scholarly journals Review of antihemophilic factor injection for the routine prophylaxis of bleeding episodes and risk of joint damage in severe hemophilia A

2010 ◽  
pp. 59 ◽  
Author(s):  
Chris Rossbach
Keyword(s):  
Hemophilia A ◽  
Joint Damage ◽  
Severe Hemophilia ◽  
Routine Prophylaxis ◽  
Bleeding Episodes ◽  
Antihemophilic Factor

Animal Testing of Retroviral-Mediated Gene Therapy for Factor VIII Deficiency

1999 ◽  
Vol 82 (08) ◽  
pp. 555-561 ◽  
Author(s):  
Douglas Jolly ◽  
Judith Greengard
Keyword(s):  
Gene Therapy ◽  
Factor Viii ◽  
Hemophilia A ◽  
Joint Damage ◽  
Coagulation Factor ◽  
The United States ◽  
Severe Hemophilia ◽  
Factor Viii Gene ◽  
Bleeding Episodes

IntroductionHemophilia A results from the plasma deficiency of factor VIII, a gene carried on the X chromosome. Bleeding results from a lack of coagulation factor VIII, a large and complex protein that circulates in complex with its carrier, von Willebrand factor (vWF).1 Severe hemophilia A (<1% of normal circulating levels) is associated with a high degree of mortality, due to spontaneous and trauma-induced, life-threatening and crippling bleeding episodes.2 Current treatment in the United States consists of infusion of plasma-derived or recombinant factor VIII in response to bleeding episodes.3 Such treatment fails to prevent cumulative joint damage, a major cause of hemophilia-associated morbidity.4 Availability of prophylactic treatment, which would reduce the number and severity of bleeding episodes and, consequently, would limit such joint damage, is limited by cost and the problems associated with repeated venous access. Other problems are associated with frequent replacement treatment, including the dangers of transmission of blood-borne infections derived from plasma used as a source of factor VIII or tissue culture or formulation components. These dangers are reduced, but not eliminated, by current manufacturing techniques. Furthermore, approximately 1 in 5 patients with severe hemophilia treated with recombinant or plasma-derived factor VIII develop inhibitory humoral immune responses. In some cases, new inhibitors have developed, apparently in response to unnatural modifications introduced during manufacture or purification.5 Gene therapy could circumvent most of these difficulties. In theory, a single injection of a vector encoding the factor VIII gene could provide constant plasma levels of factor in the long term. However, long-term expression after gene transfer of a systemically expressed protein in higher mammals has seldom been described. In some cases, a vector that appeared promising in a rodent model has not worked well in larger animals, for example, due to a massive immune response not seen in the rodent.6 An excellent review of early efforts at factor VIII gene therapy appeared in an earlier volume of this series.7 A summary of results from various in vivo experiments is shown in Table 1. This chapter will focus on results pertaining to studies using vectors based on murine retroviruses, including our own work.

Factor V G1691A and Factor II G20210A Mutations and Clinical Expression of Severe Hemophilia A (< 2%) in Children: Impact on Bleeding Episodes and Joint Damage.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3095-3095
Author(s):  
Ulrike Nowak-Gottl ◽  
Carmen Escuriola ◽  
Rosemarie Schobess ◽  
Christine Duering ◽  
Christoph Bidlingmaier ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Joint Damage ◽  
Factor V ◽  
Severe Hemophilia ◽  
Clinical Expression ◽  
Protein C Deficiency ◽  
Prothrombotic Risk Factors ◽  
Factor V G1691a ◽  
Bleeding Episodes ◽  
Highly Correlated

Abstract It has been recently shown that the first bleeding onset in children with severe hemophilia A (HA) carrying prothrombotic risk factors is significantly later in life than in non-carriers.1 The present multicenter study was performed to determine whether the factor (F) V G1691A or the F II G20210A are associated with decreased annual bleeding episodes (ABE) in 106 pediatric PUP patients with severe HA (Intron 22 58.6%) consecutively admitted to German pediatric hemophilia treatment centers. Treatment was initiated according to the frequency of bleedings, and most patients received on demand therapy with a switch over to prophylactic therapy 3x/week (40–60 IU/kgKG factor VIIII concentrate) when more than three bleedings (range 2–6) had occurred into the same joint (n=49). Prospective median(range) patient follow-up was 14(4–35) years. Heterozygosity of the FV mutation was found in 8 subjects, homozygosity in one, and 5 children carried the FII mutation once combined with protein C-deficiency. Carriers of the FV and FII mutations had significantly fewer ABE than non-carriers (p=0.004). 66 of 106 PUP patients developed at least one target joint with a median(range) Pettersson score of 1(0–12) available in 57 patients clearly dependent on age (p=0.039) as well as ABE (p=0.037). The “Nuss” joint score available in 33 subjects highly correlated with the Pettersson score (p=0.007). Data presented here give evidence that the clinical expression of severe HA in children is influenced by the co-expression of the FV and FII mutation.

