scholarly journals Phase 4 Safety and Efficacy Study of Antihemophilic Factor (Recombinant) in Previously Treated Chinese Patients With Severe/Moderately Severe Hemophilia A

2021 ◽  
Vol 27 ◽  
pp. 107602962198981
Author(s):  
Yongqiang Zhao ◽  
Yu Hu ◽  
Jie Jin ◽  
Xielan Zhao ◽  
Xuefeng Wang ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Bleeding Event ◽  
Chinese Patients ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
Safety And Efficacy ◽  
On Demand ◽  
Previously Treated ◽  
Hemostatic Efficacy ◽  
Antihemophilic Factor

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

scholarly journals Interim Analysis of the Extension Study with rVIII-SingleChain in Previously Untreated Patients (PUPs) with Severe Hemophilia A (CSL627-3001)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 162-162
Author(s):  
Elena Santagostino ◽  
Kathelijn Fischer ◽  
Christoph Koenigs ◽  
Claudia Djambas Khayat ◽  
Samantha Lucas ◽  
...  
Keyword(s):  
Research Funding ◽  
Low Dose ◽  
Hemophilia A ◽  
High Titer ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
Safety And Efficacy ◽  
Inhibitor Development ◽  
On Demand ◽  
Peak Titer

Background: rVIII-SingleChain is a novel B-domain truncated recombinant Factor VIII comprised of covalently bonded FVIII heavy and light chains designed to have a high binding affinity to von Willebrand factor. Aims: This multicenter, open-label, phase III extension study investigates the safety and efficacy of rVIII-SingleChain for prophylaxis and on-demand treatment of bleeding episodes in 50 previously untreated patients (PUPs) for at least 50 Exposure Days (EDs). An ITI substudy was implemented to allow the use of rVIII-SingleChain to attempt inhibitor eradication for PUPs who develop an inhibitor to FVIII. Method: PUPs with severe hemophilia A (no prior exposure to any FVIII product, and endogenous Factor VIII <1%) were assigned by the investigator to a prophylaxis or on-demand treatment regimen. Inhibitors were assessed monthly. Patients diagnosed with an inhibitor to FVIII (two consecutive central laboratory [CL] results of ≥0.6 BU/mL) could be enrolled into the ITI substudy or remain in the main study. The ITI substudy regimens are: 50 IU/kg 3x/week (low), 100 IU/kg daily (medium), or 200 IU/kg daily (high). Inhibitor eradication was defined as two consecutive CL results of <0.6 BU/mL. One subject was withdrawn per protocol due to high titer inhibitor diagnosis prior to ITI substudy implementation. Results: As of March 28, 2019, 23 PUPs were treated with rVIII-SingleChain. Median age: 1 y (range 0-5). Mean (SD) time on study: 21.6 (12.6) months. Race distribution; Asian 2, Black 7, White 14. There have been 147 bleeding events treated with rVIII-SingleChain rated for hemostatic efficacy by the investigator. While patients were inhibitor negative, the overall treatment success (rating of excellent/good) was 93%, and the annualized spontaneous bleeding rate (AsBR) was 0.58. The adverse event profile was as expected, as the most frequently occurring adverse events were upper respiratory tract infections and inhibitors. Twelve subjects (52%) [95% CI 31%, 73%] were diagnosed with an inhibitor to FVIII; 6 (26%) high titer (peak titer ≥5 BU/mL), and 6 (26%) low titer (peak titer <5 BU/mL). Seven of 11 inhibitor