Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A
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.
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.
Key Points A novel recombinant factor VIII with prolonged half-life, rFVIIIFc, was developed to reduce prophylactic injection frequency. rFVIIIFc was well-tolerated in patients with severe hemophilia A, and resulted in low bleeding rates when dosed 1 to 2 times per week.
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.
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.
Abstract Introduction and Objective: Patients with severe hemophilia A repeatedly bleed into joints and subsequently develop target joints and arthropathy. BAX 855, a polyethylene glycol pegylated, full-length, recombinant factor VIII built on ADVATE, demonstrates an extended half-life, efficacy, and safety for prophylaxis and the treatment of bleeding in patients with severe hemophilia A. Target joint status was evaluated in an ad-hocanalysis of integrated efficacy data from previously treated adolescent and adult patients who participated in the pivotal (completed) and continuation (ongoing) studies. Methods: The number of target joints, defined as a single joint with ≥3 spontaneous bleeding episodes in any consecutive 6-month period, were analyzed over 3 consecutive 6-month periods in patients who received twice weekly BAX 855 prophylaxis at 40-50 IU/kg. Results: After approximately 6 months of twice weekly prophylaxis during the pivotal study, 101 adolescent and adult patients continued treatment in the continuation study, 51 of whom were treated with twice weekly prophylaxis for 18 consecutive months. At screening 29.4% (15/51) of these patients had no target joints, 19.6% (10) had 1 target joint, 21.6% (11) had 2, and the remaining 29.4% (15) had 3 or more. After the first 6-month treatment period, the percent of patients with no target joints increased to 66.7% (34 patients), including 19 patients in whom 1 or more target joints had resolved and 15 patients who remained target joint-free from screening. Of note, for the 15 patients with 3 or more target joints at screening, all of their target joints resolved after the first 6 months of treatment with BAX 855. This trend was maintained after the second 6-month treatment period. After the third 6-month period of twice weekly prophylaxis, the percent of patients with no target joints further increased to 82.4% (42), which included the 15 patients who remained target joint-free from screening. Nine patients had 1 or more unresolved target joint after 18 months of twice weekly prophylaxis, and in 6 of these patients, 1 to 3 other target joints had resolved. Overall, there were 89 target joints at screening which reduced to 14 after 18 months of twice weekly prophylaxis. Of those, 10 target joints changed status (eg, were present, resolved, and then re-appeared) and only 4 target joints (in 4 patients) persisted as unresolved through each of the 3 consecutive 6-month treatment periods. Conclusions: These results demonstrate the efficacy of continuous twice weekly prophylaxis with BAX 855 for preventing and resolving the majority of target joints. Disclosures Engl: Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Patrone:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Abbuehl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership.
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.
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.
