PEGylated biologics in haemophilia treatment: Current understanding of their long‐term safety

Baumann, Andreas

doi:10.1111/hae.13875

Cited by 13 publications

(12 citation statements)

References 8 publications

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“…However, PEG levels in these five patients remained stable over the duration of the extension phase. These plasma PEG measurements are in line with predictions based on simulations of preclinical data 11 . No PEG‐related safety concerns (ie PEG‐related AEs, anti‐PEG antibodies, neurological findings [as performed by the investigator] or renal abnormalities) were reported in the extension.…”

Section: Discussionsupporting

confidence: 80%

PROTECT VIII kids extension study: Long‐term safety and efficacy of BAY 94‐9027 (damoctocog alfa pegol) in children with severe haemophilia A

et al. 2021

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Introduction BAY 94‐9027 (damoctocog alfa pegol; an extended half‐life PEGylated recombinant factor VIII [FVIII]) demonstrated efficacy and safety in previously treated paediatric patients (PTPs) aged <12 years with severe haemophilia A in the PROTECT VIII Kids study (NCT01775618). Aim To evaluate the long‐term safety of BAY 94‐9027 in PTPs aged <12 years at enrolment. Methods In the PROTECT VIII Kids study, boys <12 years with severe haemophilia A were enrolled in two age cohorts (6–<12 years and <6 years) and treated prophylactically twice weekly, every 5 days or every 7 days, with BAY 94‐9027 for ≥50 exposure days (EDs). Patients who had completed ≥50 EDs and ≥6 months in the main study or 12‐week safety expansion study were eligible to participate in the extension. Primary safety variable was frequency of inhibitor development; main efficacy variable was annualised bleeding rate (ABR). Results Of 73 PTPs from the main/expansion studies, 59 (81%) entered the extension phase for a median (range) duration of 5.0 (0.4–5.9) years. Overall, 39 patients completed ≥5 years of treatment. No patients developed FVIII inhibitors/anti‐PEG antibodies, and two patients aged <6 years discontinued. Median ABR for total bleeds was 1.5 (<6 years) and 1.9 (6–<12 years). Total ABR improved in the extension vs. the main study. In the last 12 months of treatment, median spontaneous ABR was 0.0 in both age groups. Conclusions BAY 94‐9027 showed long‐term safety and efficacy for the prevention and treatment of bleeds in younger and older paediatric patients with severe haemophilia A.

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Section: Discussionsupporting

confidence: 80%

PROTECT VIII kids extension study: Long‐term safety and efficacy of BAY 94‐9027 (damoctocog alfa pegol) in children with severe haemophilia A

et al. 2021

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“…Properties of the conjugated PEG are known to be driving factors that influence the PK properties of PEGylated proteins [33]. Both the size of the PEG molecule and the type of conjugation are thought to play a role, and it is hypothesized that the differences in these features employed in damoctocog alfa pegol and rurioctocog alfa pegol could contribute to the superior PK profile of damoctocog alfa pegol observed in the current study.…”

Section: Discussionmentioning

confidence: 80%

Direct comparison of two extended half-life PEGylated recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A

et al. 2020

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An open-label, crossover randomized study was performed to compare the pharmacokinetics (PK) of damoctocog alfa pegol and rurioctocog alfa pegol, two recombinant factor VIII (FVIII) products indicated in patients with hemophilia A, both conjugated to polyethylene glycol to reduce clearance and extend time in circulation. Adult patients (N = 18) with severe hemophilia A (FVIII < 1 IU/dL), previously treated with any FVIII product for ≥ 150 exposure days, were randomized to receive a single 50 IU/kg infusion of damoctocog alfa pegol followed by rurioctocog alfa pegol, or vice versa, with ≥ 7-day washout between doses. FVIII activity was measured using the one-stage clotting assay. PK parameters, including area under the curve from time 0 to the last data point (AUC0–tlast, primary parameter), dose-normalized AUC (AUCnorm), and time to threshold, were calculated based on 11 time points between 0.25 and 120 h post-dose and evaluated using a noncompartmental model. Due to differences in batch-specific vial content used for the study, actual administered median doses were 54.3 IU/kg for damoctocog alfa pegol and 61.4 IU/kg for rurioctocog alfa pegol. Based on actual dosing, a significantly higher geometric mean (coefficient of variation [%CV]) AUCnorm was observed for damoctocog alfa pegol (43.8 h kg/dL [44.0]) versus rurioctocog alfa pegol (36.0 h kg/dL [40.1, P < 0.001]). Based on population PK modeling, median time to reach 1 IU/dL was 16 h longer for damoctocog alfa pegol compared with rurioctocog alfa pegol. No adverse events or any immunogenicity signals were observed. Overall, damoctocog alfa pegol had a superior PK profile versus rurioctocog alfa pegol. Trial registration number: NCT04015492 (ClinicalTrials.gov identifier). Date of registration: July 9, 2019

