Bleeding Phenotype with Various Bay 94-9027 Dosing Regimens: Subanalyses from the Protect VIII Study

Abstract Introduction: Factor VIII (FVIII) products with a longer half-life may allow for longer intervals between treatments for patients with hemophilia A and may facilitate prophylaxis tailored to an individual’s bleeding phenotype. BAY 94-9027, a PEGylated FVIII product, demonstrated an extended half-life in a phase 1 trial and was well tolerated and efficacious in a phase 2/3 study with dosing intervals up to every 7 days. In this subanalysis of the phase 2/3 trial, bleeding frequency calculated based on the BAY 94-9027 prophylactic dosing regimen during the study was compared with reported bleeding frequency in the 12 months before enrollment. Also, on-study annualized bleeding rates (ABRs) for joint, spontaneous, and trauma bleeds are presented by treatment group. Methods: PROTECT VIII was a multinational, partially randomized, open-label, 36-week study in previously treated patients aged 12–65 years with severe hemophilia A and no history of FVIII inhibitors. Patients received BAY 94-9027 for 36 weeks either on demand or prophylactically. Patients were assigned to 1 of 3 prophylaxis dosing regimens based on the number of bleeds observed during a 10-week run-in period, during which all patients in the prophylaxis arm were treated with 25 IU/kg BAY 94-9027 2x/week. Patients with ≤1 breakthrough bleed during the 10-week period were randomized 1:1 to BAY 94-9027 45–60 IU/kg every 5 days or 60 IU/kg every 7 days. Patients with ≥2 breakthrough bleeds received 30–40 IU/kg BAY 94-9027 2x/week. ABR and annualized joint bleeding rate (AJBR) for the 12 months before the study (collected retrospectively at screening) were compared with values calculated in patients previously treated with prophylaxis who used BAY 94-9027 prophylaxis during the study (weeks 0–36 for the combined prophylaxis groups [including the 10-week period]; weeks 10–36 for the 3 assigned prophylaxis dosing regimens). ABRs for joint, spontaneous, and trauma bleeds during the study were analyzed for the on-demand and combined prophylaxis groups (weeks 0–36) and in relation to patients’ BAY 94-9027 dosing regimen (weeks 10–36). Results: The intent-to-treat population comprised132 patients (prophylaxis, n=112; on demand, n=20). In patients previously treated with prophylaxis, median ABR and AJBR during BAY 94-9027 prophylaxis (weeks 0–36) were lower than corresponding prestudy values; ABR and AJBR during weeks 10–36 for every-5-day, every-7-day, and 2x/week BAY 94-9027 dosing were also lower than or comparable to prestudy values (Table). Median ABRs for joint, spontaneous, and trauma bleeds were lower for the combined prophylaxis groups (weeks 0–36) compared with the on-demand group (combined prophylaxis groups: 1.5, 1.4, and 0.0, respectively; on-demand group: 16.3, 14.3, and 9.1). In the prophylaxis arms (weeks 10–36), median ABRs for joint, spontaneous, and trauma bleeds were 2.1, 0.0, and 0.0 for 2x/week dosing; 1.9, 0.0, and 0.0 for every-5-day dosing; and 1.9, 1.9, and 0.0 for every-7-day dosing. Abstract 1526. Table. Bleeding Frequency During BAY 94-9027 Prophylaxis vs Prestudy Values Combined Prophylaxis, 2x/week, week 10–36 Every 5 Days, Every 7 Days, week 0–36(n=87)* Required† (n=9) Not Randomized‡ (n=6) week 10–36(n=34) week 10–36(n=37) ABR, median Prestudy 5 12 5.5 3 2 Study 2.82 8.7 0.75 1.48 2.88 P value 0.0015 0.2445 0.0766 0.0039 0.4981 AJBR, median Prestudy 2 9 3.5 2 2 Study 1.46 7.24 0 1.40 1.39 P value 0.0045 0.3484 0.0673 0.0131 0.4111 P values (paired Student’s t test) are nominal, as no multiplicity control was applied. *n=86 for AJBR. †Patients with ≥2 breakthrough bleeds in weeks 0–10. ‡Patients with ≤1 bleeds in weeks 0–10 who were not randomized (randomized arms were filled). Conclusions: BAY 94-9027 prophylaxis resulted in lower ABRs and AJBRs during the 36-week study period compared with prestudy values in patients previously treated with prophylaxis. Subgroup analyses based on prophylactic dosing regimens (including dosing intervals of up to every 7 days) showed that patients who were randomized based on bleeding phenotype during the 10-week run-in period achieved bleeding control that was better than or comparable to their prestudy levels, highlighting the value of individualized phenotype-based dosing with BAY 94-9027. In addition, prophylaxis with BAY 94-9027 resulted in reduced joint, spontaneous, and trauma bleeds compared with on-demand treatment. Disclosures Boggio: Bayer, Baxter, Novo Nordisk, CSL Behring, Grifols, and Pfizer: Consultancy. Hong:Bayer HealthCare: Employment. Wang:Bayer HealthCare Pharmaceuticals: Employment. Michaels:Bayer HealthCare Pharmaceuticals: Employment.