Effects of “Primary Prophylaxis” and “On-Demand” Therapy on the Clinical Expression of Severe Hemophilia A in Children - Results of a Multicenter Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3146-3146
Author(s):  
Rosemarie Schobess ◽  
Karin Kurnik ◽  
Wolfhart Kreuz ◽  
Frauke Friedrichs ◽  
Anne Krumpel ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Bleeding Episode ◽  
Joint Damage ◽  
Primary Prophylaxis ◽  
Secondary Prophylaxis ◽  
Outcome Variable ◽  
Severe Hemophilia ◽  
On Demand ◽  
Imaging Results ◽  
Bleeding Episodes

Abstract Background: Patients with severe hemophilia A (HA) can either be treated by regular FVIII infusions twice or thrice per week (prophylaxis), or only in case of bleeding episodes (on-demand). Whereas prophylaxis reduces the number of bleeding episodes and may therefore prevent the development of hemophilic arthropathy, recommendations regarding age and dose at start of prophylactic regimens are still a matter of debate. The present cohort study was performed to investigate the role of “primary prophylaxis” versus “on-demand” therapy in HA children. The outcome variable was imaging-proven hemophilic joint damage. Methods: 42 children were initially treated with primary prophylaxis following the first bleeding episode, and were frequency-matched (year of birth, catchment area) to 67 patients receiving “on-demand” therapy with an early switch to “secondary prophylaxis”. Results: In multivariate analysis adjusted for the HA mutation type and the presence or absence of thrombophilia, the Pettersson score investigated at a median age of 12.5 years in joints with at least one documented bleeding episode was no significantly different between the two patient groups (p=0.944), and no statistically significant differences were found in patients with target joints (p=0.3), or in children in which synovitis had occurred (p=0.77). Imaging results obtained showed a substantial agreement (87.14%) beyond that expected by chance alone (42.4%) between local and central readers in the patients tested (kappa=0.77; Z= 17.27; p < 0.001). Conclusion: In cases with severe HA where primary prophylaxis is impossible, the procedure to switch from “on-demand” to early secondary prophylaxis can be achieved in the majority of young children affected. In addition, the needs of parents around the time of diagnosis of severe HA could be better addressed.

Effect on Joint Health of Routine Prophylaxis with Bayer’s Sucrose-Formulated Recombinant Factor VIII (rFVIII-FS) in Adolescents and Adults Previously Treated on Demand: MRI Analyses from the 3-Year Spinart Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2854-2854 ◽  
Author(s):  
Bjorn Lundin ◽  
Walter Hong ◽  
David Raunig ◽  
Sylvia Engelen ◽  
Charles Peterfy ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Factor Viii ◽  
Structural Damage ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
On Demand ◽  
Routine Prophylaxis ◽  
Bayer Healthcare ◽  
Adolescents And Adults ◽  
Bleeding Episodes

