Background
Surgical procedures impose hemostatic risk to people with hemophilia, which may be minimized by optimal factor (F) replacement therapy.
Methods
This analysis evaluates the efficacy and ...safety of extended half‐life factor replacement recombinant FVIII and FIX Fc fusion proteins (rFVIIIFc and rFIXFc) during surgery in phase 3 pivotal (A‐LONG/Kids A‐LONG and B‐LONG/Kids B‐LONG) and extension (ASPIRE and B‐YOND) studies. Dosing regimens were determined by investigators. Injection frequency, dosing, blood loss, transfusions, and hemostatic response were assessed.
Results
Forty‐five major (n = 31 subjects) and 90 minor (n = 70 subjects) procedures were performed in hemophilia A; 35 major (n = 22) and 62 minor (n = 37) procedures were performed in hemophilia B. Unilateral knee arthroplasty was the most common major orthopedic procedure (hemophilia A: n = 15/34; hemophilia B: n = 8/24). On the day of surgery, median total dose in adults/adolescents was 81 IU/kg for rFVIIIFc and 144 IU/kg for rFIXFc; most major procedures required ≤2 injections (including loading dose). Through days 1–14, most major procedures had ≤1 injection/day. Hemostasis was rated excellent (rFVIIIFc: n = 39/42; rFIXFc: n = 29/33) or good (n = 3/42; n = 4/33) in evaluable major surgeries, with blood loss comparable with subjects without hemophilia. Most minor procedures in adults/adolescents required one injection on the day of surgery, including median loading dose of 51 IU/kg (rFVIIIFc) and 80 IU/kg (rFIXFc). No major treatment‐related safety concerns were identified. No subjects developed inhibitors or serious vascular thromboembolic events.
Conclusions
rFVIIIFc and rFIXFc were efficacious and well tolerated for the management of perioperative hemostasis across a wide spectrum of major and minor surgeries in hemophilia.
The first‐line treatment for mild‐to‐moderate bleeding episodes in patients with haemophilia and inhibitors in Brazil is currently activated prothrombin complex concentrate (aPCC), with recombinant ...activated factor VII (rFVIIa) used as second‐line therapy or as a last resort. The aim of this study was to determine the cost and effectiveness of these treatments from the perspective of the Brazilian National Health Service. A decision analysis model was constructed to assess total direct medical costs (including drug costs, costs of outpatient or inpatient care, ambulance transportation and cost of concomitant medications) of first‐line treatment with aPCC or rFVIIa. Clinical outcome and resource utilization data were obtained both retrospectively and prospectively and validated by the consensus of an expert panel of Brazilian haematologists. A total of 103 bleeds in 25 patients were included in the analysis. rFVIIa resolved bleeds more quickly (4.4 h) than aPCC (62.6 h) and was more effective (100% vs. 56.7% respectively). Mean total direct medical costs (from initiation to cessation of bleed) were estimated to be US$13 500 (aPCC) and US$7590 (rFVIIa). Extensive sensitivity analyses confirmed the cost‐effectiveness of rFVIIa. Compared with aPCC, rFVIIa was more effective and less expensive when used as first‐line treatment for mild‐to‐moderate bleeding episodes in patients with haemophilia and inhibitors in Brazil. rFVIIa should be considered a first‐line treatment for the management of these patients.
Introduction
Recombinant factor IX Fc fusion protein (rFIXFc) has demonstrated efficacy for treatment of haemophilia B in the Phase 3 B‐LONG and Kids B‐LONG studies. However, long‐term rFIXFc safety ...and efficacy data have not yet been reported.
Aim
To report long‐term rFIXFc safety and efficacy in subjects with haemophilia B.
Methods
B‐YOND (NCT01425723) was an open‐label extension for eligibl previously treated subjects who completed B‐LONG or Kids B‐LONG. Subjects received ≥1 treatment regimen: weekly prophylaxis (WP), individualized interval prophylaxis (IP), modified prophylaxis or episodic treatment. Subjects could switch regimens at any time. The primary endpoint was inhibitor development.
Results
Ninety‐three subjects from B‐LONG and 27 from Kids B‐LONG (aged 3‐63 years) were enrolled. Most subjects received WP (B‐LONG: n = 51; Kids B‐LONG: n = 23). For subjects from B‐LONG, median (range) treatment duration was 4.0 (0.3‐5.4) years and median (range) number of exposure days (EDs) was 146 (8‐462) EDs. Corresponding values for paediatric subjects were 2.6 (0.2‐3.9) years and 132 (50‐256) EDs. No inhibitors were observed (0 per 1000 subject‐years; 95% confidence interval, 0‐8.9) and the overall rFIXFc safety profile was consistent with prior studies. Annualized bleed rates remained low and extended‐dosing intervals were maintained for most subjects. Median dosing interval for the IP group was approximately 14 days for adults and adolescents (n = 31) and 10 days for paediatric subjects (n = 5).