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Multicenter Pharmacokinetic Evaluation of rFVIII-Fc (Elocta) in a Real Life and Comparison with Non-Extended Half-Life FVIII Concentrates

Blood ◽

10.1182/blood-2018-99-110036 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1196-1196 ◽

Cited By ~ 1

Author(s):

Claire Pouplard ◽

Laurent Sattler ◽

Anne Ryman ◽

Valérie Eschwege ◽

Emmanuel De Maistre ◽

...

Keyword(s):

Half Life ◽

Hemophilia A ◽

Conflicts Of Interest ◽

Phase 1 ◽

Real Life ◽

Strongly Correlated ◽

Chromogenic Assay ◽

Significant Prolongation ◽

Previously Treated ◽

The Impact

Abstract Background: The use of extending half-life (EHL) FVIII or FIX products is today a current strategy in Hemophilia A (HA) patients for improving prophylaxis and reducing the number of IV injections. Fc fusion technology is based on the use of the neonatal Fc receptor and endogenous Fc recycling pathway, thereby prolonging the half-life (T1/2) of rFVIII-Fc. A single dose phase 1/2 pharmacokinetic (PK) study performed in 16 severe HA patients demonstrated a prolonged T ½ of rFVIII-Fc equal to 18.8 hours (mean) compared to 12.2 hours with one conventional rFVIII (Malhangu et al. Blood 2014). The aim of the present study was to analyze PK data collected with Elocta® in "real life" i.e. in a large cohort of patients treated in 13 different French hemophilia care centers, and results were compared to those obtained with conventional FVIII, when available. Importantly, this study was performed without any involvement of Sobi, the pharmaceutical company that provides Elocta® in France. Patients and methods: 113 severe Hemophilia A (HA) patients with the following characteristics were included: mean age 30 years (range 3 - 70); weight 65 Kg (17-125); total FVIII-Fc dose injected 2650 IU (500-5750); FVIII-Fc IU/Kg: 41 (25 - 59); VWF Ag 98% (41-279). The FVIII recovery (R) was calculated as follows: (body weight (Kg) x observed increased in FVIII (%))/administered dose (IU/Kg). The T1/2 was calculated with the following formula: Ln2/((Ln FVIII% T1 - Ln FVIII%T2)/T2 - T1)), with T1 ≥ 4 hours and T2 ≥ 24 hours. Results were compared to those performed with conventional FVIII (non EHL-FVIII) in 48 patients (Advate® n = 14, Refacto® n = 2, Helixate®/Kogenate®/Kovaltry® n = 29, Factane® n = 3) Results: rFVIII-Fc activity measured by one stage clotting assay (OSA) was 20% lower than those obtained with chromogenic assay (CSA) in samples with FVIII levels higher than 20%, but this difference was lower than 10% when FVIII levels < 20%. Therefore, rFVIII-Fc recovery (R) always appeared lower when measured with OSA (Mean 2.38, range 1.33 - 5.7) than with CSA (mean 2.82, ranges 1.35 - 5.5) (p < 0.0001). No correlation was found between this recovery and age, weight, injected doses or VWF Ag levels. Mean T1/2 measured with rFVIII-Fc equaled 15 hours whatever the measurement method used (OSA or CSA), and was strongly correlated with vWFAg levels (R2 = 0.57). Using OSA, significantly lower recovery (1.86 vs. 2.49, p = 0.0002) and T1/2 values (11.75 vs. 15.13 hours, p = 0.0004) were measured in children (< 10 years, n = 19) compared to adults. Similar differences were evidenced with data obtained by CSA (recovery : 2.26 vs. 2.93, p = 0.0009 and T1/2 : 11.4 vs. 15.6 h, p = 0.004, n = 14 children < 10 years). PK parameters of FVIII-Fc were compared to those obtained with non EHL-FVIII (rFVIII or pdFVIII) in 47 patients (mean T1/2 equal to 10.0 hours; range 5.3 - 21.2), and half-lives of these two categories of products were well correlated (r2 = 0.57). However, the apparent benefit provided by FVIII-Fc was variable from one patient to another, with a mean T1/2 rFVIII-Fc / T1/2 FVIII ratio ranging from 0.6 to 2.4 (mean 1.4). Interestingly, the increase in T1/2 with FVIII-Fc was lower than 20% only in patients previously treated with BHK-derived rFVIII i.e. Helixate®/Kogenate®/ Kowaltry® (n=10). Whatever the FVIII injected (FVIII-Fc or other non EHL-FVIII), the T1/2 measured was also strongly correlated to vWF levels, which were significantly lower in patients for whom the mean T1/2 rFVIII Fc / T1/2 FVIII ratio was > 1.3 (mean 79% vs 116% in the others, p=0.017). Conclusion: This study is the first to report PK data obtained with rFVIII-Fc (Elocta®) in a large group of HA patients. Our results confirm the benefit of rFVIII-Fc in most HA patients, adults or children, but also emphasize the impact of vWF on half-life of rFVIII-Fc or conventional non EHL-FVIII. Indeed, the benefit of rFVIII-Fc clearly appears higher in patients with lower vWF levels, with a more significant prolongation of T1/2. Disclosures No relevant conflicts of interest to declare.