Abstract Introduction: The benefits of primary prophylaxis with a factor VIII (FVIII) product in pediatric patients with severe hemophilia A are well established. Fewer data are available on the benefits of secondary prophylaxis (started after ≥2 joint bleeds but before the onset of documented joint disease). The 3-year SPINART study compared the efficacy and safety of routine prophylaxis vs on-demand treatment in adolescents and adults with severe hemophilia A, all of whom were treated with Bayer's sucrose-formulated recombinant FVIII (rFVIII-FS). Primary 3-year data on magnetic resonance imaging (MRI) joint assessments in SPINART have been recently reported. Here we present additional analyses of the SPINART 3-year MRI data. Methods: SPINART was a 3-year, randomized, controlled, parallel-group, open-label study conducted at 31 centers in the United States, Bulgaria, Romania, and Argentina. Male patients aged 12–50 years were eligible for SPINART if they had severe hemophilia A (FVIII:C <1%), ≥150 exposure days to any FVIII product, no current evidence or history of FVIII inhibitors, no prophylaxis for >12 consecutive months in the past 5 years, and 6–24 documented bleeding events or treatments in the previous 6 months. Eligible patients were randomly assigned 1:1 to on-demand treatment or prophylaxis. Patients assigned to prophylaxis received rFVIII-FS 25 IU/kg 3 times weekly; in patients with ≥12 bleeding episodes per year, dose increases of 5 IU/kg were permitted at years 1 and 2. All patients underwent MRI assessments at baseline and year 3 to evaluate the structure of 6 index joints (knees, ankles, elbows). Each MRI was read by 3 radiologists blinded to treatment assignment who independently completed the Extended MRI (eMRI) scale. The eMRI scale has 2 domains (soft tissue, osteochondral), and total eMRI scores range from 0 to 45 based on soft-tissue domain scores of 0 to 9 and osteochondral domain scores of 0 to 36; higher eMRI scores indicate greater joint structural damage. Change from baseline to year 3 in eMRI total score based on all 6 index joints was analyzed for the following baseline characteristics: region (US vs non-US), age (≤29 vs >29 years), and number of bleeding episodes in the previous 6 months (<8 vs ≥8). For patients with target joints, change from baseline to year 3 in eMRI scores in the worst target joint was analyzed using analysis of covariance adjusted for bleeding frequency during the prior 6 months. Results: Eighty-four patients (42 per treatment group) were enrolled in the SPINART study. Target joint analysis data for patients with target joints who completed the study were available for 28 on-demand and 20 prophylaxis patients. Least squares (LS) mean change from baseline to year 3 in eMRI total score in the analyzed target joint was 0.91 (95% CI, –0.06 to 1.88) and 1.09 (95% CI, 0.12–2.07) for the on-demand and prophylaxis groups, respectively; the difference was not statistically significant (LS mean difference, 0.18; 95% CI, –1.05 to 0.70; P=0.68). Results for the subgroup analyses are shown in the Table. Table.eMRI Total Score (Mean ± SD Change From Baseline to Year 3)Region Age, y Number of Bleeds in Past 6 MonthsUSNon-US≤29 >29 <8≥8On demand0.56±0.77 (n=14)1.24±1.35 (n=16)1.34±1.21 (n=18)0.29±0.70 (n=12)0.88±0.83 (n=4)0.93±1.20 (n=26)Prophylaxis1.05±1.36 (n=10)0.61±1.70 (n=22)0.46±1.88 (n=17)1.08±1.15 (n=15)0.91±0.69 (n=11)0.67±1.91 (n=21) Conclusions: Over 3 years of treatment, change in eMRI total score for target joints was similar for the on-demand and prophylaxis groups in SPINART. In the prophylaxis group, progression of joint structural damage after 3 years of treatment, as indicated by changes in eMRI total scores based on all 6 index joints, did not differ by number of bleeding episodes in the preceding 6 months but appeared to be less pronounced among younger patients compared with older patients and among those in the non-US group compared with the US group; results by age and region in the on-demand group were opposite of those seen in the prophylaxis group. These results must be interpreted with caution given the small patient numbers, the possibility that the study duration was not sufficient to show changes on MRI, and the fact that target joints were assessed. These results may underscore the importance of preventing target joint development and show that once a target joint has developed, MRI may not show reversal of pre-existing damage despite prophylaxis. Disclosures Lundin: Bayer: Received reimbursement from Bayer for symposium attendance, Received reimbursement from Bayer for symposium attendance Other; Bayer HealthCare : Employed by the Center for Medical Imaging and Physiology at Skåne University Hospital and is under contract to Bayer HealthCare for work performed for SPINART Other. Hong:Bayer HealthCare: Employment. Raunig:Employed by ICON Medical Imaging and is under contract to Bayer HealthCare for work performed for SPINART on the validation of the eMRI scale and Colorado Adult Joint Assessment Scale.: Consultancy. Engelen:Bayer HealthCare: Employment. Peterfy:Spire Sciences, Inc.: Owner of Spire Sciences, Inc., which provides central image analysis services to pharmaceutical and medical device companies. Other. Werk:Bayer HealthCare: Under contract to Bayer HealthCare for work performed for SPINART. Other. Manco-Johnson:Bayer: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Young adult outcomes of childhood prophylaxis for severe hemophilia A: results of the Joint Outcome Continuation Study

2020 ◽  
Vol 4 (11) ◽  
pp. 2451-2459 ◽  
Author(s):  
Beth Boulden Warren ◽  
Dianne Thornhill ◽  
Jill Stein ◽  
Michael Fadell ◽  
J. David Ingram ◽  
...  
Keyword(s):  
Hemophilia A ◽  
High Titer ◽  
Controlled Trial ◽  
Joint Damage ◽  
Severe Hemophilia ◽  
Young Adult Outcomes ◽  
Delayed Initiation ◽  
Joint Health ◽  
Bleeding Episodes ◽  
Magnetic Resonance Imaging Mri

