Objective:
While a new generation of therapies for patients with Hemophilia A are available, it is unclear what patient characteristics, perceptions, and barriers are associated with the decision to switch FVIII replacement therapies. This study assessed patient characteristics, health history, and reasons for switching from a FVIII product with more frequent dosing (³3x infusions/week) to a product with less frequent dosing (≤2x infusions/week) from patient/caregiver and physician perspectives.
Methods:
Data collection was a mix of qualitative and quantitative procedures. The qualitative portion consisted of two online discussion forums: patients (n=17) and caregivers of patients (n=11) receiving a FVIII product dosed ³3x/week, and patients (n=22) and caregivers of patients (n=5) who switched to a product dosed ≤2x/week. The quantitative portion was a retrospective medical chart review (n=207) which captured variables (e.g., bleed rate, treatment history) 6 months pre- and 6 months post-switching to a product with less frequent dosing.
Summary:
Prominent drivers among patients for starting a FVIII product with less frequent dosing included: 1) experiencing diminished effectiveness while on a product dosed ³3x/week resulting in increased breakthrough bleeding, 2) experiencing vein access issues, and 3) beginning prophylaxis as opposed to on-demand infusions after a bleed.
Key barriers to changing included: 1) fears regarding the process of switching being complicated, time consuming, and costly, 2) perceived risks associated with switching, and, 3) possible lack of healthcare provider support.
Physicians were most likely to report that patients switched products because they sought a newer product with twice weekly dosing or less per FDA-approved dosing recommendations (35.3%), followed by patient requested the switch (30.4%), and patient sought a reduction in infusion frequency to improve adherence (27.5%).
Switching to a product with less frequent dosing was associated with improvements in patient-reported bleeding-related outcomes. Patients were more likely to self-administer the treatment post-switch (63.8%) compared with pre-switch (48.8%; p<0.001) and had fewer infusions per week post-switch (2.8 vs. 3.3; p<0.001). Patients’ annualized bleed rate was lower (5.9) post-switch compared with pre-switch (7.7; p<0.001).
Both the number of spontaneous joint bleeds and joint bleeds after trauma or injury were lower (3.2 and 2.7) post-switch (3.6 and 4.3; p=0.044 and p<0.001). The bleeding event was less likely to be classified as moderate or severe (34.5% and 5.9%) post-switch compared with pre-switch (55.0% and 10.0%; p<0.001 and p=0.049). Fewer infusions were required to resolve the bleeding event post-switch (2.6 vs. 3.2; p<0.001).
A prominent reason why patients switch treatment is to improve bleeding-related outcomes. Indeed, we found that switching to a FVIII product with less frequent dosing was associated with improved patient-reported bleeding-related outcomes. These findings are critical for improving patient outcomes and support the FDA mandate to incorporate patient perspectives in the regulatory process.
This study will evaluate hemophilia treatment center (HTC) services provided to women with hemophilia A or B (Factor VIII or Factor IX level [ 50%). The American Thrombosis and Hemostasis Network (ATHN) maintains a confidential national database for patients with bleeding and clotting disorders. Utilizing this existing ATHNdataset, the study will analyze the effect of gender on the delivery of comprehensive care in patients with hemophilia A and B. The project will focus on how gender impacts three specific components of care: identification of patients with factor VIII or IX deficiency, inclusion of patients in the comprehensive care model, and monitoring of joint bleeding as a key component of comprehensive care provided by HTCs. Demonstrating gender-based disparities in comprehensive care would provide evidence for making changes to improve the clinical care provided to women with hemophilia. This study will add to the knowledge regarding the care of women with hemophilia, helping to inform future studies of this under-researched population.
Objective:
As a single gene disorder of Factor VIII (FVIII), hemophilia A (HA) is an ideal candidate for gene therapy. We present results from an ongoing Phase 1/2 study of valoctocogene roxaparvovec (BMN 270; AAV5-FVIII-SQ) gene transfer in patients with severe HA.
Methods:
As of 16 April 2018, 13 subjects (6E13 vg/kg, n=7; 4E13 vg/kg, n=6) received a single intravenous dose of valoctocogene roxaparvovec, an AAV5 vector containing a B-domain-deleted FVIII gene. Safety, efficacy, immunogenicity, and other endpoints are being evaluated.