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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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177lu-Satetraxetan-Lilotomab in the Treatment of Patients with Indolent Non-Hodgkin B-Cell Lymphoma (NHL), Phase 1/2 Safety and Efficacy Data from Four Different Pre-Dosing Regimens

Blood ◽

10.1182/blood.v128.22.1780.1780 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1780-1780 ◽

Cited By ~ 1

Author(s):

Arne Kolstad ◽

Ulf Madsbu ◽

Matthew Beasley ◽

Michael Bayne ◽

Tim Illidge ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Marginal Zone ◽

Phase 1 ◽

Phase 2 ◽

Dosing Regimen ◽

B Cell Malignancies ◽

Dosing Regimens ◽

Equity Ownership ◽

Pre Treatment

Abstract 177Lu-Satetraxetan-lilotomab (Betalutin®) is a novel CD37-binding IgG1 antibody labelled with the beta-emitter lutetium-177, in a ready-to-use formulation currently in Phase 1/2 clinical development for the treatment of Non-Hodgkins lymphoma. CD37 is an internalizing transmembrane antigen highly expressed on most B-cell malignancies, and is a promising therapeutic target. The optimisation of the pre-dosing regimen prior to administration of 177Lu-Satetraxetan-lilotomab may result in an improved safety and efficacy profile. The phase 1 stage of this study is designed with 4 arms to test different pre-dosing regimens (no pre-dosing, rituximab and two doses of lilotomab) on the effect of 177Lu-Satetraxetan-lilotomab. Methods: Patients with relapsed incurable NHL of follicular grade I-IIIA, marginal zone, mantle cell, lymphoplasmacytic and small lymphocytic subtypes and with platelet counts ≥ 150 x109/l were eligible for inclusion in the study. All patients received pre-treatment with rituximab (375 mg/m2) to deplete peripheral B cells and improve biodistribution of the labelled antibody. Pre-dosing with lilotomab (cold anti-CD37 antibody) was given in arms 1 and 4 or rituximab in arm 3, within 4 hours of 177Lu-Satetraxetan-lilotomab to block binding in the non-tumour tissue. The pre-treatment and pre-dosing regimen used in each arm is summarised below: Arm 1: rituximab day1 and 8, lilotomab (40 mg) plus Betalutin day 29 Arm 2: rituximab day 1 and 8, Betalutin day 29 Arm 3: rituximab day 1, rituximab plus Betalutin day 15 Arm 4: rituximab day 1, lilotomab (100 mg/m2) plus Betalutin day 15 The starting dose for Arm 1 was10 MBq/kg and was 15 MBq/kg for arm 2, 3 and 4 and in phase 2. Response was assessed by FDG PET/CT scans at 3 and 6 months post-treatment and then by CT scan up to 5 years after treatment. The results of the protocol specified interim analysis will be presented. Results: A total of36 patients have been enrolled into