Long-term safety and efficacy results from the phase 3b, open-label, multicentre Continuation study of rurioctocog alfa pegol for prophylaxis in previously treated patients with severe haemophilia A.

INTRODUCTION: Previous studies reported the efficacy and safety profile of extended half-life PEGylated recombinant factor VIII (FVIII) rurioctocog alfa pegol (TAK-660, SHP660, BAX 855) in preventing bleeding in haemophilia A patients. AIM: This study evaluated long-term safety and efficacy of rurioctocog alfa pegol for prophylaxis and treatment of bleeding in previously treated children and adults. METHODS: In this phase 3b, prospective, open-label, multicentre study (NCT01945593), eligible patients ≤ 75 years with severe haemophilia A (FVIII < 1%) received prophylactic rurioctocog alfa pegol in a fixed dose (FD, twice-weekly or less frequent) or pharmacokinetic (PK)-tailored dose regimen. Co-primary endpoints were incidence of confirmed FVIII inhibitory antibody development and spontaneous annualized bleed rate (ABR), analysed using a generalised linear model. Secondary endpoints included overall haemostatic efficacy, occurrence of adverse events and health-related quality of life (HRQoL). RESULTS: Overall, 216 patients were included; mean (SD) age at enrolment was 22.8 (15.7) years. No patients developed confirmed FVIII inhibitors. The point estimate (95% CI) of mean spontaneous ABR was 1.20 (0.92-1.56) among 186 patients receiving twice-weekly FD prophylaxis and 0.96 (0.54-1.71) among 25 patients receiving PK-tailored prophylaxis. Overall haemostatic efficacy was rated good or excellent in 88.6% of all bleeds. No new safety signals were observed. Patients reported improvements in HRQoL measures of pain, and physical and mental well-being. CONCLUSION: These results highlight the long-term safety and efficacy of rurioctocog alfa pegol prophylaxis in previously treated children and adults with severe haemophilia A, with a safety profile similar to previous studies and continuing ABR reduction.

Perioperative haemostasis with full-length, PEGylated, recombinant factor VIII with extended half-life (rurioctocog alfa pegol) in patients with haemophilia A: Final results of a multicentre, single-arm phase III trial.

INTRODUCTION: Rurioctocog alfa pegol (BAX 855, TAK-660) is a PEGylated, full-length, recombinant factor VIII (rFVIII) with extended half-life developed from unmodified rFVIII (antihaemophilic factor [recombinant]). AIM: To determine the perioperative haemostatic efficacy and safety of rurioctocog alfa pegol in male previously treated patients (PTPs) with severe haemophilia A. METHODS: This multicentre, single-arm, phase III study included PTPs who were to undergo major or minor elective or minor emergency surgical, dental or other invasive procedures. Rurioctocog alfa pegol dose and frequency were individualized based on patients' pharmacokinetic profiles for major surgeries and by rurioctocog alfa pegol incremental recovery for minor surgeries. Haemostatic efficacy was assessed using the Global Haemostatic Efficacy Assessment score. RESULTS: Twenty-one patients aged 16-61 years underwent 21 major and five minor surgeries. For all 24 evaluable surgeries, overall haemostatic efficacy was rated as excellent and blood loss comparable to that expected in non-haemophilic patients. No blood transfusions were required intraoperatively but were administered postoperatively for four surgeries in three patients. Five injury-related postoperative bleeding episodes occurred in five patients, of which two required additional rurioctocog alfa pegol treatment. Two non-serious adverse events of mild severity (increased ALT level and headache) were considered possibly related to rurioctocog alfa pegol. There were no deaths or treatment-related serious adverse events. No patients developed inhibitory antibodies to FVIII or persistent IgG- or IgM-binding antibodies to FVIII, PEG-FVIII or PEG. CONCLUSION: Rurioctocog alfa pegol was well tolerated and effective for perioperative use in patients with haemophilia A and showed no signs of immunogenicity.

Microsimulation to compare activity-related bleed risks between pharmacokinetic-guided rurioctocog alfa pegol prophylaxis and emicizumab.

