Impact of Systematic Pharmacokinetic (PK) Profiles in a Cohort of 29 Patients Treated with Conventional and Extended-Half Life (EHL) Products

Introduction. Prophylaxis with factor concentrates reduces bleeding events and improves quality of life for adults and children with severe hemophilia. However, the optimal dosing and infusion frequency is not yet established. Integration of PK data into decision making is gaining support, in particular at the transition between conventional and EHL products. Here we report about 29 PK data of patients affected by hemophilia treated at our centre since childhood. Improved quality of life was our first aim, supposed that decreasing frequency of infusions or increasing the target through factor level allows a more active life without increased risk of bleeding. Patients' characteristics and methods. 18 patients (62%) were ≤ 18 years of age at PK time. 16 were affected by severe hemophilia A, 5 by moderate hemophilia A, 6 by severe hemophilia B and 2 by moderate hemophilia B. At PK time, 28 patients were on prophylaxis and 1 was on demand with recombinant factor IX. Median age at onset of prophylaxis was 9 years (range 3 months-38 years). Genetic assessment was available in 24 patients. Of these, 37.5% and 62.5% were carriers of null and not null mutations respectively. 4 patients were undergone to PK with standard products (1 Octocog alfa, 1 Simoctocog alfa, 1 Octocog alfa-Kovaltry®, 1 Turoctocog alfa) in order to define timing and dosage of successive infusions, while 25 patients switched to EHL factors (15 Efmoroctocog alfa, 2 Ionoctocog alfa, 7 Albutrepenonacog alfa, 1 Eftrenonacog alfa). In 15 patients a population-based PK (popPK) according to WAPPS-Hemo program was also performed. The annualized bleeding rate (ABR) was counted from patient's home bleeding records for one year before PK until now. Results. According to PK data, 21 patients (75%) decreased infusion frequency (100% hemophilia B and 67% hemophilia A patients). The remaining 7 hemophilia A patients maintained the same timing in order to increase the through factor level. Notably, 1 hemophilia B patient switched from on demand treatment to prophylaxis with EHL product due to the more acceptable schedule. 66% of null mutation patients and 73% of not null mutation patients decreased timing. Of 28 patients available at follow-up, 32%, 50% and 18% decreased, increased and maintained the same annual average factor consumption/kg, respectively. All patients had a good adherence after switch. In particular, the on demand patient started a regular prophylaxis with optimal compliance. ABR displayed a reduction with a median of 0 (range 0-5) after PK analysis compared to 1 (range 0-12) before the switch. Full PK vs popPK data obtained using at least two individual PK sampling points were almost similar. Conclusions. Our results remark the necessity of PK study especially in children due to the inter-individual variability independent of genetic assessment. Regarding factor IX, PK allowed us to propose timing even longer than that recommended by prescribing indications resulting in a better personalized prophylaxis. Moreover, our study demonstrates that a full PK analysis is feasible also in children. However, given similar results, popPK could be more feasible in most patients. Regarding consumption, the reduction of only 32% of patients reflects our aim to maintain a high safety profile in an active pediatric population. Nevertheless, the mean annualized consumption was just 0.6-fold increased in the remaining patients. This approach led us to further reduce ABR and in some cases to obtain a persistent no-bleeding status even with a full active life. Disclosures No relevant conflicts of interest to declare.

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Real World Use of Extended Half-Life Products and the Impact on Bleeding Events and Joint Health in the United States

Blood ◽

10.1182/blood-2018-99-113956 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1195-1195 ◽

Cited By ~ 1

Author(s):

Lynn M. Malec ◽

Char M Witmer ◽

Julie Jaffray ◽

Peter A. Kouides ◽

Kristina M. Haley ◽

...

Keyword(s):