negative subjects achieved >50 EDs, 1 achieved 47 EDs, and 3 achieved <20 EDs. The median ED for inhibitor development (initial result) was 10, range 4-23. All PUPs enrolled had ≥1 risk factor for inhibitor development (Table 1) including genetic mutation, age of first exposure, initial treatment reason and assigned regimen, as well as bleeding events and infections; inhibitor positive and negative subjects were comparable. Of the 12 inhibitor positive subjects, 11 continued treatment with rVIII-SingleChain, 7 were treated with approximately 50 IU/kg 3x/week (low dose ITI), 3 with an increased prophylaxis regimen, 1 with no change in regimen, and 0 with high or medium dose ITI regimen (Table 2). Eight of 11 (73%) inhibitor positive subjects (2 high titer, 6 low titer) achieved eradication; 5 low titer subjects were eradicated within 6 months. The clinically relevant inhibitor subjects (2 high titer, and 1 persistent low titer) achieved eradication in a median of 15.7 months, 2 using low dose ITI, and 1 using increased prophylaxis. Eradicated patients were negative for a median of 13.6 months, and no inhibitor relapse was observed. Three remaining inhibitor positive patients are early in their rVIII-SingleChain inhibitor treatment (2.1, 3.5, and 5.4 months). Detailed analysis of the antibody signature was performed, and revealed epitope isotypes and subclass distribution comparable to other FVIII molecules. Conclusion: Overall, rVIII-SingleChain demonstrates a positive benefit:risk profile for safety and efficacy in PUPs. The crude high titer inhibitor rate is 26% which is consistent with other rFVIII products, whereas the crude low titer inhibitor rate is currently 26% which is on the higher end in comparison to other rFVIII products. Immunological analyses suggest a low affinity antibody population in subjects with low titer inhibitors. The majority of subjects (73%) who continued treatment with rVIII-SingleChain achieved eradication on a low dose ITI or prophylaxis regimen of approximately 50 IU/kg 3x/week or less. Additional time on study for the currently enrolled subjects is required to determine the final inhibitor and eradication rates in PUPs treated with rVIII-SingleChain. Disclosures Santagostino: Pfizer: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Shire / Takeda: Consultancy, Speakers Bureau. Koenigs:Roche: Consultancy; CSL Behring: Research Funding, Speakers Bureau; Bayer Vital GmbH: Research Funding, Speakers Bureau; Biotest AG: Research Funding, Speakers Bureau; Intersero: Research Funding; Grifols: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Shire: Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau. Djambas Khayat:Novo Nordisk: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Lucas:CSL Behring: Employment. Salazar:CSL Behring: Employment. Brainsky:CSL Behring: Employment. Chung:CSL Behring: Employment. Goldstein:CSL Behring: Employment. Mahlangu:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Spark: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biomarin: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Unique: Research Funding; Catalyst Biosciences: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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 Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A