study, of which 24 are currently evaluable. Patients enrolled into the study had either follicular (n=20), mantel cell (n=2) or marginal zone (n=2) lymphoma. The number of prior therapies ranged from 1 to 8. The efficacy and safety results from patients enrolled into Arms 3 and 4 and treated with two different pre-dosing regimens will be presented for the first time. The most common toxicities observed were hematologic with all dose limiting toxicities (DLTs) being reversible and manageable and related to thrombocytopenia and neutropenia. At a dose of 15 MBq/kg, pre-dosing with 40 mg of lilotomab (Arm 1 and phase 2) reduced the incidence of hematological DLTs to 14% (2/14 patients) compared with 100% (2/2 patients) with no pre-dosing in Arm 2. No DLTs have been reported at 10 MBq/kg in either Arm 1 or 2. Fourteen serious adverse events (SAEs) were reported by 8 patients: Atrial fibrillation (n=2) and platelet count decreased (n=2) were the only SAEs reported by more than one patient. There have been no deaths and no secondary malignancies or other long-term safety events. The overall tumor response rate observed in 23 patients evaluable for efficacy was 57%, comprising 7/23 complete responses, 6/23 partial responses, 5/23 stable disease and 5/23 with progressive disease. In addition, one patient had a confirmed transformed lymphoma at 3 months. One patient is still in remission more than 3 years after treatment and two further patients are still in remission more than 2 years after treatment. Conclusions: Betalutin has the potential to be a novel, safe and effective therapy for B-cell malignancies with durable responses. Betalutin, a single dose, ready-to-use formulation, has a predictable and manageable safety profile which is improved by pre-dosing. Most AEs were haematological, all transient and reversible. Disclosures Kolstad: Nordic Nanovector: Other: Membership of Scientific Advisory Board. Illidge:Nordic Nanovector: Consultancy. Dahle:Nordic Nanovector ASA: Employment, Equity Ownership. Baylor Curtis:Nordic Nanovector: Employment. Østengen:Nordic Nanovector: Employment. Turner:Nordic Nanovector: Employment. Hartvig Larsen:Nordic nanovector: Equity Ownership. Holte:Mundipharma: Research Funding; Amgen: Research Funding.

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Fitusiran Treatment Impacts on Health-Related Quality of Life in Subjects with Hemophilia A and B with Inhibitors Assessed with the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL)

Blood ◽

10.1182/blood-2020-142266 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-24

Author(s):

Sylvia Von Mackensen ◽

Pratima Chowdary ◽

Sarah Mangles ◽

Qifeng Yu ◽

Baisong Mei ◽

...

Keyword(s):