Board Of Directors ◽

Real World ◽

Research Funding ◽

Hemophilia A ◽

Advisory Board ◽

Hemophilia B ◽

Severe Hemophilia ◽

Bleeding Events ◽

On Demand ◽

Joint Health

Abstract Background : The hemophilia treatment landscape has evolved substantially in the last several years with the approval of extended half-life (EHL) products which reduce the burden of prophylaxis. Data reported from the American Thrombosis and Hemostasis Network (ATHN) as of June 2017 indicate that 21% of patients with moderate or severe hemophilia A, and 42% of patients with moderate or severe hemophilia B, receive prophylaxis utilizing an EHL. As new treatments become available and are adopted into practice, it is important to recognize the need for evaluation of efficacy, safety, and economic impact of their use outside of the clinical trial setting. We aimed to characterize the real world impact of EHL products by collecting detailed information on bleeding rates, joint health and quality of life amongst patients cared for at ATHN-affiliated Hemophilia Treatment Centers. We hypothesized that use of EHL products were utilized in at least 30% of patients and would lead to decreased ABRs and improved joint health. To date 67 of a planned 135 subjects have been enrolled, constituting this interim analysis. Methods:Subjects were recruited from seven U.S. Hemophilia Treatment Centers. Subjects with severe hemophilia A or B ≤ 30 years of age on prophylaxis or demand therapy were eligible for enrollment. Subjects excluded from study were those with a recent joint bleed (within the last 2 weeks) or those unwilling to complete all elements of the study. Data were collected during a one-time encounter concurrent with an appointment for clinical evaluation, including demographic information, treatment regimen, product type, frequency, location and severity of all bleeds, Hemophilia Joint Health Scores (HJHS), and Quality of life (QoL). Bleeding rates in subjects receiving prophylaxis were compared with those receiving on demand therapy by type treatment, EHL vs standard half-life (SHL), and by hemophilia type. Severity of bleeding events (mild, moderate, or severe) and HJHS were compared by prophylaxis groups. Results: A total of 67 patients were enrolled and eligible for analysis. This included 58 subjects with severe hemophilia A, and 9 subjects with severe hemophilia B. The mean age of the cohort was 15 years (median 12 years, IQR 8 - 21 years). For these patients whose race information was known, 89.1% were Caucasian, 3.3% African-American, 3.3% Asian, and 4.7% were of mixed or 'other' race. Eleven out of 61 (18.0%) subjects with known ethnicity were Hispanic. Among 59 patients whose treatment type were available, the majority were on prophylaxis (n=53; 89.8%) as compared to on demand therapy (n=6; 10.2%). The average annualized bleeding rate (ABR) was 2.8 amongst all individuals. As expected, the ABR was substantially lower in those receiving prophylaxis (ABR=1.0) as compared to on demand therapy (ABR=18.6) (p<0.001). Additionally, HJHS in those receiving prophylaxis was lower (mean HJHS= 3.9), meaning less evidence of joint damage, than in those receiving demand therapy (mean HJHS= 8.8) (p=0.162). For patients with severe hemophilia A, the ABR was lower in those individuals receiving EHL (ABR= 0.5) versus SHL (ABR= 1.5), although this did not reach statistical significance (p=0.136). All subjects with severe hemophilia B enrolled to date receive EHL products (n=9) therefore no comparison of ABR could be made between EHL and SHL products; the ABR in this group was 0.9. In patients with severe hemophilia A, there was a higher HJHS for those receiving EHL (mean HJHS= 7.0) versus those receiving SHL (mean HJHS = 2.1) (p=0.053). For patients with severe hemophilia B, all of whom received EHL, the mean HJHS was lower than in the hemophilia A cohort (mean HJHS=1.2). Conclusions: We report real-world bleeding events and joint health in patients with severe hemophilia A and B utilizing EHL and SHL products across a wide U.S. geographic distribution. As anticipated, there is substantial bleed reduction with prophylaxis versus on demand therapy. In our severe hemophilia A cohort, the ABR for patients receiving EHL products was similar to ABRs reported in clinical trials, suggesting clinical trial data may be reflective of real world use. Patients with severe hemophilia A receiving EHL for prophylaxis had a lower ABR than those receiving SHL, although the early impact is not reflected in the HJHS score. Longer follow-up will be necessary to determine the impact of EHL on HJHS. Disclosures Malec: Bioverativ: Research Funding; Bayer: Consultancy; Bioverativ: Consultancy; Shire: Consultancy. Jaffray:Octapharma: Consultancy; Bayer: Consultancy; CSL Behring: Consultancy, Research Funding. Kouides:UniQure: Other: DSMB; Octapharma: Research Funding. Sidonio:Octapharma: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; CSL Behring: Other: Advisory Board; Shire: Other: Advisory Board, Research Funding; Novo Nordisk: Other: Advisory Board; Kedrion: Research Funding; Biomarin: Other: Advisory Board; Grifols: Other: Advisory Board, Research Funding; Bioverativ: Other: Advisory Board, Research Funding; Uniqure: Other: Advisory Board. Abshire:CSL: Consultancy; Shire: Consultancy; Novo Nordisk: Other: DSMB. White:Asklepios: Other: Scientific Advisory Board; Novo Nordisk: Consultancy; Shire: Other: Physician Leadership Group; Bayer: Other: GRAC; Bioverativ: Other: DSMB; Biomarin: Other: DSMB; Invitrox: Other: Scientific Advisory Board; Pfizer: Equity Ownership. Ragni:CSL Behring: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; SPARK: Consultancy, Research Funding; Shire: Research Funding; Bioverativ: Consultancy, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Sangamo: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees.

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Aminoglycoside suppression of nonsense mutations in severe hemophilia

Blood ◽

10.1182/blood-2005-03-1307 ◽

2005 ◽

Vol 106 (9) ◽

pp. 3043-3048 ◽

Cited By ~ 55

Author(s):

Paula D. James ◽

Sanj Raut ◽

Georges E. Rivard ◽

Man-Chiu Poon ◽

Margaret Warner ◽

...

