Efficacy and Safety of BAY 94-9027 (Damoctocog Alfa Pegol) Prophylaxis in Patients with Severe Hemophilia a and Comorbidities: A Post Hoc Analysis of PROTECT VIII Data

Background: The availability of factor (F)VIII replacement products has dramatically improved life expectancy for patients with hemophilia A (HA). However, older patients face distinct challenges. Age-related comorbidities such as cardiovascular disease (CVD), often involving treatments that can increase the risk of bleeding, and patients who received treatment before the advent of recombinant products, are more likely to have been exposed to blood-borne viruses carrying chronic infections. It is important to understand clinical outcomes with FVIII products in patients with HA and these comorbidities. BAY 94-9027 (damoctocog alfa pegol; Jivi) is a B-domain deleted recombinant FVIII, site-specifically PEGylated with a 60 kDa (2×30 kDa) polyethylene glycol to extend its half-life. Efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe HA were demonstrated in the phase II/III PROTECT VIII trial and its Extension. This post hoc analysis assessed bleeding rates and safety outcomes for prophylaxis patients in PROTECT VIII and its Extension, based on the presence or absence of comorbidities of interest. Patients/Methods: PROTECT VIII (NCT01580293) was a partially randomized, open-label trial of 134 males aged 12-65 years with severe HA (FVIII <1%) and ≥150 FVIII exposure days. Prophylaxis patients (n=114) received BAY 94-9027 25 IU/kg twice weekly (2×W) for a 10-week run-in period. Patients with ≤1 spontaneous joint or muscle bleed during this period were randomized to 45-60 IU/kg every 5 days or 60 IU/kg every 7 days for the main 26-week study; patients enrolling after the randomization arms were full, or with ≥2 bleeds in the run-in period, received 30-40 IU/kg 2×W. Patients completing the main study could enter an extension, continuing BAY 94-9027 on any regimen used in the main study. Baseline characteristics, annualized bleeding rates (ABR) and safety were examined for patients on prophylaxis treatment during main study and its Extension with and without comorbidities of interest. Comorbidities included human immunodeficiency virus (HIV) infection, hepatitis B or C infection (HBV or HCV), and risk factors for CVD (hypertension, hypercholesterolemia, hypertriglyceridemia and hyperlipidemia). Results: A total of 104 patients who received BAY 94-9027 prophylaxis during the main study and the Extension (data cut-off: Jan 2018) were included in this analysis. Mean (SD) age of patients was 34.3 (13.0) years with a median (Q1;Q3) of 7 (2;15) bleeds in the 12 months before enrolment. Most patients (72.1%) had target joint(s) at baseline. Before study, 22 (21.2%) patients were receiving on-demand treatment; the remaining 82 were on regular prophylaxis. Most patients (n=66, 63.5%) had ≥1 comorbidity of interest. Of those, chronic HCV infection (HCV detection, asymptomatic) was most common (40/66, 60.6%), followed by acute HCV infection (HCV detection, symptomatic, 26/66, 39.4%), HBV infection (20/66, 30.3%), hypertension (17/66, 25.8%), hyperlipidemia (7/66, 10.6%), HIV infection (5/66, 7.6%), and hypertriglyceridemia (2/66, 3.0%). Patients with comorbidities of interest were older (mean age: 41.5 vs 21.9 years, respectively) and had a higher median (Q1;Q3) number of joint bleeds in the previous 12 months (5 [1;12] vs 3 [0;10], respectively) than patients without comorbidities (n=38). Pre-study, median ABR was 6.0 and 7.0 in patients with and without comorbidities of interest respectively, which decreased to 2.9 and 1.5 respectively during the main study, and further to 1.8 and 1.2 respectively during the Extension (Figure). In all patients with comorbidities of interest, robust improvements in median ABR were observed between the 12-month pre-study period and the main study period, and were maintained or improved in the Extension. Patients with comorbidities of interest had similar numbers of drug-related adverse events (AEs; 10.6% vs 23.7%), serious AEs (39.4% vs 28.9%) and discontinuations due to AEs (1.5% vs 2.6%) than those without comorbidities of interest during main study and Extension. Conclusions: The majority of patients (63.5%) in PROTECT VIII had ≥1 comorbidity of interest. The results from this post hoc analysis indicate that long-term BAY 94-9027 prophylaxis provided excellent control of bleed rates and was well tolerated in patients with severe HA and comorbidities of interest: HIV, HBV or HCV infection or risk factors for CVD. Figure Disclosures Miesbach: Biotest: Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Freeline: Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Grifols: Speakers Bureau; Biomarin: Consultancy, Honoraria; LFB: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; UniQure: Consultancy, Honoraria, Research Funding; CSL: Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Bayer: Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Di Minno:Sanofi: Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Kedrion: Speakers Bureau; CSL: Speakers Bureau; Pfizer: Speakers Bureau; Novo Nordisk: Speakers Bureau. Santagostino:Roche: Consultancy, Speakers Bureau; Octapharma: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Spark: Speakers Bureau; Kedrion: Consultancy, Speakers Bureau; Bioverativ: Consultancy, Speakers Bureau; UniQure: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; CSL: Consultancy, Speakers Bureau; Sanofi: Speakers Bureau. Klamroth:Bayer, Biomarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, Takeda: Consultancy; Bayer, Novo Nordisk, SOBI: Research Funding. Bayh:Bayer: Employment. Soto:Bayer: Employment. Hermans:LFB: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Octapharma: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Shire: Consultancy, Honoraria, Speakers Bureau; CAF-DCF: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; CSL: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Kedrion: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau.

