2 mL during routine clinical practice factor VIII (FVIII) replacement (on-demand and prophylaxis) in children with severe (FVIII < 1%) or moderately severe (FVIII 1%-2%) haemophilia A. METHODS: This was a prospective, non-interventional, postauthorization safety surveillance study (NCT02093741). Eligible patients were previously treated with rAHF and had a negative inhibitor test result during ≤10 exposure days prior to study entry. RESULTS: Of 65 patients enrolled (0-11 years of age), 54 and 11 had severe and moderately severe haemophilia A, respectively; 56 patients received prophylaxis, and 11 had ≤50 exposure days, of which 4 had ≤4 exposure days. No patients reported local hypersensitivity reactions, treatment-related adverse events or developed inhibitors. Investigators rated overall effectiveness of rAHF 2 mL prophylaxis as excellent or good. Ninety-four bleeding events in 34 patients were treated. Haemostatic effectiveness was rated as excellent or good for 75.8% of bleeds; 86.2% of bleeds required 1 or 2 infusions. CONCLUSION: In children with severe/moderately severe haemophilia A, no hypersensitivity reactions were reported with rAHF 2 mL treatment, and the safety and effectiveness are consistent with data previously reported for rAHF 5 mL.


Assuntos
Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Água/química , Criança , Pré-Escolar , Monitoramento Epidemiológico , Fator VIII/farmacologia , Feminino , Humanos , Lactente , Recém-Nascido , Injeções , Masculino
7.
Haemophilia ; 25(5): 773-781, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31353761

RESUMO

INTRODUCTION: Rurioctocog alfa pegol (BAX 855, TAK-660) is a PEGylated, full-length, recombinant factor VIII (rFVIII) with extended half-life developed from unmodified rFVIII (antihaemophilic factor [recombinant]). AIM: To determine the perioperative haemostatic efficacy and safety of rurioctocog alfa pegol in male previously treated patients (PTPs) with severe haemophilia A. METHODS: This multicentre, single-arm, phase III study included PTPs who were to undergo major or minor elective or minor emergency surgical, dental or other invasive procedures. Rurioctocog alfa pegol dose and frequency were individualized based on patients' pharmacokinetic profiles for major surgeries and by rurioctocog alfa pegol incremental recovery for minor surgeries. Haemostatic efficacy was assessed using the Global Haemostatic Efficacy Assessment score. RESULTS: Twenty-one patients aged 16-61 years underwent 21 major and five minor surgeries. For all 24 evaluable surgeries, overall haemostatic efficacy was rated as excellent and blood loss comparable to that expected in non-haemophilic patients. No blood transfusions were required intraoperatively but were administered postoperatively for four surgeries in three patients. Five injury-related postoperative bleeding episodes occurred in five patients, of which two required additional rurioctocog alfa pegol treatment. Two non-serious adverse events of mild severity (increased ALT level and headache) were considered possibly related to rurioctocog alfa pegol. There were no deaths or treatment-related serious adverse events. No patients developed inhibitory antibodies to FVIII or persistent IgG- or IgM-binding antibodies to FVIII, PEG-FVIII or PEG. CONCLUSION: Rurioctocog alfa pegol was well tolerated and effective for perioperative use in patients with haemophilia A and showed no signs of immunogenicity.


Assuntos
Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Período Perioperatório/métodos , Adolescente , Adulto , Fator VIII/farmacologia , Feminino , Hemostasia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
8.
Ann Allergy Asthma Immunol ; 123(3): 271-279.e1, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31228628