Keyword(s):

Thrombin Generation ◽

Hemophilia A ◽

Aminoglycoside Antibiotic ◽

Bactericidal Effect ◽

Factor Ix ◽

Hemophilia B ◽

Severe Hemophilia ◽

Toxic Agent ◽

Nonsense Mutations ◽

Therapeutic Mechanism

AbstractAminoglycoside antibiotics exhibit their bactericidal effect by interfering with normal ribosomal activity. In this pilot study, we have evaluated the effect of the aminoglycoside antibiotic gentamicin on the factor VIII (FVIII) and IX levels of severe hemophiliacs with known nonsense mutations. Five patients were enrolled and each patient was given 3 consecutive days of gentamicin at a dose of 7 mg/kg intravenously every 24 hours. Two patients (patient no. 1: hemophilia A, Ser1395Stop; and patient no. 5: hemophilia B, Arg333Stop) showed a decrease in their activated partial thromboplastin time (aPTT), an increase in their FVIII (0.016 IU/mL, 1.6%) or FIX (0.02 IU/mL, 2%) levels, and an increase in thrombin generation. The remaining 3 patients (patient no. 2: hemophilia B, Arg252Stop; patient no. 3: hemophilia A, Arg2116Stop; and patient no. 4: hemophilia A, Arg427Stop) showed no response in the aPTTs or factor levels, but one (patient no. 2: hemophilia B, Arg252Stop) showed an increase in the factor IX antigen level (2%-5.5%) that persisted throughout the period of the study and was concordant with an increase in thrombin generation. Gentamicin is unlikely to be an effective treatment for severe hemophilia due to its potential toxicities and the minimal response documented in this report. This study, however, does provide a proof of principle, suggesting that ribosomal interference with a less toxic agent may be a potential therapeutic mechanism for severe hemophilia patients with nonsense mutations.

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Pharmacokinetic/Pharmacodynamic Assessment of Reformulated Recombinant Coagulation Factor IX in Adults and Children with Severe Hemophilia B

Blood ◽

10.1182/blood.v118.21.1190.1190 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1190-1190

Author(s):

JM Korth-Bradley ◽

Leonard A. Valentino ◽

Pablo Rendo ◽

Frank E. Shafer ◽

Lynne Smith ◽

...

Keyword(s):

Medical Center ◽

Coagulation Factor ◽

Factor Ix ◽

Hemophilia B ◽

Pharmacokinetic Data ◽

Severe Hemophilia ◽

Bleeding Events ◽

On Demand ◽

Coagulation Factor Ix ◽

Weekly Group

Abstract Abstract 1190 Introduction: The goal of this study was to evaluate the efficacy and safety of two prophylaxis regimens of reformulated recombinant coagulation factor IX (rFIX-R), 100 IU/kg once weekly and 50 IU/kg twice weekly, compared with on-demand treatment in subjects with severe hemophilia B. Patients and Methods: Pharmacokinetic data were collected for 47 subjects aged 6 to 64 years with severe hemophilia B. Factor IX activity (FIX:C) measurements were made immediately before rFIX-R administration and at 0.5 hours post-administration of either 100 IU/kg or 50 IU/kg doses, to assess recovery before the initiation of each weekly regimen. Another FIX:C sample was collected at least 72 hours after dosing during each regimen. All samples were analyzed at local laboratories. Results: The mean prophylactic doses of rFIX-R administered were 86 ± 29 IU/kg in the 100 IU/kg once-weekly group and 53 ± 14 IU/kg in the 50 IU/kg twice-weekly group. The treatment comparison between the two prophylaxis regimens for annualized bleeding rate was not significant (LS mean = 2.0; 95% CI, −1.2 – 5.2; n=43), although both were significantly different from the on-demand treatment period (both, P<.0001). The number of new bleeding events in each group was 51 and 35, respectively, with only 12/51 new hemorrhages occurring within 72 hours of dosing in the 100 IU/kg once-weekly group compared with 29/35 in the 50 IU/kg twice-weekly group. The pharmacokinetic results are shown in the Table. The number (%) of observed trough plasma concentrations (Ctrough) that fell into the mild (>5%) range for hemophilia were 18 (45%) and 19 (48%) for the r-FIX-R 100 IU/kg once-weekly and 50 IU/kg twice-weekly groups, respectively. However, the severe phenotype was observed in 4 (10%) and 3 (7%) subjects, respectively. Conclusions: The pharmacokinetics of r-FIX-R are dose proportional. The C0.5hr increased in proportion to the dose administered. Recovery was consistent between the two prophylaxis regimens. Both regimens provided similar therapeutic results for Ctrough. The apparent difference in time after dose of new bleeding events between the 2 regimens is intriguing and deserves further study. Disclosures: Korth-Bradley: Pfizer Inc: Employment. Valentino:Inspiration Bioscience: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center, Honoraria; CSL Behring: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center; Pfizer: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center; NovoNordisk: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center, Honoraria; GTC Biotherapeutics: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center, Honoraria; Bayer Healthcare: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center, Honoraria; Baxter Bioscience: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center, Honoraria; Biogen: Educational Grants on behalf of Dr. Valentino for Rush University Medical Center; Hemophilia and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees, Past-President. Rendo:Pfizer Inc: Employment. Shafer:Pfizer Inc: Employment. Smith:Pfizer Inc: Employment. Baumann:Pfizer Inc: Employment. Charnigo:Pfizer Inc: Employment.