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Characteristics of Bleed-Free Patients on Every-5-Day Dosing in the Protect VIII (BAY 94-9027) Study

Blood ◽

10.1182/blood-2018-99-116031 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2486-2486 ◽

Cited By ~ 1

Author(s):

Elena Santagostino ◽

Bryce A. Kerlin ◽

Claude Negrier ◽

Liu Tian ◽

Jonathan M. Ducore

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Severe Hemophilia ◽

Main Study ◽

Dose Frequency ◽

Open Label ◽

Advisory Committees ◽

Post Hoc Analysis ◽

Post Hoc

Abstract Background: BAY 94‐9027 is a B-domain-deleted recombinant factor VIII (FVIII) that is site-specifically PEGylated with a 60-kDa (2 x 30-kDa) polyethylene glycol (PEG) to extend its half-life. The efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe hemophilia A were demonstrated in the phase II/III PROTECT VIII trial, in which patients could receive prophylaxis every 7 days (E7D), every 5 days (E5D), or twice-weekly (2×W). Patients in the E5D arm had a low median annualized bleeding rate (ABR) of 1.9. This post hoc analysis was conducted to identify clinical predictors for 'best responders' (patients with ABR = 0) during E5D prophylaxis with BAY 94-9027 in PROTECT VIII. Methods: PROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with severe hemophilia A (FVIII < 1%) and ≥ 150 FVIII exposure days. Prophylaxis patients received BAY 94-9027 25 IU/kg 2×W for a 10-week run-in period. Patients with ≤ 1 spontaneous joint or muscle bleed during this period were randomized to 45‒60 IU/kg E5D or 60 IU/kg E7D for the main 26-week study period; patients enrolling after the randomization arms were full, or with ≥ 2 bleeds in the run-in period, received 30-40 IU/kg 2×W. All patients randomized to the E5D arm (n = 43) remained on this dose-frequency throughout the main study. This post hoc analysis presents a description of baseline characteristics of best responders to E5D dosing, defined as patients with ABR = 0 during the main study period; the study was not powered to support a formal statistical comparison. Results: Of 43 patients randomized to E5D dosing, 24 (55.8%) had ABR ≥ 1 and 19 (44.2%) had ABR = 0, meeting the criterion for best responders. The median (95% CI) age was slightly higher for best responders, 38 years [30.0; 47.0] versus 31.5 [24.0; 41.0]), than patients with ABR ≥ 1. In the 12 months prior to the study, best responders had lower median (95% CI) bleeds (2.0 [0.0; 5.0] versus 10.0 [3.0; 21.0]) and joint bleeds (0.0 [0.0; 2.0] versus 8.0 [2.0; 12.0]) compared with patients with ABR ≥ 1. Most patients in both groups had previously received prophylaxis prior to study (84.2% and 70.8%, respectively). Fewer best responders had target joints (57.9%, versus 70.8% of patients with ABR ≥ 1); and those who did have target joints only 36.4% had ≥ 1 target joint, versus 47.1% of patients with ABR ≥ 1. Conclusions: Overall, the 43 patients receiving BAY 94-9027 E5D prophylaxis had a low median ABR of 1.9. The 19 of these patients who had an ABR of 0 (best responders) had numerically fewer bleeds in the 12 months prior to treatment initiation, particularly joint bleeds, and numerically fewer target joints, vs patients with ABR ≥ 1. Though requiring validation in a powered study, taken together, these results suggest the applicability of E5D BAY 94-9027 dosing across patient profiles, and that patients with a similar bleed and joint profile to those analyzed here may be able to achieve ABR of 0 with E5D BAY 94-9027. Disclosures Santagostino: Bayer, Shire, CSL Behring, Pfizer, Novo Nordisk, Grifols, Kedrion, Sobi, Bioverativ, Octapharma, Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Negrier:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Sobi/Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tian:Bayer: Employment. Ducore:CSL Behring: Other: investigator; HemaBiologics: Consultancy, Other: investigator, travel support; OPKO: Other: investigator; Octapharma: Consultancy, Other: travel support, investigator , Research Funding; Bayer Healthcare: Consultancy, Other: travel support, investigator; Shire: Consultancy, Other: travel support, investigator; Pfizer: Other: investigator; Biomarin: Other: investigator; Spark Therapeutics: Consultancy, Other: investigator.

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Improvement of Efficacy Outcomes in Patients Who Switched from Sucrose-Formulated rFVIII to BAY 81-8973 Prophylaxis in the LEOPOLD Clinical Trials

Blood ◽

10.1182/blood-2020-137532 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 20-21

Author(s):

Gili Kenet ◽

Thomas Moulton ◽

Erika Soltes Rak ◽

Brian M. Wicklund ◽

Sanjay P Ahuja

Keyword(s):