Background BAY 94-9027 (damoctocog alfa pegol; Jivi®) is a B-domain-deleted recombinant factor VIII (FVIII), site-specifically PEGylated to extend its half-life compared with standard-half-life FVIII products, including sucrose formulated FVIII (FVIII-FS; Kogenate® FS/Helixate® FS). A previous pharmacokinetic study confirmed longer half-life and lower clearance with a single dose of BAY 94-9027 compared with a single dose of FVIII-FS. The phase 2/3 PROTECT VIII study (NCT01580293) demonstrated the efficacy, safety and utilization of BAY 94-9027 as prophylactic and on-demand therapy for adolescents and adults with severe hemophilia A, including during major and minor surgeries. This post hoc subgroup analysis of PROTECT VIII aimed to assess the efficacy and safety outcomes of patients with hemophilia A who were receiving FVIII-FS as FVIII replacement therapy prior to study enrollment. Methods In PROTECT VIII, 134 patients were treated with BAY 94-9027 for the main, 36-week study period. Patients with ≤1 breakthrough bleed during a 10-week run-in period treated with BAY 94-9027 25 IU/kg twice-weekly (2×W) prophylaxis were considered eligible for randomization and were thus randomized to receive BAY 94-9027 45-60 IU/kg every 5 days (E5D) or 60 IU/kg every 7 days (E7D) for the 26-week study period. Patients with >1 bleed, and thus ineligible for randomization (IFR), and those eligible for randomization but enrolled after randomized arms were full (EFR), were assigned to a 30-40 IU/kg 2×W regimen (Figure 1). In total, 114 patients received BAY 94-9027 prophylaxis and 20 patients were treated on-demand. Patients who completed the main study could enter into an optional extension, in which they could continue to receive BAY 94-9027 on any PROTECT VIII study regimen. This present analysis was designed to assess annualized bleeding rates (ABR), adverse events and FVIII utilization of a subset of PROTECT VIII patients who were previously treated with prophylaxis or on-demand FVIII-FS. Pre-study ABRs were based on patient recall of bleeding events during the 12 months prior to study entry. Results Of the 114 patients who received BAY 94-9027 prophylaxis in the PROTECT VIII main study period, 38 (33.3%) patients were previously treated with FVIII-FS (29 received prior prophylaxis, 9 received prior on-demand treatment) (Table 1). Of these, 8 (21%), 19 (50%) and 11 (29%) patients were treated with 2×W (n = 4 IFR; n = 4 EFR), E5D and E7D BAY 94-9027 regimens in PROTECT VIII, respectively. For patients treated with either prophylactic or on-demand FVIII-FS treatment in the 12-month pre-study period and who were eligible for randomization, median total and joint ABRs decreased during Weeks 10-36 with BAY 94-9027 2×W (EFR), E5D and E7D prophylaxis regimens (Figure 2). In the 29 patients who switched from FVIII-FS prophylaxis regimens only prior to PROTECT VIII study entry, median (Q1; Q3) total ABRs also decreased from 7.0 (1.0; 14.0) pre-study to 0.0 (0.0; 2.1), 2.1 (0.0; 4.2), and 4.3 (0.0; 5.7) with BAY 94-9027 2×W (EFR), E5D and E7D prophylaxis regimens, respectively. Median joint ABRs also decreased in patients who were previously treated with prophylaxis regimens only with FVIII-FS, from 3.5 (0.0; 8.5) pre-study to 0.0 (0.0; 2.1), 1.1 (0.0; 4.0), and 2.2 (0.0; 5.7) with BAY 94-9027 2×W (EFR), E5D and E7D prophylaxis regimens during the main study period, respectively. The median dose of BAY 94-9027 administered per infusion in patients who switched from either on-demand or prophylaxis regimens of FVIII-FS was 38.7 IU/kg. One patient who switched from FVIII-FS discontinued BAY 94-9027 during PROTECT VIII due to an acute, resolved, hypersensitivity episode occurring after the start of the first infusion; no study-drug-related serious adverse events were reported. Overall, of patients who were treated with FVIII-FS in the 12 months prior to PROTECT VIII study enrollment, BAY 94-9027 was well-tolerated and the safety profile was similar to that of the overall prophylaxis patient population in PROTECT VIII (Table2). Conclusions Prophylaxis with BAY 94-9027 resulted in lower median total and joint ABRs compared with prior prophylaxis or on-demand treatment with FVIII-FS, resulting in improved efficacy with a similar safety profile. Disclosures Reding: Takeda: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; BioMarin: Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Moulton:Bayer: Current Employment. Soltes Rak:Bayer: Other: Employee of Belcan, contracted with Bayer. Simpson:HEMA Biologics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Bioverativ/Sanofi: Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; CSL Behring: Consultancy, Honoraria.