Blood ◽  
2015 ◽  
Vol 126 (9) ◽  
pp. 1078-1085 ◽  
Author(s):  
Barbara A. Konkle ◽  
Oleksandra Stasyshyn ◽  
Pratima Chowdary ◽  
David H. Bevan ◽  
Tim Mant ◽  
...  
Keyword(s):  
Adverse Events ◽  
Half Life ◽  
Hemophilia A ◽  
Full Length ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
On Demand ◽  
Key Points ◽  
Prevention And Treatment ◽  
Inhibitory Antibodies

Key Points BAX 855, a pegylated full-length rFVIII with extended half-life, was highly effective in the prevention and treatment of bleeding events. No subjects receiving BAX 855 developed FVIII inhibitory antibodies nor experienced unexpected adverse events.

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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1195-1195 ◽  
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.

Safety and Efficacy Profile of rAHF-PFM for Immune Tolerance Induction as Assessed In 3 Clinical Trials (PUP ITI, PRE-PAIR, and PAIR).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3670-3670
Author(s):  
Gerald Spotts ◽  
Brigitt E. Abbuehl ◽  
Huong D. Luu ◽  
Clara K. Song ◽  
Jacqueline A. Dyck-Jones ◽  
...  
Keyword(s):  
Safety Assessment ◽  
Chart Review ◽  
Hemophilia A ◽  
Retrospective Chart Review ◽  
Severe Hemophilia ◽  
Success Rates ◽  
Plasma Albumin ◽  
Safety And Efficacy ◽  
Antihemophilic Factor ◽  
Partial Success

