Comment on “Enhanced Half-Life Recombinant Factor VIII Concentrates for Hemophilia A: Insights from Pivotal and Extension Studies”

We read with interest the recently published article by Di Minno et al[1] who present a systematic literature review of pivotal and extension studies on extended half-life (EHL) recombinant factor VIII (rFVIII) concentrates (rFVIII Fc fusion protein [rFVIIIFc], BAX 855, BAY 94–9027, and N8-GP). Among the identified results, four pivotal studies in adult patients, four pivotal studies in children, and four extension studies were included for discussion. The inferred (although not stated) aim appears to discuss the change in treatment landscape brought about by the introduction of EHL rFVIII concentrates. The authors reported data for prophylactic treatment, monthly consumption, and overall bleeding rates for each regimen. They conclude that the EHL rFVIII concentrates discussed seem to be highly effective and safe, and allow for longer dosing intervals, which reduce but do not eliminate the burden of treatment. Furthermore, the individualized tailoring of treatment, along with the requirement for less frequent dosing, allows for the optimization of hemophilia care by increasing protection from bleeding and improving patient adherence to therapy.[1]

While we agree that EHL rFVIII concentrates are highly effective, we would like to clarify inaccuracies identified in the data presented from ASPIRE,[2] a long-term (up to 5.3 years follow-up), extension study. ASPIRE assessed the safety and efficacy of rFVIIIFc in previously treated adolescent/adult patients and children with severe hemophilia A who completed the Phase 3 clinical trials A-LONG and Kids A-LONG, respectively. Of note, Di Minno et al cite the final ASPIRE results to a congress abstract[3] and not the full publication,[2] which was available for inclusion.[2] Publications describing interim results[4] [5] and a longitudinal analysis of A-LONG and ASPIRE pooled data[6] were also cited but are not relevant to include.

In ASPIRE, patients (≥12 years) were assigned to one of three prophylaxis arms: individualized prophylaxis (IP), weekly prophylaxis (WP), or modified prophylaxis (MP). Those in the IP arm received rFVIIIFc at 25 to 65 IU/kg every 3 to 5 days, or 20 to 65 IU/kg (day 1) and 40 to 65 IU/kg (day 4) twice weekly. Dose and interval were adjusted to target trough levels of 1 to 3% or higher. Patients in the WP arm received 65 IU/kg rFVIIIFc once every 7 days. The MP arm, which was not part of the pivotal study, was included in the extension study for those patients who could not adhere to prophylaxis with IP or WP. Patients who switched to this arm had their treatment further personalized by the investigator. Reasons for switching to MP could include but were not limited to: the addition of “prevention” doses before strenuous activity, targeting a factor VIII trough level >3% if the bleeding history and/or physical activity level required, and less frequent dosing. Tailoring of the dosing regimen in the MP arm meant that, although the median dosing interval was 5.0 days, there was a broad range of dosing intervals (with an interquartile range of 4.0–6.9 days).[2] Therefore, as the MP arm varied greatly between patients it is incorrect to represent it as a distinct 5 day dosing interval regimen.[1] The nature of the MP arm means that it should not have been included in Table 4 and Fig. 3 of the Di Minno et al publication but rather addressed in the same manner as the BAY 94–9027 variable frequency extension study group.[1] We would also question describing the IP arm within the ASPIRE study as a distinct 3.5 days dosing interval regimen given the interquartile range of 3.5 to 5.0 days.[2] Furthermore, rFVIIIFc data for both the IP and WP arms of the extension study should have been presented in Table 4 of the Di Minno publication in the same manner as the data for the pivotal study (i.e., displayed in merged cells for 3.5, 4.0, and 5.0 days to represent the varying dosing interval). While the WP arm was a fixed 7-day dosing interval, we would like to note that this dosing regimen is not approved by any regulatory authorities.[7] [8]

