Concizumab prophylaxis in persons with hemophilia A or B with inhibitors: patient-reported outcome results from the phase 3 explorer7 study.

Background: Patient-reported outcomes (PROs) reflect patient perceptions of disease and treatment and are important for evaluating new therapies. Objectives: Evaluate the effects of once-daily concizumab prophylaxis on health-related quality of life (HRQoL), treatment burden, and treatment preference in males aged ≥12 years with hemophilia A/B with inhibitors. Methods: Patients enrolled in the multicenter, open-label explorer7 phase 3 study (ClinicalTrials.gov identifier: NCT04083781) were randomized to receive no prophylaxis (arm 1) or concizumab prophylaxis (arm 2) or were nonrandomly allocated to concizumab prophylaxis (arms 3 and 4). The study included questionnaires to assess patients' perception of HRQoL (Haemophilia Quality of Life Questionnaire for Adults), treatment burden (Hemophilia Treatment Experience Measure), and treatment preference (Haemophilia Patient Preference Questionnaire). Results: The estimated treatment difference between patients receiving concizumab prophylaxis vs no prophylaxis at week 24 for Haemophilia Quality of Life Questionnaire for Adults "total score" was -22.6 points (95% CI, -42.5; -2.7), directionally favoring patients receiving concizumab prophylaxis. For Hemophilia Treatment Experience Measure "total score," the estimated treatment difference was -19.9 points (95% CI, -34.3, -5.6) in favor of concizumab vs no prophylaxis. The majority of patients receiving concizumab expressed a preference for concizumab over their previous treatment, the main reasons being "fewer bleeds," "require less time," and "less painful to inject." Across all PROs, there were less responses collected than anticipated, limiting interpretations. Conclusion: PROs collected during the explorer7 study showed improvements in some domains of HRQoL, treatment burden, and patient treatment preference in persons with hemophilia A or B with inhibitors receiving concizumab prophylaxis compared with no prophylaxis.

Disease and treatment burden of patients with haemophilia entering the explorer6 non-interventional study.

OBJECTIVES: We aimed to characterise baseline disease and treatment burden in a large population with haemophilia A/B, both with (HAwI/HBwI) and without (HA/HB) inhibitors. METHODS: The prospective, non-interventional explorer6 study included patients ≥12 years old with severe HA, severe/moderate HB or HAwI/HBwI of any severity, treated according to local standard of care (excluding previous/current exposure to concizumab or emicizumab). Baseline characteristics and historical clinical data were collected and patient-reported outcomes, including treatment burden, were assessed. RESULTS: The explorer6 study enrolled 231 patients with haemophilia (84 HAwI/HBwI) from 33 countries. At baseline, patients with HA/HB treated with prophylaxis had the lowest median annualised bleeding rates (ABRs; 2.0), irrespective of haemophilia type; of these patients, 27.5% (HA) and 31.4% (HB) had target joints. Patients with HAwI/HBwI treated episodically reported the highest treatment burden. Of these patients, 28.5% (HAwI) and 25.1% (HBwI) performed sports activities in the month before screening. CONCLUSION: Despite receiving routine clinical care, historical and baseline information from patients enrolled in explorer6 showed that patients with HA/HB treated episodically and patients with HAwI/HBwI had higher ABRs, higher treatment burden and participated in sports less than those with HA/HB treated with prophylaxis. Emerging treatments could be beneficial in addressing these unmet medical needs.

Immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients with severe hemophilia A: interim results from a phase 3, prospective, multicenter, open-label study.