Abstract Abstract 3670 Introduction: Development of neutralizing antibodies to FVIII is the most serious complication in the management of hemophilia A today. Eradication of the inhibitor with ITI therapy is a common treatment practice however, there are few reports of controlled studies, and much of the current ITI experience is reported from international registries and small site-based case studies. A previous case-series demonstrated successful tolerance in 9/12 (75%) patients using ADVATE [Antihemophilic Factor (Recombinant) Plasma/Albumin Free Method] (rAHF-PFM). Data on the safety and efficacy of rAHF-PFM in ITI therapy have now been formally captured in the recently completed Previously Untreated Patient (PUP-ITI) study, a retrospective chart review (PRE-PAIR), and an ongoing Prospective ADVATE ITI Registry (PAIR). Objectives: To provide a critical assessment of the safety and efficacy of rAHF-PFM in ITI therapy through a review of the cumulative data from PUP-ITI, PRE-PAIR, and PAIR. Methods: PUP study was a prospective, multicenter, open-label, clinical study in PUPs <6 years of age with severe or moderately severe hemophilia (FVIII level ≤2%) who underwent on-demand or prophylactic treatment with rAHF-PFM. Subjects who developed inhibitors against rAHF-PFM could enter the PUP-ITI study and receive ITI. PRE-PAIR was a multicenter, retrospective, chart review of PTPs of any age and any severity of hemophilia A with history of ITI with rAHF-PFM. PAIR is an ongoing non-interventional safety surveillance registry of subjects prescribed rAHF-PFM for ITI. In all three studies, the choice of ITI regimen was at the discretion of the investigator; however, for the PUP-ITI study, the ITI regimen was based on site-specific ITI data and/or institutional guidelines, or as described in peer reviewed literature. The primary endpoints for PUP-ITI and PRE-PAIR were the success rate of ITI. The PAIR report was an interim safety assessment that did not examine efficacy endpoints. For PUP-ITI and PRE-PAIR, the definitions of success required the subject to have achieved 2 consecutive negative inhibitor test results and if data available, demonstrated normalized FVIII recovery. For PRE-PAIR, partial success was defined as achieving negative titer but without normalized recovery. Results: In PUP-ITI, a total of 11 subjects initiated ITI; 3 withdrew and 8 completed ITI. In PRE-PAIR, 35 subjects were enrolled, 30 of which were evaluable per protocol. Of these 30 subjects, 20 had moderately severe to severe hemophilia A (FVIII ≤2%), and high-titer (>5 BU) inhibitor. As of Sept 4, 2010, 18 subjects had been enrolled in PAIR and were included in an interim safety assessment. Over all 3 studies, most commonly prescribed initial dose regimen in subjects with high inhibitor titer prior to initiation of ITI was 100 IU/kg QD (17/37 [46%]), followed by 200 IU/kg QD (11/37 [30%]), and any dose at a frequency of <1/day (9/37 [24%]). In the low titer inhibitor subjects the most commonly prescribed regimen were various doses with a frequency of <1/day (13/22 [59%] subjects). Of the 11 subjects in the PUP study who participated in the PUP-ITI study, 3 withdrew and 8 (72.7%) achieved success (95% CI: 43.4%, 90.3%). All 8 subjects (100%) achieved success, with 1st negative titer at a median time of 1.8 months (0.0 - 4.1 months) and the 2nd negative titer at 3.0 months (1.1 – 9.0 months). In PRE-PAIR, sum of complete and partial success rates gave a total success rate of 76.7% (23/30) in subjects who met inclusion criteria (95% CI: 59.1, 88.2%). During these 3 studies, there were no SAEs related to rAHF-PFM ITI therapy and 6 non-serious AEs in 3 subjects considered to be related to rAHF-PFM (diarrhea, vomiting, pain following bleed, mild urticaria, and mild fever). Conclusions: In 2 clinical studies of rAHF-PFM therapy in ITI treatment, rAHF-PFM was found to be efficacious in a variety of dosing regimens reflective of current standards of practice in hemophilia care. Overall success rates ranged from 72.7% in PUP-ITI to 76.7% in PRE-PAIR. Success rates in these 2 rAHF-PFM studies are similar to those reported in published literature. In all 3 ITI studies, there were no product related SAEs and 6 non-serious AEs in 3 subjects considered to be related to rAHF-PFM, suggesting that rAHF-PFM used for ITI has a similar risk profile established in routine clinical use. These data suggest that ITI treatment with rAHF-PFM was both effective and safe. Disclosures: Spotts: Baxter Bioscience: Employment. Off Label Use: ADVATE [Antihemophilic Factor (Recombinant) Plasma/Albumin Free Method] (rAHF-PFM)use in ITI therapy. Abbuehl:Baxter Bioscience: Employment. Luu:Baxter Bioscience: Employment. Song:Baxter Bioscience: Employment. Dyck-Jones:Baxter Bioscience: Employment. Guzman-Becerra:Baxter Bioscience: Employment. Wu:Baxter Bioscience: Employment. Oh:Baxter Bioscience: Employment. Zoerer:Baxter Bioscience: Employment. Sosa:Baxter Bioscience: Employment. Stephens:Baxter Bioscience: Employment. Yamamoto:Baxter Bioscience: Employment. Ewenstein:Baxter Bioscience: Employment.