BACKGROUND: Owing to a lack of clinical study data, computational modeling was used to estimate activity-related bleed risk during prophylaxis with either rurioctocog alfa pegol or emicizumab. RESEARCH DESIGN AND METHODS: A pharmacokinetic (PK)-based computational model was used to estimate factor VIII (FVIII) levels for individual patients in the PROPEL study who were treated with PK-guided rurioctocog alfa pegol prophylaxis targeting FVIII trough levels of 1-3% or 8-12%. Emicizumab was assumed to have 20% FVIII equivalency. Six hypothetical patient activity profiles were created using the National Hemophilia Foundation's physical activity risk ratings scale. For each profile and treatment regimen combination, the total bleed risk over a 2-week period was estimated relative to a patient who was participating in a low-risk activity with 0% FVIII, and the overall relative bleed risks were compared. RESULTS: For all evaluated activity profiles, rurioctocog alfa pegol prophylaxis targeting either 1-3% or 8-12% FVIII trough levels was associated with a lower estimated bleed risk compared with emicizumab prophylaxis with assumed 20% FVIII equivalency (P < 0.001). CONCLUSION: Although this model does not reflect actual patient outcomes, it suggests that PK-guided rurioctocog alfa pegol prophylaxis may reduce the bleed risk during physical activities.

Real-world study of rurioctocog alfa pegol and emicizumab in US clinical practice among patients with hemophilia A.

BACKGROUND: FVIII replacement is standard treatment for hemophilia A without inhibitors, but non-factor therapies, such as emicizumab, are changing the treatment landscape. We explore the ramifications of switching treatment. METHODS: Pharmacy database data (July 2017-May 2020) from patients with hemophilia A without inhibitors who switched to rurioctocog alfa pegol or emicizumab prophylaxis after ≥6 months' prophylaxis with another FVIII product were analyzed for total mean weekly consumption, dosing frequency, product wastage, and ABR. RESULTS: Post-switch mean weekly consumption of prophylactic rurioctocog alfa pegol and emicizumab were 6224 IU/kg and 109 mg, respectively. Dosing schedules for emicizumab were primarily weekly (48.2%) and every 2 weeks (40.0%). Most patients in the rurioctocog alfa pegol cohort received treatment twice-weekly (83.3%). Mean product wastage of emicizumab (8.4%) was significantly higher versus rurioctocog alfa pegol (-0.3%; P < 0.001). Mean annualized emicizumab and rurioctocog alfa pegol wastage during prophylaxis was 330.82 mg and -974.80 IU, respectively. ABR change was not significantly different (P = 0.527) for patients switching to emicizumab (-1.05) or rurioctocog alfa pegol (-1.53). CONCLUSIONS: Bleed rates were similar for patients receiving prophylaxis with emicizumab or rurioctocog alfa pegol after switching from prophylaxis with another FVIII. However, wastage associated with dispensing inaccuracies was greater with emicizumab.

Polyethylene glycol 20 kDa-induced vacuolation does not impair phagocytic function of human monocyte-derived macrophages.

Conjugation to polyethylene glycol (PEG) is commonly used to enhance drug delivery and efficacy by extending the half-life of the drug molecule. This has important implications for reducing treatment burden in diseases that require chronic prophylaxis, such as hemophilia. Clearance of PEG molecules with high molecular weights (≥ 40 kDa) has been reported to cause cellular vacuolation in mammals. Rurioctocog alfa pegol (PEGylated recombinant coagulation factor VIII) contains a 20-kDa PEG. This study investigated the effects of exposure to 20-kDa PEG (10 µg/ml to 10 mg/ml) on the morphology and function of human monocyte-derived macrophages (MDMs) in vitro. Exposure to PEG for 24 hours was associated with significant vacuolation only at concentrations of 1 mg/ml or more, which far exceed the levels associated with clinically relevant doses of rurioctocog alfa pegol. Immunofluorescence staining of PEG was detected in the cytoplasm of MDMs, indicating uptake into the cells. No impairment of MDM phagocytic activity (ability to ingest fluorescently labeled Escherichia coli) was observed with 24-hour exposure to PEG, even at concentrations associated with significant vacuolation. Furthermore, PEG exposure did not have significant effects on cytokine secretion in resting or lipopolysaccharide-stimulated MDMs, or on the expression of cell surface markers in stimulated MDMs. Cell viability was not affected by 24-hour exposure to PEG. In conclusion, vacuolation of human MDMs after exposure to 20-kDa PEG only occurred with PEG concentrations far in excess of those equivalent to clinically relevant doses of rurioctocog alfa pegol and did not affect MDM viability or functionality. Together, these results support the concept that PEG-mediated vacuolation is an adaptive cellular response rather than a toxic effect.

Comparison of Real-World Dose and Consumption for Two Extended Half-Life Recombinant Factor VIII Products for the Treatment of Hemophilia A in the United States.