Research Funding ◽

Hemophilia A ◽

Study Drug ◽

Study Cohort ◽

Efficacy And Safety ◽

Old Patients ◽

On Demand ◽

Adults And Children ◽

Previously Treated ◽

Bleeding Episodes

Background BAY 81-8973 (Kovaltry®) is a full-length, unmodified, recombinant factor VIII (FVIII), indicated for on-demand treatment and control of bleeding episodes, perioperative management of bleeding and routine prophylaxis to reduce the frequency of bleeding episodes in adults and children with hemophilia A. It has the same amino acid sequence as sucrose formulated FVIII (FVIII-FS; Kogenate® FS/Helixate® FS). Pharmacokinetic comparisons confirmed BAY 81-8973 to have a longer half-life and lower clearance than FVIII-FS. The objective of this analysis was to assess the efficacy and safety outcomes of patients with hemophilia A who were receiving FVIII-FS prior to enrolling into the LEOPOLD clinical studies receiving BAY 81-8973. Methods LEOPOLD I (NCT01029340) Part B and LEOPOLD Kids (NCT01311648) were Phase 3, multinational, open-label studies that included male patients with severe hemophilia A receiving on-demand or prophylactic therapy, with ≥50 exposure days to any FVIII product and no history of FVIII inhibitors. Patients in LEOPOLD I were >12 years old and received 20-50 IU/kg BAY 81-8973 prophylaxis twice-weekly (2×W) or three times a week (3×W) for up to one year. Patients in LEOPOLD Kids were ≤12 years old and received 25-50 IU/kg BAY 81-8973 ≥2×W for six months. Dosing regimens for both studies were assigned by the investigator. In this analysis, efficacy and safety are assessed in the subset of patients in LEOPOLD I Part B and LEOPOLD Kids who were previously treated with FVIII-FS. Results In LEOPOLD I, 22 (35.5%) patients were previously treated with FVIII-FS with a median age of 27.0; in LEOPOLD Kids, 24 (47.1%) patients were previously treated with FVIII-FS with a median age of 5.0 (Table 1). In general, these switch cohorts had similar patient demographics to the whole study cohort (Table 1) and any differences did not affect the final analysis. Most patients did not change their dosing frequency when starting treatment with BAY 81-8973 but most increased their dose (FVIII-FS dose is 25 IU/kg 3×W [adults] or every other day [EOD; children]; BAY 81-8973 dose is 25-40 IU/kg 2×W or 3×W [>12 years] or 25-50 IU/kg 2×W, 3×W or EOD [≤12 years]). Switching from FVIII-FS to BAY 81-8973 resulted in lower median annualized bleeding rates (ABRs) in the LEOPOLD studies. In LEOPOLD I, median (Q1; Q3) total ABR decreased from 2.5 (0.0; 9.0) in the 12 months of FVIII-FS treatment prior to study entry, to 1.0 (0.0; 6.8) (Figure 1). In LEOPOLD Kids, median total ABR decreased from 3.0 (1.0; 12.0) to 2.0 (0.0; 6.0) for 0-<6 year old patients (n = 13) and from 4.0 (0.0; 10) to 0.0 (0.0; 2.1) for 6-12 year old patients (n = 11) after switching from FVIII-FS to BAY 81-8973 (Figure 1). Joint and spontaneous median ABRs were zero for <12 year old patients treated with BAY 81-8973. There were no study-drug-related adverse events (AEs) or serious AEs (SAEs) reported in patients switching from FVIII-FS to BAY 81-8973 in either LEOPOLD I Part B or LEOPOLD Kids (Table 2). One patient in the LEOPOLD Kids main study discontinued BAY 81-8973 due to a central venous catheter-related infection after six months of treatment, which was not considered study-drug-related. No FVIII inhibitors developed in any patients in either study. Conclusions Switching from FVIII-FS to BAY 81-8973 resulted in improved bleeding control in adults and children with hemophilia A and was well-tolerated. Disclosures Kenet: PI Healthcare, CSL Behring: Honoraria; Bayer, Pfizer, Takeda, BioMarin, Novo Nordisk: Speakers Bureau; Bayer, Pfizer, Roche, Alnylam (Sanofi), Shire: Research Funding; Bayer, Pfizer, BioMarin, Takeda, Roche, Novo Nordisk, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Moulton:Bayer: Current Employment. Soltes Rak:Bayer: Other: Employee of Belcan, contracted with Bayer. Wicklund:Genentech: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Shire (Takeda): Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria. Ahuja:Genentech: Consultancy, Honoraria; Sanofi Genzyme: Consultancy, Honoraria; XaTek, Inc.: Consultancy, Patents & Royalties, Research Funding.

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Longitudinal Efficacy and Safety of N8-GP for Prophylaxis and Bleed Control in US Patients

Blood ◽

10.1182/blood-2021-147814 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3205-3205

Author(s):

Allison P. Wheeler ◽

Miguel A. Escobar ◽

Susan Kearney ◽

Janice M. Staber ◽

Adam R. Wufsus ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Treatment Success ◽