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Evaluation of Two Secondary Prophylaxis Regimens of Recombinant Factor IX(r-IX) in Moderately Severe to Severe( FIX ≤2%) Hemophilia B Patients

Blood ◽

10.1182/blood.v120.21.4628.4628 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4628-4628

Author(s):

Pablo Rendo ◽

Mary-Kate Barrette-Grischow ◽

Lynne Smith ◽

JM Korth-Bradley ◽

Robert Charnigo ◽

...

Keyword(s):

Venous Access ◽

Factor Ix ◽

Hemophilia B ◽

World Health ◽

Coagulation Disorder ◽

Severe Hemophilia ◽

Prophylactic Regimen ◽

On Demand ◽

Significant Difference ◽

Bleeding Episodes

Abstract Abstract 4628 Background: Hemophilia B is an X-linked coagulation disorder characterized by a deficiency in factor IX (FIX), which results in spontaneous or trauma-induced bleeding primarily in joints, muscles, and soft tissues. Prevention and treatment of bleeding episodes in patients with hemophilia B is based upon replacing deficient FIX, either prophylactically or on an on-demand basis, with plasma-derived or recombinant FIX products. Prophylaxis therapy (ie, long-term, regular treatment) with FIX products is endorsed by the World Health Organization, World Federation of Hemophilia, and National Hemophilia Foundation as a primary therapeutic option for individuals with severe hemophilia B. Still, the use of prophylaxis is underutilized, as shown in data from North American and European hemophilia centers, where only 21% to 55% of individuals with hemophilia B were identified as receiving prophylactic FIX therapy (Rocca A et al. Blood Transfus 2011;9:60; Aznar JA et al. Haemophilia 2011;17:542; Biss TT et al. Haemophilia 2008;14:923). Factors implicated for this phenomenon include difficulty in venous access (particularly with primary prophylaxis in children), as well as overall adherence and willingness to commit to a highly demanding treatment schedule (Valentino LA. Haemophilia 2004;10:147; Collins PW et al. Haemophilia 2011;17:2; Santagostino E. Haemophilia 2010;16:13). The potential benefits of utilizing a once-weekly prophylactic regimen versus a more frequent dosing regimen include increased convenience for patients and their caregivers owing to fewer infusions and less preparation and infusion time, and the preservation of venous access. Objective: This study aimed to compare the safety and efficacy results for 2 prophylaxis regimens of nonacog alfa in moderately severe and severe hemophilia B patients. Methods: This multicenter, open-label crossover study enrolled 50 patients with moderately severe or severe (FIX C ≤ 2%) hemophilia B. Patients were treated on demand for 16 weeks, and 47 were subsequently randomized to 1 of 2 prophylactic regimens (nonacog alfa 100 IU/kg once weekly or 50 IU/kg biweekly) for 16 weeks. Following the initial prophylactic regimen, patients underwent an 8-week washout period of on-demand (OD) therapy then were crossed over to receive the other prophylactic regimen. The primary end point was the annualized number of bleeding episodes, expressed as the annualized bleeding rate (ABR). The results of this study were previously reported (Valentino LA, et al, 2011 ISTH abstract 1293). Results: Comparisons between once-weekly and twice-weekly prophylaxis regimens are given in Tables 1 and 2 and in Figure. No thrombosis, inhibitor, or allergic reactions were reported. Survival curve analysis comparing 100 IU once weekly to 50 IU twice weekly using the Kaplan-Meier technique showed no significant difference in the timing or extent of either type of treatment failure (p=0.14 for joint, p=0.61 for soft tissue/muscle by the Chi-squared [log-rank] analysis). Conclusions: Once-weekly prophylaxis with nonacog alfa 100 IU/kg is a safe and effective alternative to twice-weekly prophylaxis at 50 IU/kg. Once-weekly dosing may present a reasonable option for patients with severe hemophilia B, offering more convenience to patients and their caregivers compared with more frequent prophylactic dosing regimens. Disclosures: Rendo: Pfizer Inc.: Employment. Barrette-Grischow:Pfizer Inc.: Employment. Smith:Pfizer Inc.: Employment. Korth-Bradley:Pfizer Inc.: Employment. Charnigo:Pfizer Inc.: Employment. Shafer:Pfizer Inc.: Employment.

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Is Hemophilia B Less Severe Than Hemophilia A? Results Of Global Coagulation Assays

Blood ◽

10.1182/blood.v122.21.2352.2352 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2352-2352 ◽

Cited By ~ 2

Author(s):

Maria Rosaria Fasulo ◽

Maria Elisa Mancuso ◽

Veena Chantarangkul ◽

Antonino Cannavò ◽

Marigrazia Clerici ◽

...