RESUMO

BACKGROUND: The subcutaneous immune globulin (SCIG) 20% product, Ig20Gly, was shown to be efficacious and well tolerated in 2 phase 2/3 North American and European studies at infusion volumes up to 60 mL/site and rates up to 60 mL/h/site in patients with primary immunodeficiency diseases. OBJECTIVE: To assess patient experience after switching to Ig20Gly with fast infusion rates and large infusion volumes/site in the North American study. METHODS: In this analysis of the open-label phase 2/3 study in which patients aged ≥2 years received weekly Ig20Gly infusions for up to approximately 1.3 years, tolerability and infusion parameters were assessed throughout the study for all patients and by prestudy treatment regimen (intravenous [IV] switchers or SC switchers). RESULTS: Overall, 61% of patients reached the infusion rate of ≥60 mL/h/site and continued at this rate for 1 or more subsequent infusions; the median infusion number when patients first reached ≥60 mL/h/site was 3. No association was found between higher infusion volumes or rates and increased incidences of local and systemic adverse events (AEs) in the total population and patients younger than 16 years. Infusion parameters and tolerability were generally comparable regardless of the route of prestudy treatment (IV or SC switchers); however, IV switchers experienced lower rates of local AEs than SC switchers and had a slightly higher median infusion volume per site and longer infusion duration vs SC switchers. CONCLUSION: High Ig20Gly infusion rates of at least 60 mL/h/site and volumes ≥60 mL/site were well tolerated during onboarding and throughout treatment, regardless of prestudy treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01218438.


Assuntos
Tolerância a Medicamentos/imunologia , Imunoglobulinas/uso terapêutico , Imunoterapia/métodos , Infusões Subcutâneas/métodos , Doenças da Imunodeficiência Primária/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte , Doenças da Imunodeficiência Primária/imunologia , Resultado do Tratamento , Adulto Jovem
9.
Blood ; 126(9): 1078-85, 2015 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-26157075

RESUMO

Current management of hemophilia A includes prophylaxis with factor VIII (FVIII) replacement every 2 to 3 days. BAX 855, Baxalta's pegylated full-length recombinant FVIII (rFVIII), was designed to increase half-life and, thus, reduce the frequency of prophylactic infusions while maintaining hemostatic efficacy. BAX 855 was evaluated in previously treated patients with severe hemophilia A who were aged 12 to 65 years. A phase 1 study compared the pharmacokinetic (PK) profile of BAX 855 with that of licensed rFVIII (Advate). In a pivotal study, the annualized bleeding rate (ABR), PK parameters, and efficacy of bleeding treatment were assessed. In the phase 1 study, the mean half-life (T1/2) and the mean residence time of BAX 855 compared with Advate were 1.4- to 1.5-fold higher. These results were confirmed in the pivotal study. The pivotal study met its primary endpoint: Prophylaxis with BAX 855 resulted in an ABR that was significantly lower than half the ABR of on-demand treatment (P < .0001). The median ABR was 1.9, and 39.6% of compliant subjects had no bleeding episodes during prophylaxis, whereas subjects treated on-demand had a median ABR of 41.5. BAX 855 was also efficacious for the treatment of bleeding episodes, with 95.9% of bleeding episodes treated with 1 to 2 infusions and 96.1% having efficacy ratings of excellent/good. No FVIII inhibitory antibodies or safety signals were identified. These studies provide evidence that BAX 855 was safe and efficacious for on-demand treatment and prophylaxis administered twice weekly in patients with hemophilia A. The trials were registered at www.clinicaltrials.gov as #NCT01736475 and #NCT01599819.


Assuntos
Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemorragia/prevenção & controle , Hemostáticos/uso terapêutico , Adolescente , Adulto , Criança , Estudos Cross-Over , Esquema de Medicação , Fator VIII/administração & dosagem , Fator VIII/química , Fator VIII/farmacocinética , Feminino , Hemostáticos/administração & dosagem , Hemostáticos/química , Hemostáticos/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/química , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Adulto Jovem
10.
J Clin Immunol ; 36(6): 571-82, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27220317