Abstract The Joint Outcome Study (JOS), a randomized controlled trial, demonstrated that children with severe hemophilia A (HA) initiating prophylactic factor VIII (FVIII) prior to age 2.5 years had reduced joint damage at age 6 years compared with those treated with episodic FVIII for bleeding. The Joint Outcome Continuation Study (JOS-C) evaluated early vs delayed prophylaxis effects on long-term joint health, following JOS participants to age 18 years in an observational, partially retrospective study. Index joint magnetic resonance imaging (MRI) scores of osteochondral (OC) damage (primary outcome), joint physical examination scores, and annualized rates of joint/other bleeding episodes (secondary outcomes) were collected. Thirty-seven of 65 JOS participants enrolled in JOS-C, including 15 randomized to prophylaxis at mean age 1.3 years (“early prophylaxis”); 18 initially randomized to episodic treatment, starting “delayed prophylaxis” at mean age 7.5 years; and 4 with high-titer inhibitors. At JOS-C exit, MRI OC damage was found in 77% of those on delayed and 35% of those on early prophylaxis for an odds ratio of OC damage, in the delayed vs early prophylaxis group, of 6.3 (95% confidence interval, 1.3, 29.9; P = .02). Annualized bleeding rates were higher with delayed prophylaxis (mean plus or minus standard deviation, 10.6 ± 6.6 vs 3.5 ± 2.1; P &lt; .001), including when only comparing time periods on prophylaxis (6.2 ± 5.3 vs 3.3 ± 1.9; P &lt; .05). In severe HA, early initiation of prophylaxis provided continued protection against joint damage throughout childhood compared with delayed initiation, but early prophylaxis was not sufficient to fully prevent damage. This trial was registered at www.clinicaltrials.gov as #NCT01000844.

Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1126-1126
Author(s):  
Karen L. Zimowski ◽  
Glaivy M. Batsuli ◽  
Paulette Bryant ◽  
Jenny McDaniel ◽  
Kelly Tickle ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Bleeding ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Acute Bleeding ◽  
Fviii Activity ◽  
Bleeding Episodes

Introduction : Emicizumab is a novel humanized bispecific antibody that mimics the function of activated coagulation factor VIII (fVIII). It has significantly changed the management of patients with hemophilia A and inhibitors by achieving baseline hemostatic control. Based on the HAVEN studies, emicizumab markedly reduces annualized bleeding rates and is FDA-approved for prophylaxis in hemophilia A patients of all ages, regardless of inhibitor status. In the HAVEN2 interim analysis, only 3/57 pediatric patients receiving emicizumab prophylaxis required treatment for an acute bleeding event after a 9-week median observation time. We report 3 patients with severe hemophilia A and a history of inhibitors receiving emicizumab prophylaxis with severe or refractory bleeding episodes to highlight the importance of vigilance and surveillance of children with severe hemophilia A on emicizumab. Methods: This retrospective analysis includes patients between 0-21 years of age with severe hemophilia A (fVIII activity < 1%) receiving emicizumab prophylaxis and admitted for the management of an acute bleeding episode following emicizumab's FDA approval in November 2017. Patients were followed at the Pediatric Hemophilia Treatment Center at the Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory and the St. Jude Affiliate Clinic at Novant Health Hemby Children's Hospital. Data collected included demographics, past medical history including inhibitor status, bleeding history, and treatment modalities, and details regarding the presentation, management, and outcome of acute severe bleeding events. Due to the nature of the study, descriptive statistics were primarily used for data analysis. Results: Three patients with severe hemophilia A receiving emicizumab prophylaxis were admitted for the management of 4 severe bleeding episodes. All patients had a history of a fVIII inhibitor. Three of the 4 bleeding episodes were trauma-induced while 1 occurred spontaneously. For the traumatic episodes, all patients presented with worsening symptoms approximately 1 week following the inciting event. All patients had a normal aPTT at the time of presentation, ruling out a significant anti-drug antibody (emicizumab level not available). A patient with a low-titer inhibitor developed an epidural hematoma following a trampoline injury and was treated with continuous infusion of recombinant factor VIII (rfVIII), adjusting the rate to achieve chromogenic fVIII activity of 100% for 14 days. Following 14 days, he was started on rfVIII 50 IU/kg Q12 hours with a goal fVIII activity of 50%. His rfVIII dosing interval was gradually weaned to every other day while in inpatient rehabilitation. As outlined in Table 1, the remaining 3 bleeding events were initially managed with recombinant activated factor VII (rfVIIa) dosed at 80-90 mcg/kg/dose with escalating frequency for an average of 8 days. However, due to lack of improvement, treatment was changed to low-dose activated prothrombin complex concentrates (aPCC; 10-15 IU/kg/dose Q12-24 hours for an average of 7 days). In all 3 of these events, the hematomas improved after treatment with aPCC. No patient experienced thrombotic microangiopathy, thrombosis, or had evidence of DIC while receiving these treatment regimens. Discussion/Conclusion: Pharmacokinetic analysis of emicizumab suggests that following the standard 4-week loading phase, trough plasma emicizumab concentrations obtained prior to a 1.5 mg/kg once weekly maintenance dose correlates with at least 10-15 IU/dL equivalent fVIII activity. This degree of thrombin generation should be sufficient to prevent severe spontaneous bleeding episodes in most patients. However it does not preclude significant trauma-induced bleeding or spontaneous bleeding in inhibitor patients. Based on our cases, providers should maintain a high index of suspicion for acute bleeding in patients receiving emicizumab prophylaxis. Serious bleeding events, although rare, may have a more insidious onset in patients receiving emicizumab. Furthermore, despite the baseline hemostasis achieved with emicizumab, acute bleeding events may still require aggressive therapy. Our cases suggest that low-dose aPCC or continuous infusion fVIII may be feasible options for treating acute bleeding events in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis. Disclosures Zimowski: Pfizer: Research Funding; National Hemophilia Foundation: Other: Medical Loan Reimbursement, Research Funding. Batsuli:Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees. Bryant:Novo Nordisk: Other: PI on Novo Nordisk sponsored Studies. McDaniel:Genentech: Membership on an entity's Board of Directors or advisory committees. Tickle:National Hemophilia Foundation: Research Funding. Meeks:Bayer: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Sidonio:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