AIM: To determine the immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients (PUPs) with severe hemophilia A (HA). METHODS: This prospective, phase 3 study (NCT02615691) was conducted in PUPs, or patients with ≤2 exposure days (EDs) prior to screening, aged <6 years with severe HA. The primary endpoint was incidence of factor VIII (FVIII) inhibitor development. This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing FVIII inhibitors or had developed a confirmed inhibitor at any time. RESULTS: Of the enrolled patients, 59/80 (73.8%) received ≥1 dose of rurioctocog alfa pegol; 54 received prophylaxis, and 35 on-demand treatment. Incidence of inhibitor development was 0.19 (10/52). Total annualized bleeding rate (95% CIs) was 3.2 (2.0-5.0) for patients receiving prophylaxis and 3.2 (1.6-6.3) for on-demand treatment. Hemostatic efficacy of most bleedings was rated as 'excellent' or 'good' after 24 hours (122/131 [93.1%]) and at resolution (161/170 [94.7%]). Five patients received ≥1 dose of rurioctocog alfa pegol for immune tolerance induction (ITI) and 1 patient was defined as having ITI success. Thirteen patients experienced 14 treatment-related adverse events, including 10 cases of FVIII inhibitor development. CONCLUSION: This is the first prospective study of rurioctocog alfa pegol for the treatment of PUPs with severe HA. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02615691).

Phase 3 Trial of Concizumab in Hemophilia with Inhibitors.

BACKGROUND: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors. METHODS: We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed. RESULTS: Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time. CONCLUSIONS: Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.).

Targeting an elevated FVIII level using personalized rurioctocog alfa pegol prophylaxis in specific patient populations with hemophilia A: post hoc subanalysis of the randomized, phase 3 PROPEL study.

Background: The phase 3, prospective PROPEL study demonstrated that pharmacokinetic (PK)-guided prophylaxis targeting elevated factor VIII (FVIII) troughs in patients with hemophilia A resulted in lower annualized bleeding rates (ABRs) and a higher proportion of patients experiencing zero bleeds in the second 6 months of treatment when targeting a FVIII trough of 8-12% versus 1-3%. Objective: To investigate the benefit of PK-guided prophylaxis with rurioctocog alfa pegol targeting two FVIII trough levels in specific patient subgroups in a post hoc analysis using data from PROPEL. Design: This is a post hoc analysis of data from the PROPEL study. The design and primary outcomes of the prospective, randomized PROPEL study (NCT02585960) have been reported previously. Methods: This post hoc analysis reports data stratified by FVIII half-life (t1/2), hemophilic arthropathy status, number of target joints at screening, previous treatment regimen, and ABR range in the 12 months before study entry. Results: Targeting an elevated FVIII trough of 8-12% was associated with higher average FVIII levels over time, regardless of FVIII t1/2 at baseline. The decrease in total ABR between the 8-12% and 1-3% arms was greatest in patients with a FVIII t1/2 of 6 to <12 h (0.7 versus 3.5); a higher number of target joints, that is, at least four target joints, at baseline (0.2 versus 1.6); the presence of arthropathy (0.1 versus 1.7); and those previously treated on-demand (0.3 versus 1.8). Conclusion: These results support the feasibility of targeting elevated FVIII levels using personalized rurioctocog alfa pegol prophylaxis. These benefits may be especially important in patients with a short FVIII t1/2 and those receiving standard prophylaxis with frequent breakthrough bleeds, arthropathy, and target joints. Registration: ClinicalTrials.gov Identifier: NCT02585960; https://clinicaltrials.gov/ct2/show/NCT02585960.

Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Fitusiran, a subcutaneous investigational siRNA therapeutic, targets antithrombin with the goal of rebalancing haemostasis in people with haemophilia A or haemophilia B, regardless of inhibitor status. We aimed to evaluate the efficacy and safety of fitusiran prophylaxis in people with severe haemophilia without inhibitors. METHODS: This multicentre, open-label, randomised phase 3 study was conducted at 45 sites in 17 countries. Male participants aged at least 12 years with severe haemophilia A or B without inhibitors, who had previously been treated on-demand with clotting factor concentrates, were randomly assigned in a 2:1 ratio to receive 80 mg subcutaneous fitusiran prophylaxis once per month or to continue on-demand clotting factor concentrates for a total of 9 months. Randomisation was stratified by the number of bleeding events in the 6 months before screening (≤10 bleeds and >10 bleeds) and by haemophilia type (haemophilia A or B). The primary endpoint was annualised bleeding rate, analysed in the intention-to-treat analysis set. Safety and tolerability were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03417245, and is complete. FINDINGS: Between March 1, 2018, and July 14, 2021, 177 male participants were screened for eligibility and 120 were randomly assigned to receive fitusiran prophylaxis (n=80) or on-demand clotting factor concentrates (n=40). Median follow-up was 7·8 months (IQR 7·8-7·8) in the fitusiran group and 7·8 months (7·8-7·8) in the on-demand clotting factor concentrates group. The median annualised bleeding rate was 0·0 (0·0-3·4) in the fitusiran group and 21·8 (8·4-41·0) in the on-demand clotting factor concentrates group. The estimated mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (3·1 [95% CI 2·3-4·3]) than in the on-demand clotting factor concentrates group (31·0 [21·1-45·5]; rate ratio 0·101 [95% CI 0·064-0·159]; p<0·0001). In the fitusiran group, 40 (51%) of 79 treated participants had no treated bleeds compared with two (5%) of 40 participants in the on-demand clotting factor concentrates group. Increased alanine aminotransferase concentration (18 [23%] of 79 participants in the safety analysis set) was the most common treatment-emergent adverse event in the fitusiran group and hypertension (four (10%) of 40 participants) was the most common in the on-demand clotting factor concentrates group. Treatment-emergent serious adverse events were reported in five (6%) participants in the fitusiran group (cholelithiasis [n=2, 3%], cholecystitis [n=1, 1%], lower respiratory tract infection [n=1, 1%], and asthma [n=1, 1%]) and five (13%) participants in the on-demand clotting factor concentrates group (gastroenteritis, pneumonia, suicidal ideation, diplopia, osteoarthritis, epidural haemorrhage, humerus fracture, subdural haemorrhage, and tibia fracture [all n=1, 3%]). No treatment-related thrombosis or deaths were reported. INTERPRETATION: In participants with haemophilia A or B without inhibitors, fitusiran prophylaxis resulted in significant reductions in annualised bleeding rate compared with on-demand clotting factor concentrates and no bleeding events in approximately half of participants. Fitusiran prophylaxis shows haemostatic efficacy in both haemophilia A and haemophilia B, and therefore has the potential to be transformative in the management of all people with haemophilia. FUNDING: Sanofi.

Eptacog beta efficacy and safety in the treatment and control of bleeding in paediatric subjects (<12 years) with haemophilia A or B with inhibitors.

INTRODUCTION: Eptacog beta is a new recombinant activated human factor VII bypassing agent approved in the United States for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors 12 years of age or older. AIM: To prospectively assess in a phase 3 clinical trial (PERSEPT 2) eptacog beta efficacy and safety for treatment of bleeding in children <12 years of age with haemophilia A or B with inhibitors. METHODS: Using a randomised crossover design, subjects received initial doses of 75 or 225 µg/kg eptacog beta followed by 75 µg/kg dosing at predefined intervals (as determined by clinical response) to treat bleeding episodes (BEs). Treatment success criteria included a haemostasis evaluation of 'excellent' or 'good' without use of additional eptacog beta, alternative haemostatic agent or blood product, and no increase in pain following the first 'excellent' or 'good' assessment. RESULTS: Treatment success proportions in 25 subjects (1-11 years) who experienced 546 mild or moderate BEs were 65% in the 75 µg/kg initial dose regimen (IDR) and 60% in the 225 µg/kg IDR 12 h following initial eptacog beta infusion. By 24 h, the treatment success proportions were 97% for the 75 µg/kg IDR and 98% for the 225 µg/kg IDR. No thrombotic events, allergic reactions, neutralising antibodies or treatment-related adverse events were reported. CONCLUSION: Both 75 and 225 µg/kg eptacog beta IDRs provided safe and effective treatment and control of bleeding in children <12 years of age.

Recombinant single-chain factor VIII in severe hemophilia: Long-term safety and efficacy in previously treated patients in the AFFINITY extension study.