RESUMO

PURPOSE: Treatment of primary immunodeficiency diseases (PIDD) with subcutaneous (SC) infusions of IgG preceded by injection of recombinant human hyaluronidase (rHuPH20) (IGHy) to increase SC tissue permeability was evaluated in two consecutive, prospective, non-controlled, multi-center studies. METHODS: Subjects >4 years of age received SC IgG replacement at a weekly dose equivalent of 108 % of their previous intravenous (IV) dose, facilitated by prior injection of 75 U/g IgG of rHuPH20. Starting with weekly SC infusions, the interval was increased (ramped-up) to a 3- or 4-week schedule. RESULTS: Eighty-three subjects (24 < 18 years; 59 ≥ 18 years) received 2729 infusions (excluding ramp-up) at a mean dose of 0.155 g/kg/week in the pivotal and 0.156 g/kg/week in the extension study. IGHy exposure exceeded 30 months in 48 subjects. During 187.7 subject-years of IGHy exposure, 2005 adverse events (AEs) (10.68 per subject-year) occurred. The rate of related systemic AEs during consecutive 1-year periods remained low; the rate of related local AEs decreased from 3.68/subject-year in months 1-12 to approximately 1.50/subject-year after 30 months of treatment. Fifteen subjects transiently developed anti-rHuPH20 binding antibody. There was no difference in AE rates in these subjects before and after the first titer increase to ≥1:160. The rate of infections during IGHy exposure was 2.99 per subject-year and did not increase during the studies. Annual infection rates were 3.02 in subjects <18 years and 2.98 in subjects ≥18 years. CONCLUSIONS: Long-term replacement therapy with IGHy was safe and effective in 83 pediatric and adult subjects with PIDD.


Assuntos
Hialuronoglucosaminidase/administração & dosagem , Imunoglobulinas Intravenosas/administração & dosagem , Síndromes de Imunodeficiência/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , Adolescente , Adulto , Idoso , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/etiologia , Criança , Feminino , Hospitalização , Humanos , Hialuronoglucosaminidase/efeitos adversos , Imunoglobulinas Intravenosas/efeitos adversos , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
11.
Blood ; 122(5): 648-57, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23777763

RESUMO

Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-∞) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved.


Assuntos
Proteínas Recombinantes/farmacocinética , Doenças de von Willebrand/tratamento farmacológico , Doenças de von Willebrand/metabolismo , Fator de von Willebrand/farmacocinética , Adolescente , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Adulto Jovem , Fator de von Willebrand/efeitos adversos , Fator de von Willebrand/uso terapêutico
12.
Biometrics ; 70(1): 103-9, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24571518

RESUMO

This article proposes a new multiple-testing approach for estimation of the minimum effective dose allowing for non-monotonous dose-response shapes. The presented approach combines the advantages of two commonly used methods. It is shown that the new approach controls the error rate of underestimating the true minimum effective dose. Monte Carlo simulations indicate that the proposed method outperforms alternative methods in many cases and is only marginally worse in the remaining situations.


Assuntos
Ensaios Clínicos como Assunto/métodos , Relação Dose-Resposta a Droga , Modelos Estatísticos , Animais , Simulação por Computador , Cricetinae , Interpretação Estatística de Dados , Humanos , Testes de Mutagenicidade/métodos , Nível de Efeito Adverso não Observado
13.
Blood Adv ; 8(11): 2726-2739, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38564770