Latest Results From The PUP-GCP Clinical Trial: A Low Inhibitor Rate In Previously Untreated Patients With Severe Hemophilia A Treated With Octanate

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3596-3596
Author(s):  
Anna Klukowska ◽  
Martina Jansen ◽  
Vladimir Komrska ◽  
Pawel Laguna ◽  
Vladimir Vdovin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Rating Scale ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Observational Period ◽  
Adverse Event Profile ◽  
On Demand ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Bleeding Episodes

Abstract Background Octanate is a highly purified, double virus inactivated, human plasma-derived factor VIII (FVIII) concentrate with all coagulation FVIII bound to its natural stabilizer VWF in a VWF:RCo/FVIII:C ratio of approximately 0.4. Five prospective GCP studies with octanate were conducted in 77 previously treated patients (PTPs) with severe hemophilia A. None of these 77 PTPs developed an inhibitor while treated exclusively with octanate. Aim To assess the immunogenicity in previously untreated patients (PUPs), a prospective clinical trial has been initiated in 2000. This included 50 PUPs with severe hemophilia A for an observational period of 100 exposure days with octanate, for at least 6 months. Methods Patients with severe hemophilia A without previous exposure to FVIII or FVIII-containing products were enrolled. Efficacy and tolerability were assessed by a 4-point verbal rating scale. Inhibitors were assessed according to modified Bethesda method prior to treatment every 3-4 exposure days (ED 1-20), and after treatment every 10 EDs (ED 21-100), but at minimum every three months. Results Two of 50 (4%) subjects developed clinically relevant inhibitor titers over the course of the study. Another two displayed inhibitors that disappeared spontaneously without change of dose or dosing interval. All inhibitors developed under on-demand treatment and before ED 50. From the 50 subjects, 42 had exceeded 50 EDs at the time of this analysis. Octanate was well-tolerated and the adverse event profile was consistent with the population studied. The hemostatic efficacy in prophylaxis and treatment of bleeding episodes was generally rated as “excellent” and no complication was reported for any surgical treatment. Conclusion Despite frequent inhibitor testing and predominant on-demand treatment, the data indicate a low overall inhibitor rate for octanate in patients who exceeded 50 exposure days (4/42) of which only 2 (4.8%) were clinically relevant. Disclosures: Klukowska: Octapharma AG: Investigator Other. Jansen:Octapharma AG: Employment. Komrska:Octapharma AG: Investigator Other. Laguna:Octapharma AG: Investigator Other. Vdovin:Octapharma AG: Investigator Other. Knaub:Octapharma AG: Employment.

scholarly journals Early Prophylaxis Provides Continued Joint Protection in Severe Hemophilia A: Results of the Joint Outcome Continuation Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 382-382 ◽  
Author(s):  
Beth Boulden Warren ◽  
Dianne Thornhill ◽  
Jill Stein ◽  
Michael Fadell ◽  
Sharon Funk ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Factor Viii ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Joint Damage ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Episodic Treatment ◽  
Bayer Healthcare