Background: US patients with hemophilia A can receive prophylaxis with extended half-life recombinant factor VIII (rFVIII) products, including efmoroctocog alfa (fragment crystallizable fusion protein) and rurioctocog alfa pegol (antihemophilic factor [recombinant], PEGylated). Objective: To evaluate dosing patterns and weekly consumption of extended half-life rFVIII products in the United States. Methods: We performed a retrospective analysis using the US Specialty Pharmacy Database (2015-2018). Included patients had a diagnosis of hemophilia A, ≥2 consecutive monthly claims for efmoroctocog alfa or rurioctocog alfa pegol for prophylaxis, and weight data. Outcome measures included weekly dosing frequency and dispensed weekly dose. Results: The analysis included 774 patients (efmoroctocog alfa, 506; rurioctocog alfa pegol, 268). Mean (SD) age was 24.2 (15.8) and 26.3 (14.9) years for patients receiving efmoroctocog alfa and rurioctocog alfa pegol, respectively; mean (SD) weight was 68.4 (36.8) and 79.8 (37.7) kg, respectively. The most frequent efmoroctocog alfa regimen was twice weekly (45.7%), followed by every 4 days (20.6%), every 3 days (9.1%), and 3 times per week (7.5%). The most frequent rurioctocog alfa pegol regimen was twice weekly (72.4%), followed by 3 times per week (8.7%), every 4 days (7.6%), and every 3 days (5.5%). The proportion of efmoroctocog alfa twice-weekly dispensing records increased from 31.5% to 50.9%, and every 4 days dispensing records decreased from 31.3% to 14.5% (2015-2018). The proportion of rurioctocog alfa pegol dispensing records remained broadly stable (2016-2018). Overall, mean (SD; median) weekly prophylactic dose was 105.4 (77.9; 92.6) IU/kg with efmoroctocog alfa, and 96.8 (41.9; 90.9) IU/kg with rurioctocog alfa pegol. Conclusion: In this database study, the most frequently observed dosing frequency was twice weekly for patients receiving efmoroctocog alfa or rurioctocog alfa pegol. The observed mean weekly consumption was slightly higher, and variation was greater, in patients receiving efmoroctocog alfa versus rurioctocog alfa pegol.

Efficacy, safety, and immunogenicity of rurioctocog alfa pegol for prophylactic treatment in previously treated patients with severe hemophilia A: a systematic review and meta-analysis of clinical trials.

Background: Patients with severe hemophilia often present with painful joint and soft tissue bleeding which may restrict them from their daily activities. The current standard of care still relies on a regular prophylactic factor VIII (FVIII), which has a high daily treatment burden. Recently, rurioctocog alfa pegol, a third-generation recombinant FVIII with a modification in its polyethylene glycol (PEG) component, has been developed. Several trials have studied this synthetic drug as bleeding prophylaxis in severe hemophilia A. This study aims to evaluate the efficacy, safety, and immunogenicity of rurioctocog alfa pegol for previously treated patients with severe hemophilia A. Methods: This study was conducted in conformity with the PRISMA guidelines. Data were retrieved from PubMed, Scopus, Cochrane Library, Wiley Online Library, and CINAHL (via EBSCOhost). Study qualities were assessed using the Methodological Index for Non-Randomized Studies (MINORS) and Modified Jadad scales. Results: Four studies involving 517 previously treated severe hemophilia A patients were included in this study. The pooled mean of total annualized bleeding rate (ABR) and hemostatic efficacy was 2.59 (95% CI = 2.04-3.14) and 92% (95% CI = 85%-97%), respectively. Only 30 (2.3%) non-serious and one (1.4%) serious adverse events were considered related to rurioctocog alfa pegol treatment. At the end of the studies, no development of FVIII inhibitory antibodies was observed. None of the developed binding antibodies to FVIII, PEG-FVIII, or PEG was correlated to the treatment efficacy and safety. Conclusions: Despite the limited availability of direct comparison studies, our analyses indicate that rurioctocog alfa pegol could serve as a safe and effective alternative for bleeding prophylaxis in previously treated hemophilia A patients. Moreover, it appears to have low immunogenicity, which further increases the safety profile of the drug in such clinical conditions.

Subgroup analysis of a phase 2/3 study of rurioctocog alfa pegol in patients with severe hemophilia A: efficacy and safety in previously treated Korean patients.