RESUMO

ABSTRACT: Rurioctocog alfa pegol is an extended-half-life full-length recombinant factor VIII (FVIII) bound to 20-kDa polyethylene glycol (PEG) that has been shown to be well tolerated and efficacious in the treatment and prevention of bleeding events in previously treated patients with severe hemophilia A. Here, we present a comprehensive analysis of immunogenicity data collected during 6 clinical studies of rurioctocog alfa pegol, including a total of 360 unique previously treated patients with severe hemophilia A. The analysis included treatment-emerging FVIII-neutralizing antibodies (FVIII inhibitors); preexisting and treatment-emerging antibodies binding to FVIII, PEG-FVIII, or PEG; and treatment-emerging antibodies binding to Chinese hamster ovary host cell proteins. Moreover, the potential association between the presence of these binding antibodies and adverse events (AEs) observed in patients was investigated, and the potential impact of these antibodies on the incremental recovery of rurioctocog alfa pegol in patients was analyzed. Overall, the data indicate that rurioctocog alfa pegol is not associated with any unexpected immunogenicity characteristics. Of 360 patients, 1 patient developed a transient FVIII inhibitor with a titer of 0.6 Bethesda units per mL, which was not associated with any serious AEs. Antibodies binding to FVIII, PEG-FVIII, or PEG were not detected at the time when the inhibitor was present. Moreover, 54 of 360 patients either entered the clinical studies with preexisting binding antibodies or developed these antibodies after exposure to rurioctocog alfa pegol. These antibodies were transient in most patients and did not show any causal relationship to either AEs or spontaneous bleeding episodes.


Assuntos
Fator VIII , Hemofilia A , Polietilenoglicóis , Humanos , Fator VIII/imunologia , Fator VIII/uso terapêutico , Fator VIII/efeitos adversos , Hemofilia A/tratamento farmacológico , Hemofilia A/imunologia , Hemofilia A/sangue , Polietilenoglicóis/uso terapêutico , Masculino , Anticorpos Neutralizantes/imunologia , Adulto , Adolescente , Animais , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/imunologia , Criança , Adulto Jovem
14.
J Thromb Haemost ; 22(1): 90-100, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37717853

RESUMO

BACKGROUND: Patients with hemophilia who have recurrent hemarthroses develop hemophilic arthropathy (HA). Regular prophylaxis with factor (F) VIII (FVIII) can reduce HA, but there is a need for objective outcome measures to evaluate treatment efficacy. OBJECTIVES: Evaluate and assess collagen turnover biomarkers in patients with hemophilia A to determine the efficacy of rurioctocog alfa pegol treatment and understand their potential as tools for guiding treatment decisions and monitoring outcomes. METHODS: Joint remodeling was assessed by analyzing serum levels of collagen remodeling products at baseline and months 3, 6, 9, and 12 in a 98 patient subset receiving pharmacokinetics-guided prophylaxis with rurioctocog alfa pegol, targeting FVIII trough levels of 1 to 3 International Units (IU)/dL or 8 to 12 IU/dL (PROPEL study, NCT0285960). RESULTS: Basement membrane metabolism-related type 4 collagen remodeling products (C4M and PRO-C4) decreased after 3 months at all time points by up to 25% at 1 to 3 IU/dL (P = .049, P < .0001) and 8 to 12 IU/dL FVIII trough levels (P = .0002, P < .0001). Interstitial tissue metabolism-related type 3 (C3M) and 5 (PRO-C5) collagen remodeling products decreased after 3 months, by up to 19% at 1 to 3 IU/dL FVIII trough level (P = .0001, P = .009) and 23% at 8 to 12 IU/dL FVIII trough level (P = .0002, P = .001). An increase of up to 12% was seen for cartilage metabolism-related type 2 collagen product (PRO-C2, not C2M) after 6 months at both trough levels (P = .01, P = .005). When stratified by prior treatment, changes in C3M (P = .03) and C4M (P = .02) levels were observed between trough levels for prior on-demand treatment but not for prophylaxis prior to study entry. CONCLUSION: Joint improvement measured by collagen remodeling biomarkers specific to the basement membrane, interstitial matrix, and cartilage was seen with pharmacokinetics-guided prophylaxis. These collagen remodeling biomarkers warrant further exploration as biomarkers to guide treatment toward improvement in HA.