Keyword(s):

Hemophilia A ◽

Phenotypic Variability ◽

Gene Mutations ◽

Factor Ix ◽

Hemophilia B ◽

Bleeding Tendency ◽

Severe Hemophilia ◽

Coagulation Assays ◽

One Stage ◽

Research Grant

Abstract Introduction Some observations suggest that severe hemophilia B (HB) may exhibit a milder bleeding tendency than severe hemophilia A (HA), however possible differences in the coagulation profile of severe HB and HA that may account for such phenotypic variability have not been extensively investigated. The aim of this study was to compare the clinical and laboratory phenotype of patients with severe HB (cases) with those with severe HA (controls) in order to ascertain potential determinants for a milder bleeding phenotype. Methods: patients with severe HB and HA (FIX and FVIII <1 IU/dL) of any age without inhibitor history followed up at a single center were asked to undergo blood sampling after a minimum wash-out period of 5 days from the last factor IX (FIX) or factor VIII (FVIII) infusion in order to perform coagulation assays including global testing by thrombin generation assay (TGA) and thromboelastography (TEG). Data on medical history, annual bleeding frequency, factor consumption, treatment regimen, orthopaedic status and FIX/FVIII gene mutations were collected from patients’ files. TGA was performed in platelet-rich plasma (PRP) with the addition of corn trypsin inhibitor (CTI) and TEG in whole citrated blood by means of the 4 channel ROTEM Gamma equipment. FIX and FVIII were measured by one-stage clotting and chromogenic assays. Results are available from the first 33 consecutive patients with severe hemophilia (16 HB and 17 HA) who agreed on and were able to maintain the required wash-out period. Age at enrolment (median: 40.8 and 41.2 years, interquartile range: 36-54 and 37-48, in HB and HA, respectively) and the proportion of patients with target joints (75% in HB and 82% in HA) were similar in the two groups. The proportion of patients on regular prophylaxis was higher in HA (41% vs 19% in HB) however not statistically different. HB patients had an older age at first bleed (median 2.8 vs 1.4 yrs in HA, p=0.05), lower prevalence of null gene mutations (13% vs 59% in HA, p<0.01) and lower rate of orthopaedic surgery (19% vs 71% in HA, p<0.01). Considering only patients treated on demand (10 HA and 13 HB), HB patients had less joint bleeds/year (median 1.4 vs 11 in HA, p=0.05), lower concentrate consumption (median 320 vs 1448 IU/kg/yr in HA, p=0.01) and a lower Hemophilia Joint Health Score (HJHS, median 5 vs 31 in HA, p<0.01). Baseline levels of FIX and FVIII were confirmed <1 IU/dL by both one-stage and chromogenic assays. The thrombin peak detected by TGA in HB was higher than in HA patients (median 30.4 vs 18.4 nM, p=0.05) but ETP values were similar. TEG testing showed that HB patients had a shorter Clotting Time (median 310 vs 598 sec in HA, p<0.01), a shorter Clotting Formation Time (median 93 vs 133 sec in HA, p<0.01) and a wider alfa-Angle (median 72 vs 65 degrees in HA, p<0.01) while Maximum Clot Firmness was similar in HA and HB patients. Conclusions: our results indicate that patients with severe HB may have a milder bleeding phenotype as compared with severe HA patients. Global coagulation assays such as TGA and TEG have the potential to reveal different coagulation profiles and to investigate correlations between clinical and laboratory phenotype in hemophilia. Further studies are warranted in order to explore the biological mechanisms that may enhance coagulation activation in hemophilia irrespective of FIX/FVIII activity in plasma. Disclosures: Fasulo: Pfizer: Unrestricted Research Grant Other. Santagostino:Pfizer: Unrestricted Research Grant Other.

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Safety, Immunogenicity, and Hemostatic Efficacy of Nonacog Gamma in Patients With Severe or Moderately Severe Hemophilia B: A Continuation Study

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029620950836 ◽

2020 ◽

Vol 26 ◽

pp. 107602962095083

Author(s):

Jerzy Windyga ◽

Oleksandra Stasyshyn ◽

Toshko Lissitchkov ◽

Vasily Mamonov ◽

Margit Serban ◽

...

Keyword(s):

Prophylactic Treatment ◽

Phase 1 ◽

Factor Ix ◽

Hemophilia B ◽

Severe Hemophilia ◽

On Demand ◽

Treatment Standard ◽

Pediatric Study ◽

Bleeding Episodes ◽

Hemostatic Efficacy

This phase 3, prospective, open-label, multicenter, continuation study (NCT01286779) investigated the use of a recombinant factor IX (FIX), nonacog gamma (BAX 326, RIXUBIS®) in patients with severe or moderately severe hemophilia B. The study population included 85 patients transitioning from a phase 1/3 pivotal study (NCT01174446), a pediatric study (NCT01488994), and 30 newly recruited patients, naïve to nonacog gamma. Patients received nonacog gamma as prophylaxis treatment (standard, modified or PK-tailored) or on-demand, as determined by the investigator. Treatment was assessed for safety, immunogenicity, hemostatic efficacy and consumption. In this study, after ≥100 exposure days, nonacog gamma resulted in no treatment-related serious adverse events, and no patients developed inhibitory antibodies to FIX. Nonacog gamma was efficacious at controlling bleeding episodes, with an 89.1% overall hemostatic efficacy rating of excellent or good, and 56% of bleeds resolved with one infusion. The annualized bleeding rate was considerably lower during prophylactic treatment (median ABR of 1.3 in 108 patients) than during on-demand treatment (median ABR of 16.5 in 13 patients). These results show that in previously treated patients and nonacog gamma-naïve patients, long-term use of nonacog gamma had acceptable safety and tolerability, and was efficacious as a prophylactic treatment for the management of bleeding episodes. NCT01286779, EudraCT: 2010-022726-33