Efficacy And Safety ◽

Advisory Committees ◽

On Demand ◽

Routine Prophylaxis ◽

Previously Treated ◽

Extension Trial

Abstract Introduction: N8-GP is an extended half-life recombinant factor VIII product indicated for use in patients with hemophilia A. The pathfinder trials evaluated routine prophylaxis and bleed control in previously treated patients aged ≥12 years (pathfinder2) and patients aged <12 years (pathfinder5), including an extension trial (pathfinder8). The objective of the present analysis was to compare the efficacy and safety of N8-GP in US vs global (including US) patients. Methods: In the pathfinder2 trial, patients aged ≥12 years with severe hemophilia A were administered N8-GP 50 IU/kg every 4 days (Q4D) as routine prophylaxis or 20 to 70 IU/kg as on-demand treatment. Patients aged <12 years received prophylaxis with N8-GP 60 IU/kg twice weekly in the pathfinder5 trial, and bleeding episodes were treated with 20 to 75 IU/kg. In the pathfinder8 extension trial, the investigator decided on which treatment arm the patient should be allocated based on previous treatment regimen and taking into account bleeding tendency. Results: See Table for efficacy in prophylaxis (median annualized bleeding rates [ABRs]) and bleed treatment (success rate). Median ABRs tended to decrease from 0.84 (global) and 0.86 (US) in pathfinder2 to 0.00 (global) and 0.00 (US) in pathfinder8 in patients aged ≥12 years on the prophylaxis regimen. In addition, in patients aged <12 years, median ABRs decreased from 0.81 (global) and 0.76 (US) in pathfinder5 to 0.00 (global) and 0.49 (US) in pathfinder8. Treatment success rates for US patients were comparable to those for global patients across trials and 100% were rated "excellent" or "good" for patients aged <12 years in pathfinder8. Overall, there were 59 treatment-related adverse events (AEs) in patients on the prophylactic regimen in pathfinder2, 13 of which occurred in US patients, and 11 treatment-related AEs in patients treated on-demand, 3 of which occurred in US patients. In pathfinder5, there were 16 treatment-related AEs, 7 of which occurred in US patients. In pathfinder8, there were 6 treatment-related AEs in patients aged ≥12 years, 3 of which were in US patients. In addition, there was 1 treatment-related AE in a non-US patient aged <12 years. AEs included rash, redness, and injection site reactions. Across trials, 1 previously treated patient (an 18-year-old, from a US site) with an intron 22 inversion developed a low-titer inhibitor at 93 exposure days to N8-GP and was withdrawn when the titer progressed to >5 Bethesda units. The patient returned to their previous FVIII product, and their inhibitor status was negative at follow-up. Conclusions: Efficacy of N8-GP was sustained during the main and extension pathfinder trials in both global and US patients. In addition, a favorable safety profile was maintained throughout the course of the program. Figure 1 Figure 1. Disclosures Wheeler: Novo Nordisk A/S: Consultancy; Bayer: Consultancy; BioMarin: Consultancy; HEMA Biologics: Consultancy; Spark: Consultancy; Takeda: Consultancy; UniQure: Consultancy. Kearney: Grifols: Research Funding; Daiichi Sankyo: Research Funding; CVS Pharmacy: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Staber: Bayer, CSL Behring, Sanofi, Takeda: Membership on an entity's Board of Directors or advisory committees. Wufsus: Novo Nordisk Inc: Current Employment. Ostrow: Novo Nordisk Inc: Current Employment. Lentz: Novo Nordisk Inc: Consultancy, Honoraria, Research Funding.

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Decrease in Overall and Joint Bleeding Rates with Extended-Interval Dosing: > 4 Years of Bay 94-9027 Prophylaxis in the Protect VIII Extension

Blood ◽

10.1182/blood-2018-99-116272 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1206-1206 ◽

Cited By ~ 1

Author(s):

Mark T. Reding ◽

Shadan Lalezari ◽

Ingrid Pabinger ◽

Monica Maas Enriquez ◽

Jonathan M. Ducore

Keyword(s):