Abstract Background: The Joint Outcome Study (JOS) was a randomized controlled trial showing that, in severe hemophilia A, prophylactic factor VIII every other day starting prior to age 30 months leads to better joint outcomes at age 6 years than enhanced episodic treatment with factor VIII for bleeding1. After conclusion of the JOS, all participants were encouraged to continue on, or to transition to, prophylaxis. Here we describe the results of the Joint Outcome Continuation Study (JOS-C), which followed the participants of the JOS to age 18 years. Methods: All participants of the JOS were eligible for the JOS-C. MRIs of 6 index joints (right and left ankles, knees, and elbows), index joint physical exam scores using the Colorado Haemophilia Paediatric Joint Physical Examination Scale2 , estimates of joint bleeding episodes, and surgery information were collected. The primary endpoint, as in the initial JOS analysis, was evidence of hemophilia-related osteochondral joint damage on MRI, scored using the extended MRI scale3. Results: Of the 65 previous participants of the JOS, 37 gave informed consent for the JOS-C study, including 18 initially randomized to prophylaxis prior to age 30 months ("early prophylaxis"), and 19 initially randomized to enhanced episodic treatment who started prophylaxis at a mean age of 7.5 years (median 6.1, range 2.7-17.1, "delayed prophylaxis"). All initially on prophylaxis in the JOS continued on prophylaxis through the JOS-C. One participant (early prophylaxis arm) failed to complete an MRI, and four others (2 early and 2 delayed prophylaxis) had their MRIs excluded for technical reasons. Four participants (3 early prophylaxis and 1 delayed prophylaxis) developed high titer inhibitors during or shortly after the JOS and were analyzed separately. Osteochondral joint damage was defined as evidence of osteochondral damage on MRI or a need for joint surgery. The relative risk of osteochondral damage in those on delayed prophylaxis as compared to those on early prophylaxis was 6.5 (95% CI 1.3, 33.6; p=0.029). At age 18, 67% of those on early prophylaxis, and only 24% of those on delayed prophylaxis had zero index joints with osteochondral damage (Figure 1). Twenty-five percent of early prophylaxis and 47% of delayed prophylaxis participants had osteochondral damage to more than one joint. Most participants had some soft tissue changes on MRI, defined as effusion, synovial hypertrophy, or hemosiderin deposition. There was no difference in risk of soft tissue damage between initial treatment groups (p=0.48). Osteochondral damage scores were available for 3 patients with inhibitors: two with refractory inhibitors had osteochondral changes on at least one joint, and one with an inhibitor that tolerized within 3 months had no osteochondral damage. Total physical exam scores were also higher in the delayed prophylaxis arm (mean 22.6, standard deviation (SD) 15.5) than in the early prophylaxis arm (mean 16.2, SD 10.5), but this difference was not statistically significant (p=0.19). Conclusion: The JOS-C demonstrates that, in severe hemophilia A, initiation of prophylaxis prior to age 30 months provides continued protection against joint damage throughout childhood. Those who started on prophylaxis later in childhood had higher risk of joint damage at age 18. Initiation of factor VIII prophylaxis in the toddler years is critical to preventing osteochondral joint damage and should not be delayed. ReferencesManco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-544.Hacker MR, Funk SM, Manco-Johnson MJ. The Colorado Haemophilia Paediatric Joint Physical Examination Scale: normal values and interrater reliability. Haemophilia. 2007;13(1):71-78.Hong W, Raunig D, Lundin B. SPINART study: validation of the extended magnetic resonance imaging scale for evaluation of joint status in adult patients with severe haemophilia A using baseline data. Haemophilia. 2016;22(6):e519-e526. Figure 1: Percentage of participants with zero joints with osteochondral damage at JOS exit (age 6 years) and JOS-C exit (age 18 years), excluding participants with inhibitors. Disclosures Warren: Bayer Healthcare: Research Funding; HTRS/Novo Nordisk: Research Funding; Bayer Hemophilia Awards Program Fellowship Project Award: Research Funding; CSL Behring Heimburger Award: Research Funding. Shapiro:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Prometic Life Sciences: Consultancy, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Bio Products Laboratory: Consultancy; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Sangamo Biosciences: Consultancy; Octapharma: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; OPKO: Research Funding; BioMarin: Research Funding. Recht:Shire: Research Funding; Biogen: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees. Manco-Johnson:Bayer AG: Honoraria, Research Funding; Novo Nordisk: Honoraria; Biogentek: Honoraria; CSL Behring: Honoraria; Baxalta, now part of Shire: Honoraria.

scholarly journals FEIBA® and Novoseven® Neutralize the Anticoagulant Effects of a Novel Small Molecule FXIa Inhibitor BMS-986177/JNJ-70033093 in Human Plasma and Whole Blood in Vitro

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Matthew W Bunce ◽  
Zheng Huang Devine ◽  
Madhu Chintala
Keyword(s):  
Human Plasma ◽  
Whole Blood ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Lag Time ◽  
Publicly Traded ◽  
Routine Prophylaxis ◽  
Control And Prevention ◽  
Bleeding Episodes