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Application of Pharmacokinetics Programs in Optimization of Haemostatic Treatment in Severe Hemophilia a Patients: Changes in Consumption, Clinical Outcomes and Quality of Life

Blood ◽

10.1182/blood.v124.21.1502.1502 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1502-1502

Author(s):

María Eva Mingot-Castellano ◽

Dana Díaz-Canales ◽

Rocio Tamayo-Bermejo ◽

Ana Isabel Heiniger-Mazo

Keyword(s):

Quality Of Life ◽

Hemophilia A ◽

Annual Rate ◽

Routine Practice ◽

Daily Routine ◽

Severe Hemophilia ◽

Bleeding Events ◽

On Demand ◽

The Impact

Abstract BACKGROUND: Replacement therapy with factor VIII (FVIII) in patients with severe hemophilia A has a high cost. To optimize this consumption without an increase in bleeding events or a delay in the recovery of these bleeds is a question of great interest for any Health System. The tools we have to tailor this treatment are clinical evolution, the use of trough levels and lately pharmacokinetic (PK) programs. OBJECTIVES: To evaluate the impact of a FVIII dose adjustment program using pharmacokinetic (PK) in daily routine practice: To analyse FVIII consumption in different treatment schedules (prophylaxis and demand) before and after the adjustment dose using PK programs.In subjects under prophylaxis scheme of treatment, to assess if this setting changes the annual rate of bleedings.To assess changes in quality of life after applying PK adjustment. PATIENTS AND METHODS: Between January 2006 and December 2013, we performed pharmacokinetic studies in adult patients with severe hemophilia A (FVIII less than 1%) and no history of inhibitor that have changed from one FVIII product to a different one in our centre. The program is a Bayesian PK analysis. FVIII levels were determined by one-stage method. Samples were taken 30 minutes (recovery non used for PK), 6, 12, 24 and 48 hours after FVIII 50ui/kg infusion. After PK study, subjects on prophylaxis were evaluated every two months to adjust scheme of treatment to trough FVIII levels between 1 to 3% in absence of bleeding. After getting the established dose patients were reviewed every 6 months. Patients on demand were evaluated every 10 to 15 doses until they got 50 doses, and then every 12 months. Demographic and diagnostic data of patients were recorded for inclusion in the program. Information about FVIII consumption and bleeding events comes from patient diaries (PD) and records from Hospital Pharmacy Department. Quality of life (QoL) was analysed using the A 36 Hemophilia-QoL questionnaire (Spanish validated version). Our Centre Ethics Committee approved the project. Everything has been done according to the Declaration of Helsinki. Patients signed written informed consent. RESULTS: Of the 16 patients included in the program only 14 have been evaluable. The excluded ones did not complete DP or CV properly. Mean age of the analysed patients was 31.7+/-9.4 years old. Mean body mass index was 25+/-2.7m2. 85% of patients suffer from haemophilic arthropathy according to Petterson Score (knee 57%, elbows 57%, ankles 85%). Four patients have been moved from plasma derived FVIII (pdFVIII) to other pdFVIII and 10 from pdFVIII to recombinant FVIII (rFVIII). Regarding to treatment regimens, 6 patients were changed from on demand to tertiary prophylaxis, 4 maintained their secondary prophylaxis and 4 continued on demand after the change of factor. The prophylaxis frequencies of infusions were every 48 hours in 2 patients, twice a week in 3 and 3 times a week in 5 of them. The mean volume of distribution, half-life (T1/2) and FVIII clearance (Acl) were 56.2±19 ml/kg, 12.9±5.9 h and 3.4±1.4 ml/kg. We found a correlation between age (p 0.03) and levels of vWF:RCo (p 0.02) with Acl. No correlation was found with body surface or VWF:Ag. Patients treated with pdFVIII have lower Acl and T1/2, 2.05 vs 3.9ml/kg (p 0.015) and 18.5 vs 10.6 h (p0.01) respectively. After trough level evaluation no increase of dose was necessary and only 2 patients decreased PK dose. The implementation of PK study has saved 20.3% of FVIII units in subjects on prophylaxis, mean and SD of pre and post PK FVIII consumption was 3137.3+/-387.9 IU/kg/year vs 2501.2+/-308.4 IU/kg/year (p 0.005). There was no change in the annual rate of bleedings after PK adjustment (2.33+/-1.2 vs 2+/-2.6, p 0.321). We found no changes in consumption in subject on demand after PK. There was an improvement in all domains of QoL test (p<0.0001) in subjects who changed from on demand to prophylaxis. This seems not to be related with PK but to prophylaxis that induces a decrease in the annual rate of bleeding of 78.5% (p 0.002). Two patients developed transitory low inhibitor titer after FVIII change with no clinical implications. CONCLUSION: In our experience, the implementation of PK programs in the treatment of severe hemophilia A reduces FVIII consumption and optimizes schemes of prophylaxis. This saving does not modify bleeding rate or quality of life of patients. Disclosures No relevant conflicts of interest to declare.