Conclusions
B‐YOND results confirm the long‐term (up to 5 years, with cumulative duration up to 6.5 years) well‐characterized safety and efficacy of rFIXFc treatment for haemophilia B.
Prophylactic factor replacement in patients with hemophilia B improves outcomes but requires frequent injections. A recombinant factor IX Fc fusion protein (rFIXFc) with a prolonged half-life was ...developed to reduce the frequency of injections required.
We conducted a phase 3, nonrandomized, open-label study of the safety, efficacy, and pharmacokinetics of rFIXFc for prophylaxis, treatment of bleeding, and perioperative hemostasis in 123 previously treated male patients. All participants were 12 years of age or older and had severe hemophilia B (endogenous factor IX level of ≤2 IU per deciliter, or ≤2% of normal levels). The study included four treatment groups: group 1 received weekly dose-adjusted prophylaxis (50 IU of rFIXFc per kilogram of body weight to start), group 2 received interval-adjusted prophylaxis (100 IU per kilogram every 10 days to start), group 3 received treatment as needed for bleeding episodes (20 to 100 IU per kilogram), and group 4 received treatment in the perioperative period. A subgroup of group 1 underwent comparative sequential pharmacokinetic assessments of recombinant factor IX and rFIXFc. The primary efficacy end point was the annualized bleeding rate, and safety end points included the development of inhibitors and adverse events.
As compared with recombinant factor IX, rFIXFc exhibited a prolonged terminal half-life (82.1 hours) (P<0.001). The median annualized bleeding rates in groups 1, 2, and 3 were 3.0, 1.4, and 17.7, respectively. In group 2, 53.8% of participants had dosing intervals of 14 days or more during the last 3 months of the study. In groups 1, 2 and 3, 90.4% of bleeding episodes resolved after one injection. Hemostasis was rated as excellent or good during all major surgeries. No inhibitors were detected in any participants receiving rFIXFc; in groups 1, 2, and 3, 73.9% of participants had at least one adverse event, and serious adverse events occurred in 10.9% of participants. These events were mostly consistent with those expected in the general population of patients with hemophilia.
Prophylactic rFIXFc, administered every 1 to 2 weeks, resulted in low annualized bleeding rates in patients with hemophilia B. (Funded by Biogen Idec; ClinicalTrials.gov number, NCT01027364.).
The therapeutic landscape for people living with hemophilia A (PwHA) has changed dramatically in recent years, but many clinical challenges remain, including the development of inhibitory antibodies ...directed against factor VIII (FVIII) that occur in approximately 30% of people with severe hemophilia A. Emicizumab, an FVIII mimetic bispecific monoclonal antibody, provides safe and effective bleeding prophylaxis for many PwHA, but clinicians still explore therapeutic strategies that result in immunologic tolerance to FVIII to enable effective treatment with FVIII for problematic bleeding events. This immune tolerance induction (ITI) to FVIII is typically accomplished through repeated long-term exposure to FVIII using a variety of protocols. Meanwhile, gene therapy has recently emerged as a novel ITI option that provides an intrinsic, consistent source of FVIII. As gene therapy and other therapies now expand therapeutic options for PwHA, we review the persistent unmet medical needs with respect to FVIII inhibitors and effective ITI in PwHA, the immunology of FVIII tolerization, the latest research on tolerization strategies, and the role of liver-directed gene therapy to mediate FVIII ITI.
•Pooled longitudinal efficacy and safety data for rFIXFc demonstrates sustained benefits in hemophilia B.•All evaluable target joints resolved during treatment, and no recurrence was reported in most ...(90%) baseline target joints during follow-up.
Display omitted
Long-term efficacy and safety of the extended half-life recombinant factor IX Fc fusion protein (rFIXFc) has been established among previously treated patients with severe hemophilia B in 2 phase 3 trials (B-LONG #NCT01027364 and Kids B-LONG #NCT01440946) and a long-term extension study (B-YOND #NCT01425723). In this study, we report post hoc analyses of pooled longitudinal data for up to 6.5 years for rFIXFc prophylaxis. In the B-LONG study, subjects ≥12 years received weekly dose-adjusted prophylaxis (WP; starting dose, 50 IU/kg), individualized interval-adjusted prophylaxis (IP; initially, 100 IU/kg every 10 days), or on-demand dosing. In the Kids B-LONG study, subjects <12 years received 50 to 60 IU/kg every 7 days, adjusted as needed. In the B-YOND study, subjects received WP (20-100 IU/kg every 7 days), IP (100 IU/kg every 8-16 days), modified prophylaxis, or on-demand dosing; switching between treatment groups was permitted. A total of 123 subjects from B-LONG and 30 from Kids B-LONG study were included, of whom 93 and 27, respectively, enrolled in the B-YOND study. The median cumulative duration of treatment was 3.63 years (range, 0.003-6.48 years) in B-LONG/B-YOND and 2.88 years (range, 0.30-4.80 years) in Kids B-LONG/B-YOND group. Annualized bleed rates (ABRs) remained low, annualized factor consumption remained stable, and adherence remained high throughout treatment. Low ABRs were also maintained in subjects with dosing intervals ≥14 days or with target joints at baseline. Complete resolution of evaluable target joints and no recurrence in 90.2% of baseline target joints during follow-up were observed. rFIXFc prophylaxis was associated with sustained clinical benefits, including long-term bleed prevention and target joint resolution, for severe hemophilia B.
