Enhanced Half-Life Recombinant Factor VIII Concentrates for Hemophilia A: Final Results from Extension Studies

We thank Horneff et al for their comment[1] on our earlier article.[2] As detailed in the introduction section, we reported on the design and results of pivotal and extension studies conducted with enhanced half-life recombinant factor VIII (EHL-rFVIII) products (Fc-fusion and PEGylated rFVIII) specifically clarifying that great caution is necessary when comparing different FVIII concentrates due to heterogeneity in characteristics of patients enrolled in each study.[3] Moreover, study design, prophylaxis schedule, prevalence of target joint, and study duration are important confounding factors, potentially affecting calculations of annualized bleeding rate (ABR) and concentrate consumption. Indeed, A-LONG and PROTECT were based on tailored prophylaxis schedules, whereas PROLONGATE and PATHFINDER 2 were characterized by a fixed-dose prophylaxis approach.[3]

As to extension studies, we cited the final ASPIRE results to a congress abstract and not the full publication,[4] because this latter was not available for inclusion when our manuscript was submitted to the Journal. For the same reason also, final results of PROTECT, PROLONGATE, and PATHFINDER 2 studies were not cited.[5] [6] [7] Although our manuscript was available online on December 2020, the final draft was submitted several months before and, because of COVID-19 pandemic outbreak, editorial procedures have been longer than expected. However, we agree with Horneff et al that in the rapidly evolving hemophilia treatment landscape, a continuous update is needed. Accordingly, we have now updated data on ABR and monthly consumption considering final reports published for ASPIRE, PROTECT, PROLONGATE, and PATHFINDER 2 ([Table 1]).[4] [5] [6] [7] Here, we report all treatment arms available in published extension studies. We agree with Horneff et al that the Modified Prophylaxis (MP) arm was included in the ASPIRE for patients who could not adhere to Individualized Prophylaxis (IP) or Weekly Prophylaxis (WP), because further personalization of the treatment at investigator discretion was performed. A significant heterogeneity in dosing intervals is found both for MP arm and for IP arm ([Table 1]). This is somehow expected, especially in studies characterized by tailoring of treatment. Indeed, also the PROTECT extension study,[4] in which specific prophylactic schedules are identified, a range of dosing intervals is reported ([Table 1]). Thus, in the attempt to provide some practical insights about ABR and monthly consumption, prophylaxis schedule imputation for the ASPIRE data was based on reported median dosing intervals. For consistency, the variable arm (VAR) included in the PROTECT extension study is reported as an every-5-days prophylaxis schedule based on median number of infusions reported. This approach, although not exempt from some margins of error, might be a compromise to estimate ABR and consumption for all EHL-FVIII concentrates and not only for those characterized by studies with distinct dosing intervals. However, translation of reported information into clinical practice should consider recommendations reported by U.S. Food and Drug Administration and European Medicines Agency in the summary of product characteristics for each EHL-FVIII concentrate ([Table 1]).

Table 1 Major outcome data of extension studies on enhanced half-life FVIII concentrates

	ASPIRE[a] efmoroctocog alfa			PROLONGATE extension[b] rurioctocog alfa pegol		PROTECT extension damoctocog alfa pegol				PATHFINDER 2 extension turoctocog alfa pegol
Treatment schedule	IP	MP	WP	FD[c]	PK-tailored	2 times/week	5 d	VAR	7 d	4 d	7 d
Number of patients	110	21	27	186	25	23	33	28	23	87	23
Infusion frequency	3.5 d[d] (3.5–5.0)	5 d[d] (4.0–6.9)	7 d[d] (7.0–7.1)	4.1 d[e] (3.9–4.2)	3.3 d[e] (3.0–3.8)	3.4 d[f] (2.5–3.8)	4.9 d[f] (3.1–5.2)	4.9 d[f] (2.9–6.7)	6.9 d[f] (5.3–7.5)	4 d	7 d
Median ABR[d]	0.7 (0.0–2.7)	4.1 (1.2–8.8)	2.2 (0.4–5.1)	1.62 (0.52–2.83)		1.6 (0.8–3.6)	1.2 (0–4.6)	3.1 (1.1–5.9)	0.7 (0–1.7)	0.8[g] (0–2.4)	1.7[g] (0.4–6.4)
Mean ABR[e]				2.23 (1.85–2.69)	2.64 (1.70–4.08)	3.46 (2.70–4.45)
Monthly consumption	345[d]	306[d]	285[d]	380[e]	470[e]	326[d]	292[d]	319[d]	261[d]	380[e]	326[e]
Zero bleed				26.5%	40%	17.4%	27.3%	3.6%	34.8%	28.8%[g]	13.1%[g]
FDA	50 IU/kg every 4 d. Adjust dose based on patient response with dosing in the range of 25–65 IU/kg at 3- to 5-d intervals In children < 6 y of age: 50 IU/kg twice weekly. Adjust dose based on patient response with dosing in the range of 25–65 IU/kg at 3- to 5-d intervals. More frequent or higher doses up to 80 IU/kg may be required			40–50 IU/kg twice weekly in adults and adolescents (12 y and older) 55 IU/kg twice weekly in children (<12 y) with a maximum of 70 IU/kg Adjust the dose and dosing intervals based on the patient's clinical response		30–40 IU/kg twice weekly Based on the bleeding episodes, the regimen may be adjusted to 45–60 IU/kg every 5 d A regimen may be further individually adjusted to less or more frequent dosing				50 IU/kg every 4 d in adolescents/adults In children (<12 y), 65 IU/kg twice weekly. A regimen may be individually adjusted to less or more frequent dosing based on bleeding episodes
EMA	50 IU/kg at intervals of 3–5 d. The dose may be adjusted based on patient response in the range of 25–65 IU/kg In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary			40–50 IU/kg twice weekly in 3- to 4-d intervals. Adjustments of doses and administration intervals may be considered based on achieved FVIII levels and individual bleeding tendency		45–60 IU/kg every 5 d. Based on patient clinical characteristics, the dose can also be 60 IU/kg every 7 d or 30–40 IU/kg two times per week				50 IU/kg every 4 d. Adjustments of doses and administration intervals may be considered based on achieved factor VIII levels and individual bleeding tendency

Abbreviations: ABR, annualized bleeding rate; EMA, European Medicines Agency; FD, fixed dose; FDA, U.S. Food and Drug Administration; IP, Individualized Prophylaxis; MP, Modified Prophylaxis; PK, pharmacokinetics; VAR, variable arm; WP, Weekly Prophylaxis.

^a Including 61 pediatric patients.

^b Including 65 pediatric patients.

^c Including 57 patients receiving prophylaxis every 5 days with an ABR of 2.10 (1.54–2.86) and 15 patients receiving prophylaxis every 7 days with an ABR of 2.74 (1.44–5.20).

^d Median values (interquartile ranges).

^e Mean values (95% confidence intervals).

^f Median values (ranges).

^g Data on entire trial duration.

Overall, final data from extension studies suggest a persistent good efficacy profile for all EHL-FVIII, with low ABR values, accompanied by a relevant percent of patients reporting zero bleed. In addition, considering the reduction in the number of intravenous injections, the overall concentrate consumption is likely lower than that usually reported with standard FVIII concentrates. However, great caution is necessary when considering the efficacy of novel therapies for hemophilia. In the frame of a multidisciplinary approach to hemophilia care, it should be mandatory to improve outcome assessment going beyond ABR and consumption data, also considering imaging, functional, and patient-reported outcomes.[8]

Publication History

Article published online:
23 December 2021

• References

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