Assuntos
Hemofilia A , Doenças Vasculares , Humanos , Hemofilia A/diagnóstico , Hemofilia A/tratamento farmacológico , Fator VIII/uso terapêutico , Colágeno , Doenças Vasculares/complicações , Biomarcadores
15.
J Allergy Clin Immunol ; 130(4): 951-7.e11, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22846381

RESUMO

BACKGROUND: Subcutaneous immunoglobulin (IGSC) replacement therapy for primary immunodeficiency (PI) is equally efficacious to intravenous immunoglobulin (IGIV), induces fewer systemic reactions, and may be self-infused. Limited SC infusion volumes and reduced bioavailability, however, necessitate multiple infusion sites, more frequent treatment, and dose adjustment to achieve pharmacokinetic equivalence. Recombinant human hyaluronidase (rHuPH20) increases SC tissue permeability and facilitates dispersion and absorption, enabling administration of monthly doses in one site. OBJECTIVE: This study investigated the efficacy and tolerability of rHuPH20-facilitated IGSC (IGHy) in patients with PI. METHODS: In this open-label, multicenter phase III study, 87 patients with PI aged ≥2 years received 10% IGIV for 3 months, then IGHy (n = 83) for approximately 14 to 18 months at 108% of the IGIV dose. IGHy infusions began weekly, increasing to 3- or 4-week intervals. RESULTS: The majority (94.0%) of IGHy infusions were administered every 3 or 4 weeks, using one site (median, 1.09/month), with a mean volume of 292.2 mL. The bioavailability of IGHy measured by area under the concentration versus time curve was 93.3% of IGIV, which is pharmacokinetically equivalent. Systemic reactions were less frequent with IGHy than with IGIV (8.3% vs 25.0% of infusions). Local reactions to IGHy were generally mild to moderate, with a rate of 0.203 per infusion. The acute serious bacterial infection rate per subject-year for IGHy was low (0.025; upper 99% CI limit, 0.046). Overall infection rates per subject-year were 2.97 for IGHy and 4.51 for IGIV. CONCLUSION: IGHy was effective, safe, and pharmacokinetically equivalent to IGIV at the same administration intervals, but it caused fewer systemic reactions. Tolerability was good despite high infusion volumes and rates.


Assuntos
Hialuronoglucosaminidase/administração & dosagem , Imunoglobulinas/administração & dosagem , Síndromes de Imunodeficiência/tratamento farmacológico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Humanos , Imunoglobulinas/efeitos adversos , Infusões Subcutâneas , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem
16.
Ther Adv Hematol ; 14: 20406207231178596, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37465396

RESUMO

Background: The phase 3, prospective PROPEL study demonstrated that pharmacokinetic (PK)-guided prophylaxis targeting elevated factor VIII (FVIII) troughs in patients with hemophilia A resulted in lower annualized bleeding rates (ABRs) and a higher proportion of patients experiencing zero bleeds in the second 6 months of treatment when targeting a FVIII trough of 8-12% versus 1-3%. Objective: To investigate the benefit of PK-guided prophylaxis with rurioctocog alfa pegol targeting two FVIII trough levels in specific patient subgroups in a post hoc analysis using data from PROPEL. Design: This is a post hoc analysis of data from the PROPEL study. The design and primary outcomes of the prospective, randomized PROPEL study (NCT02585960) have been reported previously. Methods: This post hoc analysis reports data stratified by FVIII half-life (t1/2), hemophilic arthropathy status, number of target joints at screening, previous treatment regimen, and ABR range in the 12 months before study entry. Results: Targeting an elevated FVIII trough of 8-12% was associated with higher average FVIII levels over time, regardless of FVIII t1/2 at baseline. The decrease in total ABR between the 8-12% and 1-3% arms was greatest in patients with a FVIII t1/2 of 6 to <12 h (0.7 versus 3.5); a higher number of target joints, that is, at least four target joints, at baseline (0.2 versus 1.6); the presence of arthropathy (0.1 versus 1.7); and those previously treated on-demand (0.3 versus 1.8). Conclusion: These results support the feasibility of targeting elevated FVIII levels using personalized rurioctocog alfa pegol prophylaxis. These benefits may be especially important in patients with a short FVIII t1/2 and those receiving standard prophylaxis with frequent breakthrough bleeds, arthropathy, and target joints. Registration: ClinicalTrials.gov Identifier: NCT02585960; https://clinicaltrials.gov/ct2/show/NCT02585960.