BACKGROUND: rVIII-SingleChain is a recombinant single-chain factor VIII used to treat people with hemophilia A. OBJECTIVES: The aim of this extension study was to investigate the long-term safety and efficacy of rVIII-SingleChain prophylaxis in ≥200 previously treated patients (PTPs) with hemophilia A with ≥100 exposure days (EDs). METHODS: In total, 222 patients were enrolled, of which 204 rolled over from prior rVIII-SingleChain studies. The median age was 21 years (range, 2-65 years), including 155 patients ≥12 years and 67 patients <12 years. Patients continued with their previously assigned dose and regimen, or switched at the investigator's discretion. Patients were treated for a mean duration of 31 months (range, 1-47 months), the mean ED was 342 (standard deviation, 135.5), and 212 (95.5%) patients achieved >100 EDs. When the study ended, most patients were on either a prophylaxis regimen of 34.9 (17-62) IU/kg, 3×/week (N = 88; 39.6%), or 37.2 (13-65) IU/kg, 2×/week regimen (N = 72; 32.4%). RESULTS: Hemostatic efficacy was rated excellent or good in 87.1% of assessed bleeds. The median (range) annualized bleeding rate was 1.21 (0.0-42.6), and the annualized spontaneous bleeding rate (AsBR) was 0.32 (0.0-33.0) for prophylaxis regimens. Median AsBR was similar for patients treated 3×/week and 2×/week (0.31 and 0.30, respectively). Surgical hemostatic efficacy was rated excellent or good in 100% of surgeries. No inhibitors, anaphylactic reactions, or thromboembolic events were reported in PTPs. CONCLUSION: These results confirm the safety and efficacy of rVIII-SingleChain as a long-term prophylaxis treatment modality for PTPs with severe hemophilia A.

PERSEPT 3: A phase 3 clinical trial to evaluate the haemostatic efficacy of eptacog beta (recombinant human FVIIa) in perioperative care in subjects with haemophilia A or B with inhibitors.

INTRODUCTION: Surgical procedures in persons with haemophilia A or B with inhibitors (PwHABI) require the use of bypassing agents (BPA) and carry a high risk of complications. Historically, only two BPAs have been available; these are reported to have variable responses. AIM: To prospectively evaluate the efficacy and safety of a new bypassing agent, human recombinant factor VIIa (eptacog beta) in elective surgical procedures in PwHABI in a phase 3 clinical trial, PERSEPT 3. METHODS: Subjects were administered 200 µg/kg (major procedures) or 75 µg/kg eptacog beta (minor procedures) immediately prior to the initial surgical incision; subsequent 75 µg/kg doses were administered to achieve postoperative haemostasis and wound healing. Efficacy was assessed on a 4-point haemostatic scale during the intra- and postoperative periods. Anti-drug antibodies, thrombotic events and changes in clinical/laboratory parameters were monitored throughout the perioperative period. RESULTS: Twelve subjects underwent six major and six minor procedures. The primary efficacy endpoint success proportion was 100% (95% CI: 47.8%-100%) for minor procedures and 66.7% (95% CI: 22.3%-95.7%) for major procedures; 81.8% (95% CI: 48.2%-97.7%) of the procedures were considered successful using eptacog beta. There was one death due to bleeding from a nonsurgical site; this was assessed as unlikely related to eptacog beta. No thrombotic events or anti-eptacog beta antibodies were reported. CONCLUSION: Two eptacog beta dosing regimens in PwHABI undergoing major and minor surgical procedures were well-tolerated, and the majority of procedures were successful based on surgeon/investigator assessments. Eptacog beta offers clinicians a new potential therapeutic option for procedures in PwHABI.

The safety of activated eptacog beta in the management of bleeding episodes and perioperative haemostasis in adult and paediatric haemophilia patients with inhibitors.

INTRODUCTION: Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA-approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date. AIM: To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care. METHODS: Using a randomized crossover design, 27 subjects in PERSEPT 1 (12-54 years) and 25 subjects in PERSEPT 2 (1-11 years) treated bleeding episodes with 75 or 225 µg/kg EB initially followed by 75 µg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2-56 years) received an initial preoperative infusion of 75 µg/kg (minor procedures) or 200 µg/kg EB (major surgeries) with subsequent 75 µg/kg doses administered intraoperatively and post-operatively as indicated. Descriptive statistics were used for data analyses. RESULTS: Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti-EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee. CONCLUSION: Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use.