Introduction: The standard of care for patients with hemophilia A without inhibitors is factor VIII (FVIII) replacement therapy. The availability of non-factor therapy such as emicizumab (Hemlibra®; Genentech, Inc., South San Francisco, CA, USA) is changing the treatment landscape. A model was developed from the perspective of the US healthcare system to compare the cost-effectiveness of recombinant FVIII (rFVIII) products (standard half-life [SHL] and extended half-life [EHL]) versus non-factor therapy emicizumab in the treatment of patients with severe hemophilia A without inhibitors. Methods: The Markovian model used in this analysis included 5 mutually exclusive hemophilia A-related health states: with/without target joints (TJs), with/without arthropathy, and death. Health states changed or remained constant, depending on bleeds and recovery probability. Transition to the health state "death" was derived from mortality rates in the general US population according to age. Each health state was associated with costs and utilities that were summed over time. Estimated total costs and treatment effectiveness as measured by quality-adjusted life years (QALYs; a measure of health outcome that incorporates the impact on both quantity and quality of life) for each health state were then used to calculate incremental cost-effectiveness ratios for pairwise comparisons of treatments (prophylaxis or on-demand for a pooled analysis of 6 rFVIII products [SHL and EHL] vs emicizumab prophylaxis; Table 1) over a life-time horizon. Patient data used in the model were based on a systematic literature review and clinical trial results, and network meta-analysis. Model parameters included patient baseline characteristics, change in body weight by age, prior prophylaxis or on-demand treatment, annualized bleeding rate (ABR), probability of developing or resolving TJs or arthropathy, mortality, number infusions per bleed, medical check-ups, and hospitalization. Based on these data, patients in the model were assumed to be male and 33 years of age at baseline; 72.0% had TJs and 58.4% had arthropathy. Probability of developing TJs per joint bleed was estimated to be 0.9% (prophylaxis and on-demand treatment). Probability of developing arthropathy per joint bleed was estimated to be 2.2% for patients who received prior on-demand treatment and patients who received prior prophylaxis were assumed to have no risk of developing arthropathy. The model assumed life-long adherence to the same prophylactic hemophilia treatment. Drug cost was based on 2018 average sales price and dosing was on label. The model did not include treatment-specific adverse events or inhibitor development. Results: Prophylaxis with rFVIII (SHL and EHL) was estimated to be less costly and more effective (total $13,656,238; QALYs 17.61) versus non-factor prophylaxis with emicizumab (total $16,447,843; QALYs 17.58) over an estimated 70-year lifespan of a patient with severe hemophilia A, which suggests rFVIII prophylaxis is an economically preferable strategy. Total cost consists of costs directly related to prophylactic treatment (rFVIII $12,850,894 vs emicizumab $15,555,379) and costs associated with healthcare resources (rFVIII $805,344 vs emicizumab $892,464). rFVIII prophylaxis was also estimated to be less costly and more effective (total $13,656,238; QALYs 17.61) versus on-demand rFVIII treatment (total $13,823,123; QALYs 12.29). Conclusions: In this pooled analysis of select SHL and EHL rFVIII products, the results suggest that rFVIII prophylaxis is a cost-effective long-term intervention for patients with severe hemophilia A without inhibitors compared with non-factor prophylaxis with emicizumab and on-demand rFVIII treatment. Disclosures Sun: Shire US Inc., a Takeda company: Employment, Other: a Takeda stock owner. Wu:Shire US Inc., a Takeda company: Employment, Other: a Takeda stockowner. McDermott:BresMed Health Solutions Ltd.: Employment. van Keep:BresMed Health Solutions Ltd.: Employment.