Regarding the rFVIIIFc data presented by Di Minno et al, it is unclear how this was used to calculate monthly consumption; we are unable to obtain the same results using the methodology described by the authors (calculated as: weekly dose × 52 weeks/12 months). The consumption based on our calculations (using the aforementioned method) was obtained from the final published data of the ASPIRE study,[2] and is included in [Table 1] of this letter. It is also of note that our calculations approximate more closely with those presented in Fig. 3 of the Di Minno publication, which appear higher than the numbers presented in Table 4.[1] Additionally, the annualized bleeding rates (ABR) for rFVIIIFc WP (2.2) and MP (4.1) groups in the extension study have been switched in the text of Di Minno et al, while in their Table 4 the ABR rate for the WP group is incorrectly stated as 2.5 (see [Table 1]).[1]

Table 1 Comparison of rFVIIIFc dosing regimen, associated ABRs and monthly consumption

	Results published in Table 4 of Di Minno et al[1]			Results derived from the final ASPIRE paper (Nolan et al)[2]
	IP	MP	WP	IP	MP	WP
Dosing regimen, median (IQR)	3.5	5.0	7.0	3.5 (3.5–5.0)	5.0 (4.0–6.9)	7.0 (7.0–7.1)
ABR	0.7	4.1	2.5	0.7	4.1	2.2
rFVIIIFc median weekly dose, IU/kg	–	–	–	79.5	70.6	65.7
rFVIIIFc monthly consumption,[a] IU/kg	320	280	260	344.5	305.9	284.7

Abbreviations: ABR, annualized bleeding rate; IP, individualized prophylaxis; IQR, interquartile range; MP, modified prophylaxis; rFVIIIFc, recombinant FVIII Fc fusion protein; WP, weekly prophylaxis.

^a Monthly consumption was calculated as (weekly consumption × 52) / 12.

Di Minno et al explain in the text that direct comparisons between concentrates cannot be made due to the heterogeneity of the patient characteristics and study designs.[1] However, they present data from the different studies alongside each other in both table and figure format (see Table 4 and Figs. 2, 3, and 4 of the Di Minno et al publication),[1] which invites comparison. Such comparison of data requires application of robust statistical analysis, using methods capable of adjusting for the large degree of heterogeneity that exists between the studies.[9] Tabulated and graphical representation of data risk giving the reader an incorrect inference on the efficacy of the different concentrates. Publications such as the one presented by Di Minno et al have the potential to influence clinical practice and the data they contain should be correct, source verifiable, and not misleading.

Publication History

Article published online:
08 November 2021

• References

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• 2 Nolan B, Mahlangu J, Pabinger I. et al. Recombinant factor VIII Fc fusion protein for the treatment of severe haemophilia A: final results from the ASPIRE extension study. Haemophilia 2020; 26 (03) 494-502
• 3 Nolan B, Mahlangu J, Young G. et al. ASPIRE final results confirm established safety and sustained efficacy for up to 4 years of treatment with rFVIIIFc in previously treated subjects with severe hemophilia A. Blood 2018; 132 (Supplement 1): 1192
• 4 Nolan B, Mahlangu J, Perry D. et al. Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with haemophilia A. Haemophilia 2016; 22 (01) 72-80
• 5 Nolan B, Konkle BA, Mahlangu J. et al. Efficacy and Safety of rFVIIIFc Prophylaxis in Pediatric, Adolescent, and Adult Subjects with Severe Hemophilia A over 3–4 Years: The ASPIRE Study. Res Pract Thromb Haemost 2017; PB 1774 (01) 781
• 6 Konkle B, Young G, Liesner R. et al. Long-term efficacy and safety of prophylactic treatment with recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with severe haemophilia A: final longitudinal analysis of A-LONG/ kids A-LONG and ASPIRE. Haemophilia 2019; 25 (Suppl. 01) 55
• 7 Bioverativ Therapeutics Inc. ELOCTATE® Prescribing Information 2019. Accessed September 27, 2021 at: https://www.fda.gov/media/88746/download
• 8 Swedish Orphan Biovitrum AB (publ). ELOCTA® Summary of Product Characteristics 2019. Accessed September 27, 2021 at: https://www.ema.europa.eu/en/documents/product-information/elocta-epar-product-information_en.pdf
• 9 Bowden J, Tierney JF, Copas AJ, Burdett S. Quantifying, displaying and accounting for heterogeneity in the meta-analysis of RCTs using standard and generalised Q statistics. BMC Med Res Methodol 2011; 11 (01) 41