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“…26 No long-term PEG-related safety concerns have been reported in patients after chronic treatment with other PEGylated proteins, including nonacog beta pegol and certolizumab pegol. 29 Long-term exposure data with BAY 94-9027 over 5 years has been reassuring, and more long-term data will soon be available from the PROTECT VIII Kids extension study. Hypersensitivity reactions associated with other FVIII products are uncommon.…”

Section: Discussionmentioning

confidence: 99%

“…An extensive review of safety data for PEGylated therapies showed no specific association between particular AEs and PEG exposure over a period of decades 26 . No long‐term PEG‐related safety concerns have been reported in patients after chronic treatment with other PEGylated proteins, including nonacog beta pegol and certolizumab pegol 29 . Long‐term exposure data with BAY 94‐9027 over 5 years has been reassuring, and more long‐term data will soon be available from the PROTECT VIII Kids extension study.…”

Section: Discussionmentioning

confidence: 99%

PROTECT VIII Kids: BAY 94‐9027 (PEGylated Recombinant Factor VIII) safety and efficacy in previously treated children with severe haemophilia A

Santagostino

Kenet

Fischer³

et al. 2020

Haemophilia

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Introduction: BAY 94-9027, a site-specifically PEGylated, B-domain-deleted recombinant factor VIII (FVIII) with extended half-life, demonstrated efficacy for bleed prevention and treatment in previously treated adolescents and adults with severe haemophilia A. Aim:To assess BAY 94-9027 in children with severe haemophilia A. Methods:In the two-part PROTECT VIII Kids study, boys <12 years with <1% FVIII and >50 exposure days (EDs) to FVIII were enrolled in two cohorts (<6 years; 6-<12 years) and treated with BAY 94-9027 prophylaxis twice-weekly, every 5 days, or every 7 days at physician discretion for ≥50 EDs (Part 1) or twice-weekly for 12weeks (Part 2). Annualized bleeding rate (ABR) was a primary efficacy endpoint; FVIII inhibitor development was the primary safety variable.Results: At study completion, 25 patients had been treated twice-weekly, 28 in the every-5-day group, and 8 in the every-7-day group. Median ABR for all bleeds was 2.9 (Part 1) and 2.4 (Part 2) and similar in younger and older patients; median ABR for joint bleeds was 0 for both cohorts. In the last 90 days' treatment, median ABR was 0 for younger and older patients (Part 1). Of 149 reported bleeds, 93% were treated with ≤2 infusions. Twelve patients, the majority <6 years (n = 11), discontinued due to apparent loss of efficacy or hypersensitivity. No FVIII inhibitors developed. Conclusions:In PROTECT VIII Kids, which allowed tailoring of prophylaxis to individual clinical response, BAY 94-9027 was efficacious for bleed prevention and treatment in previously treated children with severe haemophilia A. K E Y W O R D Schildren, factor VIII, haemophilia A, polyethylene glycol, prophylaxis e56 |

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PEGylated biologics in haemophilia treatment: Current understanding of their long‐term safety

Cited by 13 publications

References 8 publications

PROTECT VIII kids extension study: Long‐term safety and efficacy of BAY 94‐9027 (damoctocog alfa pegol) in children with severe haemophilia A

PROTECT VIII kids extension study: Long‐term safety and efficacy of BAY 94‐9027 (damoctocog alfa pegol) in children with severe haemophilia A

Direct comparison of two extended half-life PEGylated recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A

PROTECT VIII Kids: BAY 94‐9027 (PEGylated Recombinant Factor VIII) safety and efficacy in previously treated children with severe haemophilia A

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