Quality Of Life ◽

Hemophilia A ◽

Phase 1 ◽

Phase 2 ◽

Publicly Traded ◽

Advisory Committees ◽

Related Quality ◽

Health Related ◽

Dose Dependent

Background: Fitusiran, an investigational RNA interference treatment for people with hemophilia A or B (PwH), with or without inhibitors, has shown dose-dependent lowering of antithrombin, increase in thrombin generation, and decrease in bleeding frequency in clinical trials. The novel mechanism of action and long pharmacodynamic effect enables once-monthly subcutaneous administration. This sustained hemostatic protection and less burdensome administration may improve patient-reported outcomes (PRO). Objective: To evaluate changes in PRO in terms of patient-relevant improvements in health-related quality of life (HRQoL) in PwH with inhibitors (PwHI) on prophylactic fitusiran treatment. Methods: Fitusiran was evaluated in a phase 1 dose-escalation study (NCT02035605) followed by a phase 2 open-label extension (OLE) study (NCT02554773) with monthly subcutaneous fixed doses of 50 mg or 80 mg. HRQoL was assessed using the Haem-A-QoL and the EuroQol 5 Dimensions (EQ-5D) questionnaires at baseline and at end of study in a cohort of 17 PwHI (Hemophilia A, n=15; Hemophilia B, n=2) from the phase 1 study. Results: Subjects previously treated on-demand or prophylactically had a mean (standard deviation [SD]) age of 34.6 (10.3) years and a mean (SD) number of bleeding episodes in the 6 months before baseline of 16.6 (10.7). Mean (SD) changes from baseline to end of study (day 84 or later) in Haem-A-QoL total (-9.2 [11.2]) and physical health (−12.3 [15.1]) domain scores suggest clinically meaningful improvement (lower scores indicate better HRQoL). Numeric reduction (i.e., improvement) in all other domains appeared to be dose-dependent (greater improvement in the 80 mg group) (Table 1). Changes in EQ-5D utility and EQ-VAS scores were not clinically meaningful. Further analyses in PwH with and without inhibitors from the phase 2 OLE will be presented. Conclusions: Fitusiran prophylaxis may improve HRQoL - particularly the Haem-A-QoL 'Physical health' domain (painful swelling, joint pain, pain with movement, difficulty walking, and time to get ready) as shown in a cohort of 17 PwHI . Additional analyses from ongoing OLE and phase 3 studies are planned to quantify the patient-relevant changes with fitusiran treatment in all hemophilia patients over time. Disclosures Von Mackensen: Sanofi, Bayer, Sobi, Chugai, Kedrion, Spark: Consultancy; Biotest, Sobi, CSL Behring: Honoraria; Novo Nordisk, Sobi: Research Funding. Chowdary:BioMarin: Honoraria; Bayer, CSL Behring, Freeline, Novo Nordisk, Pfizer and Sobi: Research Funding; Chugai, CSL Behring, Novo Nordisk, Pfizer, Roche, Sobi: Speakers Bureau; Bayer, Chugai, CSL Behring, Freeline, Novo Nordisk, Pfizer, Roche, Sanofi, Shire (Baxalta), Sobi, Spark: Membership on an entity's Board of Directors or advisory committees. Mangles:Roche, Takeda, Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi, Octapharma, Novo Nordisk, Shire and Roche/Chugai: Other: travel funding. Yu:Sanofi: Other: was an employee and stockholder of Sanofi, at the time of study; Albireo Pharmaceuticals, Inc: Current Employment. Mei:Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson:Sanofi: Current Employment, Current equity holder in publicly-traded company. Dasmahapatra:Sanofi: Current Employment, Current equity holder in publicly-traded company.

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A Population Pharmacokinetic Model for Concizumab Based on Phase 1 and Phase 2 Trial Data

Blood ◽

10.1182/blood-2020-140255 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-4

Author(s):

Trine Høyer Rose ◽

Christian Hollensen ◽

Henrik Agersø ◽

Rune Viig Overgaard

Keyword(s):