Hemophilia B is an X-linked coagulopathy caused by absence of functional coagulation factor IX (F.IX). Previously, we established an experimental basis for gene transfer as a method of treating the ...disease in mice and hemophilic dogs through intramuscular injection of a recombinant adeno-associated viral (rAAV) vector expressing F.IX. In this study we investigated the safety of this approach in patients with hemophilia B. In an open-label dose-escalation study, adult men with severe hemophilia B (F.IX < 1%) due to a missense mutation were injected at multiple intramuscular sites with an rAAV vector. At doses ranging from 2 × 1011vector genomes (vg)/kg to 1.8 × 1012vg/kg, there was no evidence of local or systemic toxicity up to 40 months after injection. Muscle biopsies of injection sites performed 2 to 10 months after vector administration confirmed gene transfer as evidenced by Southern blot and transgene expression as evidenced by immunohistochemical staining. Pre-existing high-titer antibodies to AAV did not prevent gene transfer or expression. Despite strong evidence for gene transfer and expression, circulating levels of F.IX were in all cases less than 2% and most were less than 1%. Although more extensive transduction of muscle fibers will be required to develop a therapy that reliably raises circulating levels to more than 1% in all subjects, these results of the first parenteral administration of rAAV demonstrate that administration of AAV vector by the intramuscular route is safe at the doses tested and effects gene transfer and expression in humans in a manner similar to that seen in animals.
Summary
In the phase 3 B‐LONG (Recombinant Factor IX Fc Fusion Protein rFIXFc in Subjects With Haemophilia B) study, rFIXFc demonstrated a prolonged half‐life compared with recombinant factor IX ...(rFIX), and safety and efficacy for prophylaxis and treatment of bleeding in subjects with moderately‐severe to severe haemophilia B. In this B‐LONG sub‐analysis, rFIXFc was evaluated for efficacy in subjects requiring major surgery. Dosing was investigator‐determined. Assessments included dosing, consumption, bleeding, transfusions and haemostatic response. A population pharmacokinetics model of rFIXFc was used to predict FIX activity. Twelve subjects underwent 14 major surgeries (including 11 orthopaedic surgeries); most subjects (11/12) received rFIXFc prophylaxis before surgery (range, ~2 weeks–12 months). Investigators/surgeons rated haemostatic responses as excellent (n = 13) or good (n = 1). In most surgeries (85·7%), haemostasis from the pre‐surgical dose until the end of surgery was maintained with a single rFIXFc infusion. Blood loss was consistent with similar surgeries in subjects without haemophilia. The strong correlation (R2 = 0·9586, P < 0·001) between observed and population pharmacokinetic model‐predicted FIX activity suggests surgery did not impact rFIXFc pharmacokinetics. No unique safety concerns or inhibitors were observed. In conclusion, rFIXFc was safe and efficacious, with prolonged dosing intervals and low consumption, when used perioperatively in haemophilia B. Surgery did not appear to alter rFIXFc pharmacokinetics.
Introduction: The phase 3 B-LONG study (NCT01027364) demonstrated the safety, efficacy, and pharmacokinetics of recombinant factor IX Fc fusion protein (rFIXFc) for the prevention and treatment of ...bleeding episodes in adults and adolescents with severe hemophilia B. The ongoing rFIXFc extension study B-YOND (NCT01425723) is evaluating long-term safety and efficacy of rFIXFc in children and adults with hemophilia B. Safety and efficacy data for adult and adolescent subjects from the second B-YOND interim data cut are reported here.
Methods: The B-LONG study enrolled males aged ≥12 years with severe hemophilia B (≤2 IU/dL endogenous factor IX FIX activity) who had received prior treatment with FIX. Subjects completing B-LONG could enroll in 1 of 4 treatment groups in B-YOND: weekly prophylaxis (WP; 20-100 IU/kg every 7 d), individualized prophylaxis (IP: 100 IU/kg every 8-16 d), modified prophylaxis (MP; for subjects not achieving optimal prophylactic dosing with IP or WP), or episodic treatment (ET). Subjects could change treatment groups at any point in B-YOND. The primary endpoint was development of inhibitors (neutralizing antibody value ≥0.6 BU/mL as measured by the Nijmegen-modified Bethesda assay). Secondary outcomes included annualized bleeding rate (ABR) and rFIXFc exposure days (EDs). The incidence of adverse events (AEs), treatment of bleeding episodes, and weekly dosing and dosing intervals are also reported. Here, data are reported from the second interim data cut of B-YOND (11 September 2015) for subjects treated with ≥1 dose of rFIXFc.