Cost-Effectiveness of Prophylaxis with Anti-Inhibitor Complex Concentrate in Patients with Hemophilia A and Inhibitors: Results From the Pro-FEIBA Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4187-4187 ◽  
Author(s):  
Alessandro Gringeri ◽  
Cindy A. Leissinger ◽  
Paolo Cortesi ◽  
Hyejin Jo ◽  
Lorenzo Mantovani
Keyword(s):  
Body Weight ◽  
Cost Effectiveness ◽  
Incremental Cost ◽  
Hemophilia A ◽  
Bleeding Event ◽  
Incremental Cost Effectiveness Ratio ◽  
Cost Effectiveness Ratio ◽  
Bleeding Events ◽  
Patient Cost ◽  
On Demand

Abstract Abstract 4187 Introduction: Prophylaxis with anti-inhibitor complex concentrate (AICC; FEIBA NF, Baxter Healthcare Corporation, Westlake Village, CA) has been shown to safely and significantly decrease the frequency of joint and other bleeding events in patients with severe hemophilia A and inhibitors. Nonetheless, AICC prophylaxis is an expensive therapeutic intervention, and evidence of its cost-effectiveness is needed to guide healthcare decision-making in this era of global economic downturn. Methods: Hemophilia A patients >2 years of age with inhibitors and using bypassing therapy to treat bleeding were enrolled in a prospective, randomized, crossover study comparing 6 months of AICC infused prophylactically at a dose of 85U/kg ± 15% on 3 nonconsecutive days per week with 6 months of AICC used on-demand for bleeding episodes at a dose of 85 U/kg ± 15%. The 2 treatment periods were separated by a 3-month washout during which patients used on-demand therapy for bleeding. Clotting factor costs were quantitated in 2011 US dollars using the US price for US patients ($1.56 per unit) and the average price in Europe for European patients ($1.13 per unit). Results: Twenty-six subjects (median age 28.7 years; range, 2.8–62.8) completed both treatment periods and were evaluable per protocol for the cost-effectiveness analysis. The per-patient cost of 6 months of AICC prophylaxis was $493,633 compared with $205,549 for on-demand therapy. These totals were calculated by adding the per-patient cost of all clotting factors used during the prophylaxis period (AICC – $489,473 and recombinant activated factor VII [rFVIIa] – $4,160) and the on-demand period (AICC – $198,862473, rFVIIa – $6,272, and FVIII – $415). The incremental cost of AICC per bleed avoided during the prophylaxis period was $35,565, or $585/kg body weight for our somewhat older study population (mean body weight 60.8 kg). Sixteen of 26 subjects (62%) experienced a ≥50% reduction in bleeding events (“good responders”). For these subjects, the per-patient cost of 6 months of AICC prophylaxis was $499,453 as compared with $202,757 for on-demand therapy. The incremental cost-effectiveness ratio for the prophylaxis versus the on-demand period was $27,282 per bleeding event avoided ($449/kg body weight). In subjects with a <50% reduction in bleeding events, the per-patient cost of 6 months of AICC prophylaxis was $484,320 compared with $210,015 for on-demand therapy. The incremental cost-effectiveness ratio for the prophylaxis versus the on-demand period was $76,196 per bleeding event avoided. Discussion: The magnitude of the difference in factor costs during the prophylaxis and on-demand treatment periods was proportional to the corresponding difference in bleeding rate. During the on-demand period, factor cost was reduced by 58% compared with the prophylaxis period, whereas during the prophylaxis period, bleeding events were reduced by 62% compared with the on-demand period. The incremental cost effectiveness ratio was more favorable in good responders and is attributable to the marked difference in prophylactic efficacy. These costs do not reflect the potential benefits of prophylaxis, including fewer hospitalizations and days lost from work or school and prevention of long term complications, such as worsening joint disease and disability. After taking into consideration the bleeding rate, the cost of on-demand therapy is consistent with those previously reported in hemophilia A patients without inhibitors. The incremental cost of AICC per bleed avoided during the prophylaxis period suggests that prophylaxis may will be most cost-effective in those who experience a good response in bleed reduction and in children, who may also derive additional benefit through the prevention of joint disease and long-term disability. Disclosures: Gringeri: Baxter: Speakers Bureau. Leissinger:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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