Summary:
FVIII activity is presented as median levels over 4-week intervals. In the 6E13 cohort, FVIII activity plateaued by Week 20 post-valoctocogene roxaparvovec, with median levels between Weeks 20-104 in the non-hemophilic range ([range] 46-122 IU/dL); Week 104 median FVIII activity was 46 IU/dL ([range] 6-145 IU/dL). In the 4E13 cohort, median [range] FVIII activity increased to just below the normal range (NR) at Week 52 [n=6]: 32 [3-59] IU/dL. Prior FVIII prophylaxis subjects had median [interquartile range, IQR] annualized FVIII infusions decline from 139 [122-157] (6E13) and 156 [126-183] (4E13) to 0 [0-0.4] and 0 [0-1] 4 weeks post-infusion through last follow-up; median [IQR] annualized bleeding rates post-infusion were 0 [0-0] in both cohorts (no bleeding episodes in 5 subjects in each cohort). Mild, grade 1, asymptomatic alanine aminotransferase (ALT) increases were reported in six of seven 6E13 and four of six 4E13 subjects; one 4E13 subject had a grade 2 ALT increase. Peak ALT levels ranged from 44-141 U/L (upper limit of normal=43 U/L). All subjects had a normal ALT level at last follow-up and all subjects were off of corticosteroid therapy. No subjects developed inhibitors to FVIII.
Conclusions:
Gene transfer with valoctocogene roxaparvovec in subjects with severe HA resulted in sustained, clinically relevant FVIII activity that reduced self-reported bleeding and exogenous FVIII use 2 years post-infusion in the 6E13 cohort. FVIII activity in the 4E13 cohort was maintained at the upper range of mild HA 1 year post-infusion. Both doses enabled achievement of long-term therapeutic levels of FVIII activity and prevention of hemophilia-related bleeding with a favorable safety profile.
Objective:
BAY 81-8973 (Kovaltry®) is a full-length, unmodified recombinant human factor VIII (FVIII) for prophylaxis and treatment of bleeds in patients with hemophilia A. Safety and efficacy of BAY 81-8973 in children, adolescents, and adults were established in the LEOPOLD clinical trials. This analysis reports interim data from the LEOPOLD Kids extension study for patients with ≥100 exposure days (EDs) to BAY 81-8973 in the main study plus extension study.
Methods:
In LEOPOLD Kids, boys aged ≤12 years with severe hemophilia A and ≥50 EDs to FVIII received BAY 81-8973 (25–50 IU/kg) ≥2 times/wk for ≥50 EDs. Patients completing the main study could enroll in an ongoing extension study for ≥100 EDs.
Summary:
Of 51 patients who completed the main study, 46 (90.2%) entered the extension study (aged <6 years, n=22; aged 6–12 years, n=24). Patients were treated for a median (range) of 1494 (175–1989) days and accumulated 546 (67–1011) EDs in the extension study. Median (quartile [Q]1; Q3) dose per prophylaxis infusion was 37.7 (33.1; 41.8) and 30.9 (29.1; 34.9) IU/kg for younger and older patients, respectively; annual prophylaxis dose was 4984 (3679; 6529) and 4089 (3283; 5555) IU/kg. Median (Q1; Q3) annualized number of total bleeds was 2.0 (0.2; 4.2) and 1.8 (0.5; 3.0) for younger and older patients, respectively; annualized total bleed rate was 3.0 (0; 6.0) and 0 (0; 6.4) for these patients in the main study. Median (Q1; Q3) annualized total bleeds within 48 hours of prophylaxis infusion was 0.8 (0; 1.7) and 1.0 (0.1; 1.6) in younger and older patients in the extension study. Response was excellent/good in 337/405 bleeds (83.2%); data were missing for 22 (5.4%) bleeds. Most bleeds (93.5%) were mild/moderate and were spontaneous (42.4%) or trauma related (53.6%). One patient experienced a mild treatment-related serious adverse event (transient very low FVIII inhibitor titer concurrent with acute infection and positive immunoglobulin G anticardiolipin) and remained in the extension study. No change in treatment was required, and the patient was clinically well.
Conclusions:
Data from the LEOPOLD Kids extension study show that BAY 81-8973 provides safe and effective long-term prophylaxis in children with severe hemophilia A treated for a median of 4.1 years, confirming safety results observed in the main study.
Objective:
N9-GP is a glycoPEGylated recombinant factor-IX (rFIX) product that provides approximately two times incremental recovery, five times half-life, and 10 times area under the plasma concentration-time curve compared with standard rFIX. Phase 3 single-dose (40 IU/kg) in adults showed incremental recovery 2.34 %/IU/kg and 17% mean FIX activity at 7 days. This analysis investigates N9-GP 40 IU/kg as a single-dose on-demand (OD) treatment for hemophilia B, focusing on predictors of a second dose.