Results: 93/115 subjects (81%) who completed B-LONG enrolled in B-YOND. As of the second interim data cut, 21 subjects had completed B-YOND, 61 subjects were ongoing in B-YOND, and 11 subjects had discontinued (1 due to lack of efficacy, 2 lost to follow up, 4 withdrawal by subject, and 4 other reasons). From the start of B-LONG to the second B-YOND interim data cut, subjects had a median 4.1 y of treatment with rFIXFc, and a median 181.0 cumulative rFIXFc EDs. In B-YOND, 68.8% of subjects had ≥100 EDs.No inhibitors were observed. The AE profile was typical of the hemophilia B population in a clinical trial and was generally similar to what is expected in the overall population of adults/adolescents with hemophilia B. There were no reports of serious allergic reactions or anaphylaxis associated with rFIXFc, and no thromboembolic events. 16/93 subjects (17.2%) enrolled in B-YOND changed treatment groups during the course of B-YOND, including 5 subjects who changed treatment groups from the start of B-YOND and then switched back to their original treatment group before the second interim data cut. 4/15 subjects changed from ET to prophylactic treatment. Among subjects treated prophylactically during B-LONG (n=71), 5.6% of subjects lengthened, 11.3% of subjects shortened, and 83.1% of subjects had no change to their dosing interval during B-YOND compared with their dosing interval in B-LONG. Overall, the median (interquartile range IQR) average dosing interval in the IP and MP groups was 13.8 (10.1-14.0) days and 6.9 (4.9-7.0) days, respectively. Compared with the end of B-LONG, the median (IQR) total weekly prophylactic dose was similar at the second B-YOND interim data cut (50.0 30.0-58.3 vs 50.0 40.0-60.0). Median (IQR) overall ABRs were low with rFIXFc prophylaxis (Figure). Median (IQR) spontaneous ABRs were also low in each prophylaxis group: WP, 1.2 (0.0-2.7); IP, 0.6 (0.3-1.9); MP, 0.3 (0.0-1.8); and ET, 3.8 (1.2-14.6). The majority of bleeding episodes were controlled with 1-2 intravenous infusions (WP: 96.9%; IP: 96.8%; MP: 96.5%; ET: 98.8%).
Conclusion: Interim data from adults and adolescents with severe hemophilia B treated with rFIXFc in B-YOND confirm the long-term safety of rFIXFc and maintenance of low ABRs with prophylactic dosing every 1-2 weeks.
This research was funded by Biogen and Sobi. Biogen and Sobi reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract and provided their final approval of all content.
Display omitted
Matsushita:CSL Behring: Honoraria, Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; KaketsuKen: Honoraria, Research Funding; JB: Honoraria, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mahlangu:Bayer: Research Funding, Speakers Bureau; Biogen: Consultancy, Research Funding, Speakers Bureau; CSL: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding; Amgen: Speakers Bureau; Biotest: Speakers Bureau; Baxalta: Consultancy. Shapiro:Kedrion Biopharma: Consultancy, Research Funding; Selexys: Research Funding; Octapharma: Research Funding; OPKO: Research Funding; ProMetic Life Sciences: Consultancy, Research Funding; PTC Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Biogen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Research Funding; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Research Funding; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pasi:Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Biogen: Consultancy, Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ragni:Baxalta: Research Funding; Genentech: Research Funding; Shire: Consultancy; Novo Nordisk: Research Funding; Biogen: Consultancy, Research Funding; CSL Behring: Research Funding; Biomarin: Consultancy; Alnylam Pharmaceuticals: Consultancy, Research Funding; SPARK: Research Funding; Tacere Benitec: Consultancy; OPKO: Research Funding; Vascular Medicine Institute: Research Funding. Ozelo:Novo Nordisk: Research Funding, Speakers Bureau; Bayer: Research Funding; Baxter: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Research Funding; Biogen: Research Funding. Baker:Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Other: Conference travel support ; Baxter: Other: Conference travel support , Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Astellas: Research Funding; CSL Behring: Research Funding; Biogen: Membership on an entity's Board of Directors or advisory committees. Yuan:Biogen: Employment, Equity Ownership. Ramirez-Santiago:Biogen: Employment, Equity Ownership. Ferrante:Sobi: Employment. Lethagen:Sobi: Employment.