Blood ◽  
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.

scholarly journals Indication, Resource Consumption and Clinical Outcomes of Prophylaxis in Adult Patients with Severe Hemophilia a in Routine Clinical Practice

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5052-5052
Author(s):  
María Eva Mingot-Castellano ◽  
Laura González-Díaz ◽  
Rocio Tamayo-Bermejo ◽  
Ana Isabel Heiniger-Mazo
Keyword(s):  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Adult Patients ◽  
Annual Rate ◽  
Joint Disease ◽  
Routine Practice ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
On Demand ◽  
Trough Levels

Abstract Background: Prophylaxis is the treatment of choice in patients with severe hemophilia A to prevent the development of haemophilic arthropathy and to preserve musculoskeletal function. In adult patients, there is no defined consensus on the indication, dose and frequency of prophylaxis. Because of the high cost of this scheme of treatment, it is basic to optimize it in routine practice. Objectives: To describe the profile of adult severe hemophilia A patients treated on prophylaxis, the reasons to indicate it and type of prophylaxis dose and frequency of infusions. In patients on tertiary prophylaxis, to assess the annual rate of bleeding and factor VIII (FVIII) consumption during prophylaxis scheme and to compare them with the period on demand. To analyze whether the implementation of programs of pharmacokinetics (PK) and trough levels adjustment optimize the results of prophylaxis. To evaluate adherence to prophylaxis and safety of this scheme of treatment. Patients and Methods: We included in our study adult patients (older than 18 years old) who suffer from severe hemophilia A (less than 1% of FVIII), with no history of inhibitor at the moment of the inclusion. These patients have been treated with a long term prophylaxis in our center between January 2006 and December 2013. We define the type of prophylaxis according to WFH criteria. Tertiary prophylaxis is defined by Petterson score higher than 3. The dose and frequency of prophylaxis is based on PK study. The program is a Bayesian PK analysis. FVIII levels were determined by one-stage method. Samples were taken 30 minutes (recovery, not used for PK), 6, 12, 24 and 48 hours after FVIII 50ui/kg infusion. After PK study, subjects were evaluated every two months to adjust scheme of treatment using trough FVIII levels between 1% and 3% in absence of bleeding. After getting the established dose, patients were reviewed every 6 months. Adherence has been calculated as a percentage (number of weeks each year with the right dose and frequency of infusions divided into the number of weeks of the year in which the subject has no active bleeding or is subjected to invasive procedures, then multiply the result by 100). 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. Our Centre Ethics Committee approved the project. Everything has been done according to the Declaration of Helsinki. Patients signed written informed consent. Results: We evaluated 18 patients, median age at starting prophylaxis 30 years old (IQR, 17 to 40.5 years old). The type of prophylaxis was primary in 2 patients, secondary in 2 and tertiary in the rest. The reasons to indicate tertiary prophylaxis included prevent progression of hemophilia joint disease (11), central nervous system haemorrhage (2) and antiplatelet drugs needed because of stroke (1). 16 patients have been treated with recombinant FVIII and 2 with plasma derived FVIII. FVIII individual patient dose was calculated based on PK study (mean volume of distribution 51.1±6.0 mL/kg, half-life 13.2 ±5.8 hours and plasma clearance 3.0 ±1.0 mL/kg). Prophylaxis dose frequency was twice a week (8), three times a week (7) and every 48 hours (3). No dose increases were required after trough levels adjustment. Thanks to through levels adjustment, FVIII consumption of these patients was reduced in 31.3%. Tertiary prophylaxis reduces annual rate of bleedings in 88.3% (mean 2.3 on prophylaxis vs 20.8 on demand, p <0.0001). Median annual consumption of FVIII in patients on tertiary prophylaxis was 2557.8 IU/kg/year vs 1696.8 IU/kg/ year on demand period (p. 0.312). This 50,7% increase in FVIII consumption is smaller if the indication of tertiary prophylaxis is the prevention of joint disease. In this case the increase in consumption is 24.5%. The median adherence was 84% (IQR, 69-95%), with no difference between types of prophylaxis (p, 0.125). We report no adverse events. Conclusions: In our experience, the majority of adult patients with hemophilia A are on tertiary prophylaxis. In this group of patients, prophylaxis reduces ostensibly the incidence of bleedings but with a higher economic cost. The reason to indicate a scheme of prophylaxis may change the cost-effectiveness of this treatment. Adult patients have a good adhesion to treatment, similar to the one reported in children. Disclosures No relevant conflicts of interest to declare.

scholarly journals Immunogenicity, Efficacy and Safety of Rurioctocog Alfa Pegol in Previously Untreated Patients with Severe Hemophilia a: Interim Results from an Open-Label Multicenter Clinical Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3184-3184
Author(s):  
Robert F. Sidonio ◽  
Christine Knoll ◽  
Flora Peyvandi ◽  
Oleksandra Stasyshyn ◽  
Ali Bulent Antmen ◽  
...  
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Publicly Traded ◽  
Open Label ◽  
Inhibitor Development ◽  
On Demand ◽  
Fviii Inhibitor ◽  
Hemostatic Efficacy ◽  
Recombinant Fviii