Rate Constant ◽

Drug Disposition ◽

Hemophilia A ◽

Phase 1 ◽

Population Pharmacokinetic ◽

Phase 2 ◽

Publicly Traded ◽

Phase 3 ◽

Target Mediated Drug Disposition ◽

Population Pk

Introduction Concizumab is a high-affinity anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in clinical investigation for the subcutaneous (SC) treatment of patients with hemophilia. The data generated from phase 1 and 2 concizumab trials have been used to develop a population pharmacokinetic (PK) model with the aim of supporting dose selection for phase 3 trials. WMethods The objective of this study was to develop a model to describe the PK of concizumab across administration routes in various groups of patients with hemophilia to generate a generally applicable population PK model of concizumab. The model was developed based on available PK data from four phase 1 trials (for both intravenous [IV] and SC concizumab administration) and two phase 2 trials (for SC concizumab administration). Trial populations in the phase 1 trials included both healthy subjects and patients with hemophilia, whilst the phase 2 trials enrolled patients with hemophilia A or B with inhibitors and patients with hemophilia A without inhibitors. A structural population PK model was first developed based on phase 1 data and the final population PK model was then estimated using data from both phase 1 and phase 2 trials. Simulations were performed for phase 3 concizumab exposure using a full parametric simulation (n=10,000), including both inter-individual and intra-individual variability for the selected population. Randomly sampled body weights from a normal distribution with mean and variance corresponding to body weight distribution from phase 2 trials were used to simulate patient profiles. WResults The population PK dataset used for the model comprised 1,504 observations from 119 subjects (89 patients and 30 healthy individuals), with a mean age of 35 years (range: 18-65 years) and mean body weight of 74.4 kg (range: 47.1-130 kg). The PK model parameters were first estimated based on phase 1 data alone, and after fixing the majority in order to ensure robustness of the model only a few parameters were re-estimated based on phase 1 and 2 data combined. The PK model (Figure 1) was evaluated by standard goodness-of-fit plots and qualification assessments. Using visual predictive checks, it was shown that the model was able to reproduce the median and the 5th and 95th percentiles of the observed concizumab concentrations from phase 1 and 2 trials, and so it was deemed suitable for simulation purposes. The PK model suggested a target-mediated drug disposition following concizumab binding to TFPI at the endothelium, and subsequent elimination of the complex to account for the non-linear elimination. WConclusions The developed model accurately described the PK of concizumab delivered at a wide dose range by either SC or IV administration to both healthy subjects and patients with hemophilia A or B with and without inhibitors. The model was used for simulations to select the dosing regimen for subsequent phase 3 studies. Figure 1. Concizumab pharmacokinetic model. Structure of the final concizumab PK model for SC and IV dosing with target-mediated drug disposition via the endothelial TFPI. CL, clearance; doseiv, intravenous dose; dosesc, subcutaneous dose; IV, intravenous; ka, absorption rate constant; kcom, elimination rate constant of the concizumab-TFPI complex; kon and koff, rate constants for binding of concizumab to the endothelial TFPI; ktr, rate constant from the transit compartment; Q, inter-compartmental clearance; Rtot, amount of endothelial TFPI available for concizumab binding; SC, subcutaneous; TFPI, tissue factor pathway inhibitor; V, volume. Figure Disclosures Høyer Rose: Novo Nordisk A/S: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Hollensen:Novo Nordisk: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Agersø:Novo Nordisk A/S: Current Employment. Viig Overgaard:Novo Nordisk A/S: Current Employment, Current equity holder in publicly-traded company.

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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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Latest Results From The PUP-GCP Clinical Trial: A Low Inhibitor Rate In Previously Untreated Patients With Severe Hemophilia A Treated With Octanate

Blood ◽

10.1182/blood.v122.21.3596.3596 ◽

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.

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

Blood ◽

10.1182/blood-2015-03-630897 ◽

2015 ◽

Vol 126 (9) ◽

pp. 1078-1085 ◽

Cited By ~ 126

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.

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Evaluation of the Safety, Immunogenicity, and Hemostatic Efficacy of Nonacog Gamma (BAX326) in Previously Treated and Naïve Patients with Severe or Moderately Severe Hemophilia B: A Continuation Study

Blood ◽

10.1182/blood-2018-99-111295 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1197-1197

Author(s):

Jerzy Windyga ◽

Oleksandra Stasyshyn ◽

Werner Engl ◽

Srilatha D. Tangada

Keyword(s):