Methods:
In the paradigm™2 pivotal trial of previously treated adult/adolescent patients (≤2% FIX), the FDA requested that a group receive OD treatment prior to US enrollment into prophylaxis. This case-by-case analysis evaluated OD treatment in relationship to bleed type/pattern and prestudy treatment regimen. Hemostatic efficacy was reported by patients on a 4-point scale.
Summary:
Fifteen patients were enrolled for OD treatment (13 severe, two moderate); 13 were previously treated OD and two with prophylaxis. Overall, 14/15 patients experienced 143 bleeds during 26 weeks, of which 120 (84%) in 13 patients were treated with one dose. Seven patients (five severe, two moderate) treated all bleeds (62) with one dose (36 ‘excellent’ and 26 ‘good’ response). The other seven patients, described below, experienced 58 bleeds (72%) treated with one dose (seven ‘excellent’, 49 ‘good’, one ‘moderate’, one not reported); their other 23 bleeds (28%) required ≥2 doses (17 ‘good’, six ‘moderate’). Two of these seven had 4/11 (36%) recurrent target joints (TJ) bleeds/rebleeds treated with additional doses. An 18-year-old previously treating with plasma-derived FIX (pdFIX), 76 IU/kg/bleed, had three right elbow TJ bleeds in two months treated with one, five, and two doses. A 27-year-old previously on prophylaxis (pdFIX 100 IU/kg every 3 days and 100 IU/kg/bleed) had two bleeds in a right ankle TJ in 2 weeks treated with two doses (including one for early rebleeding) and six doses prior to withdrawing from the study. Another four patients with bleeds requiring multiple doses had been historically treated with multiple high FIX doses (IU/kg x doses per bleed: 60×2, 80×2, 80×2, and 81×3) with prescribed dosing of 120, 160, 160, and 243 IU/kg/bleed; they reported 63 bleeds, of which 45 (71%) were treated with a single 40-IU/kg dose, 17 with two, and one with four doses. Average N9-GP dosing was 44.0, 74.7, 97.9, and 52.8 IU/kg/bleed (63%, 53%, 39%, and 78% reduction in FIX use per episode). The last patient was treated prestudy with 10 IU/kg/bleed had seven bleeds (six treated with one dose, mean 46.8 IU/kg/bleed).
Conclusions:
N9-GP 40 IU/kg was effective as a single-dose OD bleed treatment (84%). Additional dose(s) for some bleeds were associated with recurrent TJ bleeds in patients not on prophylaxis or patients previously taking multiple high doses for bleeding.
Background:
Inherited factor X deficiency is an autosomal recessive bleeding disorder with an estimated occurrence rate of 1:1,000,000¹. Historically, bleeding symptoms have been treated with topical therapies, antifibrinolytic agents, fresh frozen plasma (FFP) or plasma-derived FIX concentrates (PCCs). In 2015, the first factor X (FX) concentrate was approved in the U.S.
Objective:
This organization was interested in reviewing clinical outcomes such as perceived pain and unplanned hospitalizations of adults and children with FX disease currently being treated in the home with Coagadex®. METHODS: This organization conducted a retrospective review of a population of seven adult and pediatric patients. Patients were surveyed for pain, bleeding episodes, hospitalizations/ ER visits, dosing parameters and administration methods pre/post initiation of FX therapy. There were 3 children, 12 years old and under and four adults. Ages ranged from 5-60 years old with the average age of 27.9. There were five males and two females. The average length of treatment was 6.4 months. One patient was naïve, six converted from other therapies. Dose ranges administered by caregivers or self-infusion were 750 -2800 IU (26-61 IU/Kg). One patient was on-demand and six were administering prophylaxis therapy.
Results:
There were two converted prophylaxis patients reported pain with PCC’s and none with FX; one on-demand naïve patient stated his pain was markedly improved with prn administration of FX; four converted prophylaxis patients with no prior pain history reported no changes in pain on FX therapy. For on-demand patients treating bleeding episodes, three reported a decrease in the number of bleeding episodes, three were unchanged and one reported one additional bleeding episode. A total of ten hospitalizations or emergency room visits were reported during the six months prior to initiation of FX treatment and only one in the six months following initiation of treatment.
Conclusion:
Early recognition and home treatment with FX concentrate allows for prompt resolution of bleeding symptoms, decreased pain and decreased hospitalization or emergency room visits. Further investigation is needed to determine cost-savings for decreased hospitalization/ ER visits.References:Brown, D.L. & Kouides, P.A. (2008). Diagnosis and treatment of Inherited Factor X deficiency. Haemophilia. (14). 1176-1182. Retrieved from: https://www.hemophilia.org/sites/default/files/document/files/DiagnosisAndTreatmentOfInheritedFact…