BACKGROUND: The efficacy and safety of extended half-life, full-length, pegylated recombinant factor VIII rurioctocog alfa pegol [BAX 855, ADYNOVATE (USA)/ADYNOVI (Europe); Baxalta US Inc., a Takeda company, Lexington, MA, USA] was investigated in previously treated Korean patients with severe hemophilia A (HA). METHODS: A post hoc data analysis from the international, multicenter, phase 2/3 PROLONG-ATE study of rurioctocog alfa pegol in patients with severe HA (NCT01736475) determined annualized bleeding rates (ABRs) and rates of adverse events (AEs) in Korean patients treated in this study. RESULTS: All 10 enrolled Korean patients receiving rurioctocog alfa pegol (9 prophylaxis, 1 on-demand) completed the study [median (range) age, 28.0 (12-50) yr; weight, 64.8 (45-90) kg; 8 patients had ≥1 target joint at screening]. Median (range) ABR was 1.9 (0.0-14.5) for patients on prophylaxis and 62.2 for the patient receiving on-demand treatment. The hemostatic efficacy of rurioctocog alfa pegol was rated "excellent" or "good" and only single infusions were required per bleeding episode. ABRs improved in most patients compared with prestudy values. No dose adjustments were required for prophylaxis, and the dosing frequency was reduced in 8 patients, compared with their previous prophylaxis regimen. No serious AEs were reported; all 9 nonserious AEs (in 3 patients) were mild in severity and unrelated to the study treatment. CONCLUSION: This post hoc analysis of a small group of Korean patients with severe HA indicated that rurioctocog alfa pegol was effective, and no serious AEs were observed. For most patients, the dosing frequency was also reduced compared with their previous regimen.

Polyethylene Glycol Exposure with Antihemophilic Factor (Recombinant), PEGylated (rurioctocog alfa pegol) and Other Therapies Indicated for the Pediatric Population: History and Safety.

Polyethylene glycol (PEG) is an inert, water soluble polymer, used for decades in pharmaceuticals. Although PEG is considered safe, concerns persist about the potential adverse effects of long-term exposure to PEG-containing therapies, specifically in children, following the introduction of PEGylated recombinant factor products used for the treatment of hemophilia. Given the absence of long-term surveillance data, and to evaluate the potential risk, we estimated PEG exposure in the pediatric population receiving PEGylated therapies with pediatric indications administered intravenously or intramuscularly. We used a range of pediatric weights and doses based on prescribing information (PI) or treatment guidelines. PIs and reporting websites were searched for information about adverse events (AEs). For a child weighing 50 kg on the highest prophylactic dose of a FVIII product, the range of total PEG exposure was 40⁻21,840 mg/year; for factor IX (FIX) products, the range was 13⁻1342 mg/year; and for other products, the range was 383⁻26,743 mg/year, primarily as a derivative excipient. No AE patterns attributable to PEG were found for any of these products, including potential renal, neurological, or hepatic AEs. Our analyses suggest the pediatric population has had substantial exposure to PEG for several decades, with no evidence of adverse consequences.

Subgroup analysis of a phase 2/3 study of rurioctocog alfa pegol in patients with severe hemophilia A: efficacy and safety in previously treated Korean patients

BACKGROUND: The efficacy and safety of extended half-life, full-length, pegylated recombinant factor VIII rurioctocog alfa pegol [BAX 855, ADYNOVATE (USA)/ADYNOVI (Europe); Baxalta US Inc., a Takeda company, Lexington, MA, USA] was investigated in previously treated Korean patients with severe hemophilia A (HA). METHODS: A post hoc data analysis from the international, multicenter, phase 2/3 PROLONG-ATE study of rurioctocog alfa pegol in patients with severe HA (NCT01736475) determined annualized bleeding rates (ABRs) and rates of adverse events (AEs) in Korean patients treated in this study. RESULTS: All 10 enrolled Korean patients receiving rurioctocog alfa pegol (9 prophylaxis, 1 on-demand) completed the study [median (range) age, 28.0 (12–50) yr; weight, 64.8 (45–90) kg; 8 patients had ≥1 target joint at screening]. Median (range) ABR was 1.9 (0.0–14.5) for patients on prophylaxis and 62.2 for the patient receiving on-demand treatment. The hemostatic efficacy of rurioctocog alfa pegol was rated “excellent” or “good” and only single infusions were required per bleeding episode. ABRs improved in most patients compared with prestudy values. No dose adjustments were required for prophylaxis, and the dosing frequency was reduced in 8 patients, compared with their previous prophylaxis regimen. No serious AEs were reported; all 9 nonserious AEs (in 3 patients) were mild in severity and unrelated to the study treatment. CONCLUSION: This post hoc analysis of a small group of Korean patients with severe HA indicated that rurioctocog alfa pegol was effective, and no serious AEs were observed. For most patients, the dosing frequency was also reduced compared with their previous regimen.