Research Funding ◽

Hemophilia A ◽

Extension Study ◽

Study Patient ◽

Severe Hemophilia ◽

Main Study ◽

Dose Frequency ◽

Open Label ◽

On Demand ◽

Intent To Treat

Abstract Introduction: BAY 94-9027 is a B-domain-deleted recombinant factor VIII (FVIII) that is site specifically PEGylated with a 60-kDa (2 × 30-kDa) polyethylene glycol (PEG) to extend its half-life. The efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe hemophilia A were demonstrated in the phase II/III PROTECT VIII trial. This analysis provides an updated assessment of the frequency of bleeds and joint bleeds with BAY 94-9027 prophylaxis during the PROTECT VIII trial and its extension of more than 4 years. Methods: PROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with severe hemophilia A (FVIII < 1%) and ≥ 150 previous exposure days (ED). Prophylaxis patients received 25 IU/kg twice weekly for a 10-week run-in period. Patients with ≤ 1 spontaneous joint or muscle bleed during this period were randomized to 45-60 IU/kg every 5 days (E5D) or 60 IU/kg every 7 days (E7D) for the main 26-week study period; patients enrolling after the randomization arms were full, or with ≥ 2 bleeds in the run-in period, received 30-40 IU/kg twice weekly (2×W). Following completion of the main PROTECT VIII trial, patients could enter an extension, continuing BAY 94-9027 prophylaxis on any regimen used in the main study. Prophylaxis patients who switched regimen after 7 days of the extension were analyzed together in a variable frequency group. Overall and joint annualized bleeding rates (ABRs) were calculated based on documentation in electronic patient diaries. Here, we present data for patients receiving prophylaxis. Results: The intent-to-treat population in the PROTECT VIII extension study included 121 subjects (prophylaxis, n = 107; on demand, n = 14) of the 134 patients previously included in the main study (13 did not continue into the extension). At data cut-off (31 January 2018), patients had spent a median time of 3.9 years in the study since enrolment. Patients in the prophylaxis arms had spent a median (range) of 1163 (449; 1579) days in the extension study (approx. 3.2 years), with a median of 211 (96; 318) ED. Most (71) patients had completed 3 years of treatment, 53 had completed 4 years and 33 had completed 5 years of treatment with BAY 94-9027. During the extension, most patients in the 2×W, E5D, or E7D groups did not change regimen (96%, 78% and 65%, respectively). Eleven patients (E5D, 7; E7D, 4) switched to 2×W treatment. Median ABR was 1.6 in prophylaxis patients in the extension, while median joint ABR was 0.9. These values were lower than ABRs during the 6-month main study, of 2.1 and 1.9 for ABR and joint ABR, respectively. In the extension, ABR remained low across all prophylaxis regimens (Table). These values were lower than ABRs for the corresponding treatment groups in the main study (Table). Joint ABR also remained low across extension study patient groups receiving different BAY 94-9027 prophylaxis regimens, and again this was lower than joint ABR in the main study for each group (Table). Conclusions: In the PROTECT VIII extension study, the majority (79/107, 74%) of prophylaxis patients remained on the same dose-frequency of BAY 94-9027during total time in the extension study. Median ABR and joint ABR were lower over the 3-5 years of extension study than in the main study for prophylaxis patients; this was true for the combined prophylaxis cohort and for the 2×W, E5D and E7D BAY 94-9027 prophylaxis groups. Bleed rates were lowest for patients who stayed in the E7D group. Taken together, these results demonstrate that the 2×W, E5D and E7D dose-frequency options for BAY 94-9027 prophylaxis allow patients a decreasingly low rate of bleeds and joint bleeds once treated with a suitable individual regimen. Disclosures Reding: Genentech: Other: Advisory Board. Pabinger:Bayer, Baxalta/Shire, Novo, Pfizer, Biotest, CSL Behring: Honoraria; CSL Behring and Novo.: Research Funding. Maas Enriquez:Bayer: Employment. Ducore:HemaBiologics: Consultancy, Other: investigator, travel support; OPKO: Other: investigator; CSL Behring: Other: investigator; Octapharma: Consultancy, Other: travel support, investigator , Research Funding; Pfizer: Other: investigator; Biomarin: Other: investigator; Spark Therapeutics: Consultancy, Other: investigator; Shire: Consultancy, Other: travel support, investigator; Bayer Healthcare: Consultancy, Other: travel support, investigator.