17.
Expert Rev Hematol ; 16(10): 793-801, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37646148

RESUMO

AIM: To determine the immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients (PUPs) with severe hemophilia A (HA). METHODS: This prospective, phase 3 study (NCT02615691) was conducted in PUPs, or patients with ≤2 exposure days (EDs) prior to screening, aged <6 years with severe HA. The primary endpoint was incidence of factor VIII (FVIII) inhibitor development. This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing FVIII inhibitors or had developed a confirmed inhibitor at any time. RESULTS: Of the enrolled patients, 59/80 (73.8%) received ≥1 dose of rurioctocog alfa pegol; 54 received prophylaxis, and 35 on-demand treatment. Incidence of inhibitor development was 0.19 (10/52). Total annualized bleeding rate (95% CIs) was 3.2 (2.0-5.0) for patients receiving prophylaxis and 3.2 (1.6-6.3) for on-demand treatment. Hemostatic efficacy of most bleedings was rated as 'excellent' or 'good' after 24 hours (122/131 [93.1%]) and at resolution (161/170 [94.7%]). Five patients received ≥1 dose of rurioctocog alfa pegol for immune tolerance induction (ITI) and 1 patient was defined as having ITI success. Thirteen patients experienced 14 treatment-related adverse events, including 10 cases of FVIII inhibitor development. CONCLUSION: This is the first prospective study of rurioctocog alfa pegol for the treatment of PUPs with severe HA. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02615691).


Assuntos
Fator VIII , Hemofilia A , Humanos , Fator VIII/efeitos adversos , Hemofilia A/tratamento farmacológico , Estudos Prospectivos , Hemorragia/tratamento farmacológico
18.
Immunotherapy ; 14(4): 215-224, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34931880

RESUMO

Aim: This post hoc analysis evaluated the efficacy and overall tolerability of immunoglobulin (Ig) treatment modalities (intravenous Ig [iv.Ig], subcutaneous Ig [sc.Ig] and facilitated sc.Ig [fsc.Ig]). Materials & methods: A total of 30 participants with primary immunodeficiency diseases aged ≥2 years sequentially received iv.Ig, sc.Ig and fsc.Ig during consecutive clinical studies. Results: For iv.Ig, sc.Ig and fsc.Ig, rates of validated acute serious bacterial infections/participant-year (0, 0.09 and 0.04, respectively) and all infections/participant year (4.17, 3.68 and 2.42, respectively) were similarly low; rates of systemic and local causally related adverse events/participant-year were 5.60, 1.93 and 0.88, respectively and 0.13, 0.92 and 1.57, respectively. Conclusion: fsc.Ig provided similar efficacy to iv.Ig and sc.Ig. Clinical Trial registration: NCT00546871, NCT00814320, NCT01175213 (ClinicalTrials.gov).


Assuntos
Infecções Bacterianas/epidemiologia , Imunização Passiva/métodos , Imunoglobulinas/uso terapêutico , Doenças da Imunodeficiência Primária/tratamento farmacológico , Doenças da Imunodeficiência Primária/epidemiologia , Adolescente , Criança , Pré-Escolar , Comorbidade , Feminino , Humanos , Imunoglobulinas/administração & dosagem , Infusões Subcutâneas , Masculino , Doenças da Imunodeficiência Primária/imunologia , Estudos Retrospectivos , Resultado do Tratamento
19.
J Clin Immunol ; 31(3): 323-31, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21424824