Abstract Background Turoctocog alfa is a B-domain truncated recombinant factor VIII (rFVIII) product for the prevention and treatment of bleeds in patients with hemophilia A. The ongoing guardian™2 trial using turoctocog alfa consists of a main trial with planned visits, a surgery subtrial for patients who need to undergo surgery during the main trial, and an on-demand subtrial based on a regulatory requirement to collect data for at least 10 patients treated on-demand for 6 months. The guardian™2 trial is an open-label, prospective, international extension to pivotal trials in adults and adolescents (aged 12-65 years; guardian™1) and children (aged <12 years; guardian™3). Patients who completed the pharmacokinetic trials (NN7008-3600, NN7008-3893, or NN7008-4015), and new patients involved in the on-demand subtrial, also participated in guardian™2. We report an analysis of new long-term safety and efficacy data from the main guardian™2 trial and on-demand subtrial of turoctocog alfa. Methods Male patients with severe hemophilia A (FVIII ≤1%) without inhibitors (<0.6 Bethesda units [BU]) were enrolled from 19 countries. Turoctocog alfa was used prophylactically (20-50 IU/kg every second day or 20-60 IU/kg three times weekly) and on-demand (20-200 IU/kg/day) to treat bleeds. The primary safety endpoint was inhibitor development (≥0.6 BU/mL). All adverse events were reported. The main efficacy endpoints included hemostatic success when treating bleeds (excluding patients with missing evaluations), number of turoctocog alfa infusions required to stop bleeds, annualized bleeding rate (ABR), and consumption of turoctocog alfa. Safety and efficacy were assessed at the interim cut-off date, March 25, 2015. Results Prophylaxis and on-demand treatment were received by 199 and 19 patients, respectively (equivalent to 589 and 12.5 years of exposure to turoctocog alfa, respectively). Turoctocog alfa was used to treat 1508 bleeds in 162 patients receiving prophylaxis, and for 320 bleeds in 19 patients receiving on-demand treatment. No FVIII inhibitors, hypersensitivity, allergic reactions, or other safety concerns were reported in the main trial or on-demand subtrial for any patients. Treatment of bleeds was successful ('excellent' or 'good' response) in 90% of patients receiving prophylaxis and in 97% of those treated on-demand; the overall proportion of bleeds stopped with 1-2 injections was 90.7%, and 95.7% taking up to three injections. The median ABR (bleeds/patient/year) was 1.48 (mean Poisson estimated ABR: 2.56) for patients treated prophylactically, and 30.3 (mean Poisson estimated ABR: 25.56) for patients treated on-demand. Mean turoctocog alfa consumption (IU/kg/year/patient) was 5335 for patients on prophylaxis and 1707 for patients treated on-demand. Mean prophylactic dose was 32 IU/kg. Mean dose for treatment of bleed from start to stop was 61 IU/kg for patients on prophylaxis and 44 IU/kg for patients treated on-demand. Conclusion The latest data from the ongoing guardian™2 trial demonstrate the long-term safety and efficacy of turoctocog alfa for the prevention and treatment of bleeds in patients with severe hemophilia A. No FVIII inhibitors or other safety concerns have been reported. Compared with on-demand treatment, prophylaxis resulted in ~3-fold higher consumption of turoctocog alfa, and a 90% reduction in bleed rates. Disclosures Janic: Pfizer: Other: Paid Instructor, Research Funding; Bayer: Other: Paid Instructor, Research Funding; Baxter: Other: Paid Instructor, Research Funding; Novo Nordisk: Other: Paid Instructor, Research Funding; Octopharma: Research Funding. Matytsina:Novo Nordisk: Employment. Misgav:Novo Nordisk: Speakers Bureau. Ozelo: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; Novo Nordisk: Research Funding, Speakers Bureau. Recht:Kedrion: Consultancy; Biogen Idec: Research Funding; Novo Nordisk: Consultancy, Research Funding; Baxalta: Research Funding. Korsholm:Novo Nordisk: Employment, Equity Ownership. Savic:Novo Nordisk: Other: Investigator. Santagostino:Novo Nordisk: Consultancy; Pfizer: Consultancy; Grifols: Consultancy; Sobi: Consultancy; Baxalta: Consultancy; Roche: Consultancy; CSL Behring: Consultancy; Kedrion: Consultancy; Octapharma: Consultancy; Biogen Idec: Consultancy; Bayer: Consultancy.