Background: FXIa inhibition is a promising antithrombotic drug target. BMS-986177/JNJ-70033093 (BMS-177/JNJ-3093) is a novel small molecular inhibitor of FXIa currently in Phase II clinical trials with the potential for reduced bleeding risk as compared to the currently approved oral anticoagulantsHowever, reversal of anticoagulation may still be required in patients who have uncontrolled or life-threatening bleeding or need an urgent surgical procedure. Aim: To evaluate the ability of nonspecific reversal agents (NSRAs) FEIBA®, NovoSeven®, Kcentra®, Profilnine®, BeneFix®, Novoeight®, and Cyklokapron® to neutralize the anticoagulation of BMS-177/JNJ-3093 in the activated partial thromboplastin time (aPTT), thromboelastography (TEG) and thrombin generation assay (TGA) in vitro using human plasma or whole blood. Method: aPTT and TEG were performed in human plasma and whole blood, respectively, using standard assay procedures. TGA was performed in human plasma using diluted kaolin aPTT reagent (1:10,000). JNJ-3093 was evaluated at different concentrations (0.3 -10 µM) to cover the anticipated exposures in the Phase II clinical trials. The NSRAs were evaluated at the anticipated concentrations according to the dosing information in their respective labels. Results: BMS-177/JNJ-3093 produced concentration dependent increases in aPTT (up to 4.4x at 10 μM); prolongations of lag time in TEG (2.6X); prolongations of lag time (3X) as well as reductions in peak thrombin generation (70%) in TGA. FEIBA® effectively neutralized the anticoagulant effects of JNJ-3093 in aPTT, TEG and TGA. NovoSeven® neutralized the BMS-177/JNJ-3093-induced prolongations in aPTT, prolongations in lag time in TEG and TGA assays and partially restored the peak thrombin generation in TGA. In contrast, all other NSRAs tested had negligible effects or did not show neutralization of anticoagulation induced by BMS-177/JNJ-3093 in the referenced assays Conclusion: These results demonstrate that FEIBA® and NovoSeven® can effectively neutralize the anticoagulant effects of BMS-177/JNJ-3093 in vitro. A clinical study is required to determine if these agents can reverse the anticoagulant effects of BMS-177/JNJ-3093 in patients. Table Disclosures Bunce: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Huang Devine:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Chintala:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure: FEIBA: hemophilia A and B patients with inhibitors for: control and prevention of bleeding episodes; use around the time of surgery; routine prophylaxis to prevent or reduce the frequency of bleeding episodes NovoSeven: Treatment of bleeding and prevention of bleeding for surgeries and procedures in adults and children with hemophilia A or B with inhibitors, congenital Factor VII (FVII) deficiency, and Glanzmanns thrombasthenia with a decreased or absent response to platelet transfusions; treatment of bleeding and prevention of bleeding for surgeries and procedures in adults with acquired hemophilia Kcentra: urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist therapy in adult patients with need for urgent surgery/invasive procedure or acute major bleeding Profilnine: prevention and control of bleeding in patients with Factor IX deficiency due to hemophilia B BeneFix: control and prevention of bleeding episodes or peri-operative management in adult and pediatric patients with hemophilia B Novoeight: for use in adults and children with hemophilia A for control and prevention of bleeding, perioperative management, and routine prophylaxis to prevent or reduce the frequency of bleeding episodes Cyklokapron: patients with hemophilia for short-term use to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction)

scholarly journals Problem Joints and Their Clinical and Humanistic Burden in Children and Adults with Moderate and Severe Hemophilia a: CHESS Paediatrics and CHESS II

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Paul McLaughlin ◽  
Cedric Hermans ◽  
Sohaib Asghar ◽  
Tom Burke ◽  
Francis Nissen ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Joint Damage ◽  
Severe Hemophilia ◽  
Publicly Traded ◽  
Hemophilic Arthropathy ◽  
Joint Health ◽  
Humanistic Burden