Abstract Background Management of severe hemophilia A includes on-demand treatment or prophylaxis with replacement factor VIII (FVIII) concentrate. FVIII inhibitors can develop following exposure to exogenous FVIII in approximately 30% of previously untreated patients (PUPs), typically in the first 50 exposure days (EDs), with serious complications. This is the first study evaluating the safety, immunogenicity, and hemostatic efficacy of rurioctocog alfa pegol (Adynovate ®; Baxalta US Inc., a Takeda company, Lexington, MA, USA), an extended half-life (EHL) recombinant FVIII, in PUPs with severe hemophilia A. Methods This prospective, open-label, multi-center, phase 3 study (NCT02615691) was conducted in patients ˂6 years of age with severe hemophilia A (FVIII &lt;1%). Patients were previously untreated, or had &lt;3 EDs to rurioctocog alfa pegol, octocog alfa, or plasma transfusion at any time prior to screening. Patients with detectable FVIII inhibitory antibodies at screening or a history of FVIII inhibitory antibodies prior to screening (≥0.6 Bethesda units) were not eligible. Patients received intravenous rurioctocog alfa pegol as prophylaxis (25-50 IU/kg, up to 80 IU/kg ≥1 × weekly) and/or on-demand therapy (10-50 IU/kg, up to 80 IU/kg depending on bleed severity). Prophylaxis was started before 3 years of age or after a maximum of 2 joint bleeds, whichever occurred first. The primary endpoint was the incidence of FVIII inhibitor development. Secondary endpoints included safety and efficacy (annualized bleeding rate [ABR] and hemostatic efficacy). This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing an inhibitor to FVIII or had developed a confirmed FVIII inhibitor at any time. The data cut-off was 30 August 2019. Demographic and baseline characteristics were summarized using continuous and categorical data. The incidence of FVIII inhibitor development was calculated using the Clopper Pearson exact 95% CI computed for the proportion of patients who developed FVIII inhibitors during the study. ABR was analyzed by point and interval estimates derived from a negative binomial model with treatment regimen as a covariate. The number and percentage of patients reporting adverse events (AEs) and serious AEs (SAEs) was recorded for all patients receiving rurioctocog alfa pegol. Informed consent and ethics approval were obtained. Results As of the data cut-off, 59 (73.8%) of 80 enrolled patients had received ≥1 dose of rurioctocog alfa pegol; 18 patients (screen failures) did not meet the eligibility criteria and 4 discontinued prior to treatment. 54 patients received prophylaxis and 35 received on-demand treatment at any time during the study period. The mean (SD) patient age at baseline was 11.8 (8.2) months. The number of patients with 0 EDs prior to screening was 36 (61.0%), with 9 (15.3%) patients having 1 ED and 14 (23.7%) having 2 EDs. Overall, 32 patients had a family history of hemophilia A. A large deletion, intron 1 or intron 22 inversion, or substitution nonsense hemophilia gene mutation was present in 29 (49.2%) patients and 21 (35.6%) had either a small deletion, small duplication, or substitution missense gene mutation. Of the 52 patients who qualified for this interim analysis, 10 developed an inhibitory antibody to rurioctocog alfa pegol during the study; the incidence of inhibitor development was 0.192 (95% CI, 0.096-0.325) (10/52). Rurioctocog alfa pegol exposure data and ABRs for patients receiving prophylaxis or on-demand treatment are presented in Table 1. At bleed resolution, hemostatic efficacy was rated by patients as "excellent" for 88/269 bleeds (32.7%) and "good" for 73/269 bleeds (27.1%). Overall, 52 (88.1%) patients receiving rurioctocog alfa pegol experienced a total of 283 AEs, and 13 patients experienced 14 rurioctocog alfa pegol-related AEs (including 10 SAEs). SAEs occurred in 24 patients, 10 of whom experienced 10 treatment-related SAEs of FVIII inhibitor development. Discussion This is the first prospective study of the EHL recombinant FVIII rurioctocog alfa pegol for the treatment of PUPs with severe hemophilia A. These preliminary results demonstrate a relatively low inhibitor rate compared with other EHL recombinant FVIII products and a safety and efficacy profile consistent with that previously observed for rurioctocog alfa pegol in the treatment of bleeding episodes in patients with hemophilia A. Figure 1 Figure 1. Disclosures Sidonio: Guardian Therapeutics: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy; Biomarin: Consultancy; Genentech: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Catalyst: Consultancy. Peyvandi: Takeda: Honoraria; Spark: Honoraria; Sobi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Roche: Honoraria; Bioverativ: Honoraria; Grifols: Honoraria. Stasyshyn: Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding; Shire: Consultancy; Grifols: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau. Antmen: Takeda: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Novo Nordisk: Consultancy. Yeoh: Takeda: Honoraria; Pfizer: Honoraria; Roche: Honoraria; Grifols: Honoraria. Maggiore: IQVIA: Current Employment. Engl: Baxalta Innovations GmbH, a Takeda company: Current Employment; Takeda: Current equity holder in publicly-traded company. Allen: Takeda Development Center Americas, Inc.: Current Employment; Takeda: Current equity holder in publicly-traded company. Tangada: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc: Current Employment.

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