RESUMO

A multi-center, prospective, open-label study was conducted in primary immunodeficiency disease patients to determine the tolerability and pharmacokinetics of a 10% liquid IgG preparation administered subcutaneously. Forty-nine subjects (3-77 years old) were enrolled. Pharmacokinetic equivalence of subcutaneous treatment was achieved at a median dose of 137% of the intravenous dose, with a mean trough IgG level of 1,202 mg/dL at the end of the assessment period. The overall infection rate during subcutaneous treatment was 4.1 per subject-year. Three acute serious bacterial infections were reported, resulting in a rate of 0.067 per subject-year. A low overall rate of temporally associated adverse events (8%), and a very low rate of infusion site adverse events (2.8%), was seen at volumes up to 30 mL/site and rates ≤ 30 mL/h/site. Thus, subcutaneous replacement therapy with a 10% IgG preparation proved effective, safe and well-tolerated in our study population of subjects with primary immunodeficiency disease.


Assuntos
Agamaglobulinemia/tratamento farmacológico , Infecções Bacterianas/tratamento farmacológico , Imunodeficiência de Variável Comum/tratamento farmacológico , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Imunoglobulina G/administração & dosagem , Adolescente , Adulto , Agamaglobulinemia/complicações , Agamaglobulinemia/imunologia , Agamaglobulinemia/microbiologia , Agamaglobulinemia/patologia , Idoso , Bactérias/crescimento & desenvolvimento , Infecções Bacterianas/complicações , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Infecções Bacterianas/patologia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/microbiologia , Imunodeficiência de Variável Comum/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/microbiologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Imunoglobulina G/efeitos adversos , Imunoglobulina G/imunologia , Injeções Intravenosas , Injeções Subcutâneas , Cinética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Soluções , Resultado do Tratamento , Estados Unidos
20.
Clin Appl Thromb Hemost ; 27: 1076029621989811, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33587652

RESUMO

Antihemophilic factor (recombinant) (rAHF; ADVATE®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) is indicated for the treatment and prevention of bleeding in patients with hemophilia A. We aimed to assess the safety and efficacy of standard prophylaxis versus on-demand treatment with rAHF in previously treated Chinese patients with severe/moderately severe hemophilia A. This open-label, sequential, interventional, postapproval study (NCT02170402) conducted in China included patients of any age with hemophilia A with factor VIII (FVIII) level ≤2%. Patients received 6 months' on-demand rAHF then 6 months' rAHF prophylaxis (20-40 IU/kg every 48 ± 6 hours). The primary objective was percentage reduction in annualized bleeding rate (ABR) in the per-protocol analysis set (PPAS); secondary objectives included ABR by bleeding subtype, hemostatic efficacy, immunogenicity, and safety. Of 72 patients who received ≥1 rAHF dose, 61 were included in the PPAS. Total ABR was lower during prophylaxis (mean 2.5, 95% CI 1.5-3.7; median 0) versus on-demand treatment (mean 58.3, 95% CI 52.5-64.7; median 53.9), representing a 95.9% risk reduction. Similar findings in favor of prophylaxis were observed for all types of bleeding event by cause and location. rAHF hemostatic efficacy was rated as "excellent"/"good" in 96.1% of treated bleeding events. Transient FVIII inhibitors (0.6-1.7 BU) in 4 patients resolved before study end; no unexpected safety issues were observed. rAHF prophylaxis in this study of previously treated Chinese patients with severe/moderately severe hemophilia A resulted in a clear reduction in bleeding events versus rAHF on-demand treatment, with no change in safety profile.


Assuntos
Coagulantes/administração & dosagem , Fator VIII/administração & dosagem , Hemofilia A/tratamento farmacológico , Hemorragia/prevenção & controle , Adolescente , Adulto , Criança , Pré-Escolar , China , Coagulantes/efeitos adversos , Coagulantes/farmacocinética , Esquema de Medicação , Fator VIII/efeitos adversos , Fator VIII/farmacocinética , Hemofilia A/sangue , Hemofilia A/complicações , Hemofilia A/diagnóstico , Hemorragia/etiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
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