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Thrombin Generation As a Promising Biomarker for the Prediction of Bleeding Phenotype in Patients with Non-Severe Hemophilia

Blood ◽

10.1182/blood-2018-99-119198 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3788-3788

Author(s):

Fadi Nossair ◽

Nina Hwang ◽

Vanessa Salinas ◽

Nicole Crook ◽

Jacqueline Limjoco ◽

...

Keyword(s):

Research Funding ◽

Hemophilia A ◽

Hemophilia B ◽

P Value ◽

Severe Hemophilia ◽

Factor Activity ◽

Factor Level ◽

Bleeding Score ◽

Baseline Factor

Abstract Background: Non-severe hemophilia A and B account for 50% of patients with hemophilia, in which factor level does not consistently correlate with bleeding phenotype. Clinical decision-making in regards to timely prophylaxis initiation and tailored surgical management could be informed by a biomarker that is more predictive of bleeding phenotype. We hypothesized that a global method to assess clotting potential, such as thrombin generation (TG), is more predictive of bleeding phenotype than factor level. Objectives: Determine the ability of TG, as compared to standard baseline factor activity, to differentiate bleeding phenotype severity in patients with non-severe hemophilia. Methods: Subjects were recruited from two hemophilia treatment centers (HTCs): Rady Children's Hospital San Diego (RCHSD) and Center for Inherited Blood Disorders (CIBD). Subjects were eligible for enrollment if they were at least one year of age and had a diagnosis of non-severe congenital hemophilia A or B, or were genetically confirmed or suspected female carriers. All enrolled patients or their parents completed the standardized, self-administered pediatric bleeding questionnaire (Self-PBQ) or bleeding assessment tool (Self-BAT). Clinical and laboratory information were extracted from the medical chart, including age at diagnosis, bleeding event history, past surgical history, treatment history and factor VIII or IX gene analysis. Validation of self-reported bleeding symptoms was performed using chart-derived data. Bleeding phenotype was assessed using standard calculation of the bleeding score, as defined by the respective validated self-reported tools. For the purpose of this analysis, we defined a high bleeding score as 13 or more, while a low bleeding score was defined as 12 or less. After a washout period of 5x the standard half-life of the administered factor product, blood samples were collected at time of enrollment. Platelet poor plasma was obtained according to a strict protocol to minimize pre-analytical variables. TG was measured by means of the calibrated automated thrombogram, with three different reagents: low (1 pM of tissue factor [TF]), regular (5 pM of TF) and High (20 pM of TF). The following TG parameters were evaluated: Peak TG (Peak), estimated thrombin potential (ETP) and velocity index (VI). Results: Eighty-one subjects were enrolled. The median age of our cohort was 15.6 years (IQR 21.2, range 4.9 - 59.8), with a slight female predominance (51%) due to inclusion of female carriers. The median follow-up period at the HTC was 5.3 years (IQR 7.5 years), with the majority having follow-up for at least three years. Enrolled patients had the following diagnoses: mild hemophilia A (70%), mild hemophilia B (3%), moderate hemophilia A (13%), moderate hemophilia B (3%), hemophilia A carriers with normal factor VIII levels (10%) and hemophilia B carriers with normal factor IX levels (1%). Median age at diagnosis was 8 years (IQR 26.3, range 0.1 - 56.1), which strongly correlated lower baseline factor activity (r=0.573, p-value < 0.0001). The median baseline factor activity was 21% (IQR 26, range 2 - 249). Factor exposure occurred in 46% of patients (n=37), of which 5 patients were on prophylaxis at time of enrollment. Chronic arthropathy was present in 2 patients (one with mild hemophilia A and one with moderate hemophilia A) and none of the patients had a history of an inhibitor. The majority of patients had a low bleeding score (74% vs. 26%). Baseline factor level and TG values obtained with regular reagent (5 pM of TF) showed significant correlation with bleeding score (r = -0.229 to -0.237, p-value < 0.05), while values obtained with other reagents did not show a significant correlation. Sensitivity/specificity analysis revealed the following optimal cutoff values for differentiating between bleeding severities, as obtained from TG with regular reagent: ETP (<1240 nM min), Peak (<130 nM) and VI (<23 nM/min), with analysis results as shown in Table 1. Conclusion: Even though both TG and baseline factor level had comparable correlation with bleeding severity, all TG values with 5 pM TF showed a much higher sensitivity outcome and greater ability to differentiate between bleeding severities in this population. This approach shows potential for predicting bleeding severity in patients with non-severe hemophilia and should be validated in long-term prospective studies. Disclosures Nossair: Novo Nordisk: Other: Conference - Haemophilia Acadamy; Novo Nordisk: Research Funding. Hwang:BPI: Consultancy; Bayer: Consultancy; Hema Biologics: Consultancy; Shire: Consultancy; Bioverativ: Other: PI in clinical research study. Thornburg:ATHN: Research Funding; Bayer Pharmaceuticals: Research Funding; Biomarin: Consultancy; CSL Behring: Research Funding; Bioverativ: Consultancy; Genentech: Speakers Bureau; Octapharma: Research Funding; NovoNordisk: Research Funding; Shire: Research Funding; Johns Hopkins All Children's Hospital: Research Funding; Bluebird Bio: Consultancy.