Introduction Severe hemophilia A (SHA) is characterized by spontaneous (non-trauma related) bleeding episodes into the joint space and muscle tissue, leading to progressive joint deterioration and chronic pain. Chronic joint damage is most often associated with severe hemophilia, however more recent research has illustrated that people with moderate hemophilia A (MHA) also experience hemophilic arthropathy and functional impairment. The need to measure joint health in children as well as adults, is underscored by findings from the Joint Outcome Continuation Study, which found that FVIII prophylaxis was insufficient to protect joints from damage, from childhood through adolescence in severe HA (Warren et al., 2020). The objective of this analysis is to gain a more patient-centric understanding of the clinical, economic and humanistic burden associated with 'Problem Joints', a measure of joint morbidity developed in consultation with an expert panel to overcome limitations with existing measures, in people with MHA and SHA. Methods A descriptive cohort analysis was conducted, utilizing retrospective, cross-sectional real-world data from the 'Cost of Haemophilia in Europe: a Socioeconomic Survey' (CHESS Paeds and CHESS II), studies of adult and pediatric persons with hemophilia. The analysis population is comprised of children (17 and below) with MHA or SHA in CHESS Paeds, and adults aged 20 and over with MHA or SHA in CHESS II. To account for the possibility that persons aged 18 or 19 in CHESS II may have participated in CHESS Paeds, these individuals were excluded from the analysis. Physician-reported clinical outcome data and patient/caregiver-reported quality of life were analyzed. A problem joint (PJ) is defined as having chronic joint pain and/or limited range of movement due to compromised joint integrity (i.e. chronic synovitis and/or hemophilic arthropathy). Analyses were stratified by number of PJs: none, 1 PJ, and 2+ PJs. We report retrospective data of the 12 months prior to study enrollment, on annualized bleeding rate (ABR), prevalence of target joints (TJ), as defined by the International Society on Thrombosis and Haemostasis, and EQ-5D-/5L/Y/Proxy score. Results are presented as mean (standard deviation) or N (%). Results Among 785 participants (N = 464 SHA; N = 321 MHA) in CHESS Paeds, mean age and BMI were 10.33 (4.63) and 22.50 (17.07), respectively. Of 493 participants (aged 20 and above) in CHESS II (N = 298 SHA; N = 195 MHA), the mean age and BMI were 38.61 (14.06) and 24.55 (2.92), respectively. Current inhibitor to FVIII replacement was more prevalent in children than in adults (10% vs. 5%). In CHESS II, approximately 40% of people with MHA and 49% with SHA had one or more PJs, respectively [1 PJ (23% vs. 28%); 2+ PJs (16% vs. 21%)]. In CHESS Paeds, approximately 14% of children with MHA and 18% with SHA had at least one PJ, respectively [1 PJ (9% vs. 14%); 2+ PJs (5% vs. 3%)]. TJs were less prevalent with MHA in comparison to SHA, in both adults (24% vs. 45%) and children (13% vs. 22%). Clinical burden was higher among both children and adults with PJs compared to those with no PJs. ABR correlates with the number of PJs, in those with MHA and SHA in CHESS II (Figure 1). Similarly, PJs were associated with higher ABR across MHA and SHA in CHESS Paeds (Figure 2). Hemophilia-related hospitalizations were higher in both adult and pediatric participants with PJs. In CHESS II, MHA with no PJs had fewer [0.73 (1.23)] hospitalizations compared to having those with 1 PJ [1.38 (1.11)] or 2+ PJs [1.28 (1.25)]. Similarly, children with MHA with 2+ PJs had 1.60 (1.92) hemophilia-related hospitalizations, compared to 1.38 (1.92) with 1 PJ and 0.71 (1.14) with no PJs. PJs were associated with impaired quality of life. In CHESS II, MHA and SHA EQ-5D-5L values in persons with no PJs were 0.81 (0.19) and 0.79 (0.18), respectively, compared to 0.65 (0.16) and 0.62 (0.23) with 1 PJ, and 0.65 (0.14) and 0.51 (0.33) in with 2+ PJs. A similar trend was observed in EQ-5D-Y and EQ-5D-proxy scores in CHESS Paeds. Conclusions Data from CHESS Paeds and CHESS II demonstrate an association between chronic joint damage, as measured by the 'problem joint' definition, and worsening clinical and quality of life outcomes, across both MHA and SHA. Further analyses will seek to expand upon the initial results presented here, to investigate the wider elements of burden associated with compromised long-term joint health. Disclosures McLaughlin: BioMarin: Consultancy; Novo Nordisk: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Roche/Chugai: Speakers Bureau; Takeda: Speakers Bureau. Hermans:Novo Nordisk: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Sobi: Consultancy, Research Funding, Speakers Bureau; Biogen: Consultancy, Speakers Bureau; CAF-DCF: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; Shire, a Takeda company: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; WFH: Other; EAHAD: Other; Octapharma: Consultancy, Speakers Bureau; Kedrion: Speakers Bureau; LFB: Consultancy, Speakers Bureau. Asghar:HCD Economics: Current Employment. Burke:HCD Economics: Current Employment; University of Chester: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Nissen:GSK: Research Funding; Novartis: Research Funding; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment. Aizenas:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Meier:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Dhillon:HCD Economics: Current Employment; F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. . O'Hara:F. Hoffmann-La Roche Ltd: Consultancy; HCD Economics: Current Employment, Current equity holder in private company.

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