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Long-Term Risk Factors for Occult Cancer Detection in Patients with Unprovoked Venous Thromboembolism: A Post-Hoc Analysis of the Reverse Study

Blood ◽

10.1182/blood-2018-99-113023 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1230-1230

Author(s):

Nathan Cantor ◽

Marc Carrier ◽

Marc A. Rodger ◽

Gabrielle Veillet-Lemay ◽

Elham Sabri ◽

...

Keyword(s):

Risk Factors ◽

Venous Thromboembolism ◽

Cancer Diagnosis ◽

Research Funding ◽

Anticoagulation Therapy ◽

Post Hoc Analysis ◽

Occult Cancer ◽

Post Hoc ◽

D Dimer

Abstract Background: The diagnosis of an unprovoked (i.e., in the absence of any risk factors) venous thromboembolism (VTE) may be a sign of an underlying cancer. Previous estimates of the incidence rate of occult cancer in patients with unprovoked VTE are as high as 5-10%. However, screening methods to detect cancer early in these patients are of limited clinical value and previous identification of risk factors focused on short-term cancer diagnosis. Therefore, this study will assess the long-term incidence and risk factors of cancer in unprovoked VTE patients. Methods: This retrospective study is a post-hoc analysis of the REVERSE (Recurrent Venous Thromboembolism Risk Stratification Evaluation) study. Patient data was collected following an initial six-month course of anticoagulation therapy and were followed for a mean time period of 5.0 years (range 1 month-8 years). We performed univariable analysis to test the strength of association between each potential predictor variable and occult cancer diagnosis. Furthermore, using forward model selection we created a multivariable model with optimal predictive value for cancer diagnosis. Results: Among 663 patients presenting with unprovoked VTE, 38 (5.7%) subsequently developed a new cancer diagnosis during the follow-up period. The most common types of cancers diagnosed were prostate (21%) and colorectal cancer (16%). Univariate analysis revealed age > 65 (OR 2.59; 95% CI 1.31-4.49, P= 0.0036), elevated D-Dimer (OR 2.71; 95% CI 1.38-5.31, P=0.026) and pulmonary vein obstruction (PVO) score (OR 4.34 95% CI 1.26-14.92, P=0.023) as the strongest predictors of occult cancer. Only D-Dimer (Adj.-OR 2.72 95% CI 1.39-5.32) remained in the multivariate model and no other factor significantly improved the model's fit. Conclusion: Patients with an unprovoked VTE remain at an elevated risk of developing cancer following anticoagulation therapy. Age > 65 years old, elevated D-Dimer, and PVO in pulmonary embolism patients are among potential risk factors for developing occult cancer. More studies are needed to validate these potentially important risk factors. Disclosures Carrier: BMS: Honoraria, Research Funding; Leo Pharma: Research Funding; Pfizer: Honoraria; Bayer: Honoraria. Rodger:Biomerieux: Research Funding. Kovacs:Daiichi Sankyo Pharma Development: Research Funding; Bayer: Research Funding.

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Improved Bleeding Outcomes in Patients Who Switched From Sucrose-Formulated rFVIII to BAY 94-9027 Prophylaxis in PROTECT VIII

Blood ◽

10.1182/blood-2020-137565 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-7

Author(s):

Mark Reding ◽

Thomas Moulton ◽

Erika Soltes Rak ◽

Mindy L Simpson

Keyword(s):

Single Dose ◽

Adverse Events ◽

Half Life ◽

Research Funding ◽

Hemophilia A ◽

Main Study ◽

On Demand ◽

Study Enrollment ◽

Previously Treated ◽

To Receive

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.

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