Phase 1 ◽

Hemophilia B ◽

Phase 2 ◽

Severe Hemophilia ◽

Employment Equity ◽

On Demand ◽

Pivotal Study ◽

Pediatric Study ◽

Equity Ownership ◽

Hemostatic Efficacy

Abstract Introduction: The severe or moderately severe deficiency of coagulation factor IX (FIX) in patients with hemophilia B causes frequent and potentially serious bleeding, whereby joint bleeding can be one of the more serious complications. Management of bleeding episodes (BE) involves on-demand or prophylaxis replacement therapy for FIX. This study evaluated the safety profile and efficacy of a recombinant FIX, nonacog gamma (BAX326, RIXUBIS®, Shire, Lexington, MA, USA), for treatment of bleeding in adults and children with severe (FIX level <1 IU/dL) or moderately severe (FIX level 1-2 IU/dL) hemophilia B. Methods: This phase 3, prospective, open-label, multicenter, continuation study (NCT01286779) comprised patients from a phase 1/3 pivotal study (NCT01174446), a phase 2/3 pediatric study (NCT01488994), and naïve patients aged 2-70 years at screening. Nonacog gamma treatment was administered at the discretion of the investigator. Patients who transferred from earlier studies received on-demand treatment or prophylaxis, while naïve patients received only prophylaxis. Prophylactic dosing was standard (SP; 40-60 IU/kg in patients ≥12 years of age or 40-80 IU/kg in patients <12 years of age, twice weekly), modified (MP; ≤100 IU/kg, as determined by the investigator), or tailored to the patient's pharmacokinetic profile (PK; ≤120 IU/kg). One dose (75 ± 5 IU/kg) was given at each of the study visits to assess incremental recovery of nonacog gamma over time. The primary outcome measure was the occurrence of adverse events (AE) and serious AEs (SAE), regarded as possibly or probably related to nonacog gamma. Secondary outcomes included additional safety, annualized bleeding rate (ABR), hemostatic efficacy rating at resolution of bleed, and number of infusions per bleeding episode. Results: The study enrolled 117 patients, from 40 sites in 16 countries, of which 115 patients (74 patients with severe hemophilia, and 41 patients with moderately severe hemophilia) received treatment with nonacog gamma. All patients were male, with 21 patients <12 years of age and 94 patients ≥12 years of age.These included 65 patients from the phase 1/3 pivotal study, 20 patients from the phase 2/3 pediatric study and 30 naïve patients. Of 115 patients included in the full ananlysis set, 110 were treated with a prophylaxis regimen (SP, 108 patients; MP, 26 patients; PK, 3 patients ) and 13 patients received nonacog gamma on demand. Patients could switch between treatment regimens and may therefore be included in more than one regimen. A total of 459 AEs were reported in 85 (73.9%) patients; 443 nonserious AEs in 85 patients and 16 SAEs in 9 patients. The most commonly reported AEs included: nasopharyngitis (55 in 25 patients), arthralgia (48 in 15 patients), and pyrexia (23 in 14 patients). Only 2 nonserious AEs (positive antibody (Ab) tests to rFurin) in 2 patients, were considered nonacog gamma-related. These tests were negative by the time of study completion and considered transient. None of the SAEs were deemed related to nonacog gamma. No patients developed Abs to FIX, there were no thrombotic events or severe allergic reactions during or after treatment, and no significant treatment-related changes in vital signs. Clinical efficacy of nonacog gamma was rated as excellent or good in 991 (89%) of 1112 BEs. For all BEs, a mean (± SD) number of 1.8 (± 1.65) infusions were required until bleed resolution (Table 1). For on-demand treatment, the median ABR was 16.5 (n=13), whereas for overall prophylaxis the median ABR was 1.3 (n=108) (Table 2). Disclosures Windyga: Alnylam, Baxalta, Bayer, Novo Nordisk, Octapharma, Rigel Pharmaceuticals, Roche, Sanofi, Shire, SOBI: Research Funding; Alexion, Baxalta, Bayer, CSL Behring, Ferring Pharmaceuticals, Novo Nordisk, Octapharma, Rigel Pharmaceuticals, Roche, Sanofi, Shire, Siemens, SOBI, Werfen: Membership on an entity's Board of Directors or advisory committees. Stasyshyn:CSL Behring, Novonordisk, Shire: Honoraria; Novonordisk, Pfiser , Shire: Speakers Bureau. Engl:Shire: Employment, Equity Ownership. Tangada:Shire: Employment, Equity Ownership.

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