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Low Dose Secondary/Tertiary Prophylaxis Is Feasible and Effective in Resource Limited Setting in South India for Children with Hemophilia

Blood ◽

10.1182/blood.v128.22.2336.2336 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2336-2336 ◽

Cited By ~ 2

Author(s):

Neeraj Sidharthan ◽

Vijayakumar Narayana Pillai ◽

Sheena Mathew ◽

Remya Sudevan ◽

Dinkar Viswam ◽

...

Keyword(s):

Low Dose ◽

Prophylactic Treatment ◽

Hemophilia A ◽

Functional Independence ◽

Hemophilia B ◽

Clotting Factor ◽

School Absenteeism ◽

Severe Hemophilia ◽

On Demand ◽

Hospitalization Rates

Abstract Prophylaxis for Hemophilia is globally accepted as a treatment strategy compared to on-demand therapy in the care of persons with hemophilia (PwH) . Prophylaxis is rarely practized in low and middle income countries due to several reasons such as ill-affordability of clotting factor concentrates ( CFCs), lack of awareness, absence of comprehensive / home care infrastructure and misconcepts regarding treatment among general population. The South Indian state of Kerala had been providing CFCs free of cost for on-demand treatment. A recent initiative was started in Hemophilia Treatment Centre(HTC), Aluva , Ernakulam district to provide secondary/tertiary prophylaxis free of cost to children with severe hemophilia (Factor level <1%, aged 5-15 yrs) as a joint effort from HTC and the local government. A clinical audit was done in 11 children at this center for a period of twelve months (6 months retrospectively for on-demand treatment and 6 months prospectively for prophylactic treatment). Among all patients with severe hemophilia, eight have Hemophilia A and the remaining three have Hemophilia B. They were previously treated with CFCs/plasma/cryoprecipitate, a few of them had established joint disease and all of them had absence of inhibitors. These children were initiated on low dose prophylaxis with plasma derived CFCs. Factor VIII concentrate was given at a dose of 20-40 U/kg in 2 divided doses per week for Hemophilia A and Factor IX concentrate at 25-40 U/Kg once a week for Hemophilia B. Outcomes were measured at two time points - at the end of secondary/tertiary prophylactic treatment period and at the end of preceding six months of on-demand treatment. The variables taken as outcome measures were changes in bleed rates, Hemophilia joint health score (HJHS), Functional independence score in Hemophilia (FISH), hospitalization rates and school absenteeism. A reduction in the bleed rate was seen from the transition of on demand treatment to secondary/tertiary prophylactic treatment (14.9 vs 0.91, p 0.005). Similar reductions were seen for hospitalization rates (12.45 vs 2.36 days, p 0.005) and school absenteeism (78.55 vs 1.27 days, p 0.01) respectively(Fig 1 a). FISH and HJHS scores were either maintained or improved during the prophylaxis period.(Fig 1b, 1c). None of the children developed inhibitors during the study period. The estimated cost of CFCs for on demand treatment per patient was 1314.4 USD and 1691.8USD during prophylaxis. The factor consumption for on demand treatment for 6 months was 968.24 IU/Kg and that of secondary/tertiary prophylaxis was 1077.96 IU/Kg respectively. We conclude that low dose prophylaxis for severe Hemophilia in a developing economy is feasible and has marked clinical benefits with greater well-being when compared to on demand therapy. In countries with resource constraints low dose secondary/tertiary prophylaxis should be considered as a therapeutic option over on demand therapy for children with severe Hemophilia in the light of its potential benefits . Disclosures No relevant conflicts of interest to declare.

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MOLECULAR MECHANISMS OF INHIBITOR DEVELOPMENT IN HEMOPHILIA

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2020.001 ◽

2020 ◽

Vol 12 (1) ◽

pp. e2020001

Author(s):

Davide Matino ◽

Paul Tieu ◽

Antony Chan

Keyword(s):

Neutralizing Antibodies ◽

Molecular Mechanisms ◽

Hemophilia A ◽

Risk Identification ◽

Hemophilia B ◽

Lifetime Risk ◽

Pathophysiological Mechanism ◽

Severe Hemophilia ◽

Inhibitor Development

The development of neutralizing antibodies in hemophilia is a serious complication of factor replacement therapy. These antibodies, also known as “inhibitors”, significantly increase morbidity within the hemophilia population and lower the quality of life for these patients. People with severe hemophilia A have an overall 25-40% lifetime risk of inhibitor development, compared to that of 5-15% lifetime risk in those with moderate/mild hemophilia A. The risk is lower in hemophilia B population (about 1-5%) and occurrence of inhibitors is almost only seen in patients with severe hemophilia B. The understanding of the pathophysiological mechanism leading to the development of inhibitors in patients with hemophilia has improved considerably over the last 2 decades. Identification of early biomarkers which predict inhibitor development in previously untreated patients with hemophilia will assist in risk identification and possible early intervention strategies. In this review, we aim to summarize the molecular mechanisms of inhibitor development in hemophilia and to identify potential areas in need of further investigation.

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