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\begin{document}

\title{Practical Challenges Associated with Efanesoctocog Alfa (ALTUVIIIO)
Prophylaxis in a 19-month-old}



\author[1]{Jessica N. Mistretta}%
\author[1]{Maria G. Español}%
\author[1]{Michael Tarantino}%
\author[1]{Dane C. Christ}%
\author[1]{Maureen D. Jones}%
\author[1]{Jonathan Roberts}%
\affil[1]{Bleeding \& Clotting Disorders Institute}%


\vspace{-1em}



  
  \date{June 18, 2024}


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Practical Challenges Associated with Efanesoctocog Alfa (ALTUVIIIO)
Prophylaxis in a 19-month-old

with Severe Hemophilia A

Jessica N. Mistretta\textsuperscript{1}, Maria G.
Espa\selectlanguage{ngerman}ñol\textsuperscript{1,2}, Michael D. Tarantino\textsuperscript{1,2},
Dane C. Christ\textsuperscript{1}, Maureen D. Jones\textsuperscript{1},

Jonathan C. Roberts\textsuperscript{1,2}

\textsuperscript{1}Bleeding \& Clotting Disorders Institute, Peoria IL
USA

\textsuperscript{2}Departments of Pediatrics and Medicine, University of
Illinois College of Medicine at Peoria, Peoria, IL USA

\textbf{Correspondence:}

Jonathan C. Roberts, MD

427 W Northmoor Rd, Peoria IL 61614

309-692-5337

\emph{jroberts@ilbcdi.org}

\textbf{Running Title:} Challenges associated with ALTUVIIIO

\textbf{Keywords:} Hemophilia, prophylaxis, efanesoctocog alfa

\textbf{Target Journal:} Pediatric Blood and Cancer - Letter to the
Editor

\textbf{Word Count} : 846 (limit 850)

\textbf{Tables} : 2 (limit 2)

\textbf{References} : 6 (limit as needed)\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
ADVATE & Recombinant Factor VIII\tabularnewline
ADYNOVATE & PEGylated recombinant Factor VIII\tabularnewline
ALTUVIIIO & Efanesoctocag Alfa {[}Antihemophilic Factor (Recombinant),
Fc-VWF-XTEN Fusion Protein{]}\tabularnewline
CVAD & Central venous access device\tabularnewline
EMA & European Medicine Agency\tabularnewline
FVIII & Factor VIII\tabularnewline
IVIG & Intravenous Immunoglobulin\tabularnewline
rFVIII & Recombinant Factor VIII\tabularnewline
VWF & Von Willebrand Factor\tabularnewline
\bottomrule
\end{longtable}

\textbf{Introduction:}

Hemophilia A is an inherited coagulation disorder characterized by a
deficiency in factor VIII (FVIII) with severity determined by residual
FVIII activity: severe (FVIII activity \textless{}1\%), moderate (FVIII
activity 1 to 5\%), and mild (FVIII activity 5 to
40\%)\textsuperscript{1,2}. Individuals with a severe bleeding phenotype
are at increased risk for developing life-threatening bleeding events,
including spontaneous bleeds\textsuperscript{1,2}. Since the 1990's, the
standard of care has been prophylaxis with plasma-derived or recombinant
factor concentrates to prevent bleeding episodes and associated joint
damage\textsuperscript{1,2}. The majority of prophylactic FVIII
concentrates available require administration twice or thrice weekly to
effectively prevent bleeding events\textsuperscript{2,3}. Until
Efanesoctocog Alfa {[}Antihemophilic Factor (Recombinant), Fc-VWF-XTEN
Fusion Protein{]} (ALTUVIIIO), Sanofi), a once weekly injection, was FDA
approved in February 2023 for prophylactic use in adults and children
with Hemophilia A\textsuperscript{4}. Due to the large hydrodynamic
volumes of the two XTEN polypeptide chains and binding to the D'D3
fragment of VWF and Fc, there is reduced clearance and degradation rates
which allows a longer half-life and activity time\textsuperscript{,4}.

Historically, it has been challenging to administer factor VIII
concentrate in young children without the presence of a central venous
access device (CVAD). Some families choose to forgo CVADs and infuse
peripherally due to the known complications of infection, malfunction,
and thrombosis risk. We herein describe such a case and unique
challenges associated with use of ALTUVIIIO.

\textbf{Case Presentation:}

A newborn male born via uncomplicated vaginal delivery was diagnosed
with severe hemophilia A after being transferred from an outlying
hospital for continued bleeding from heel-stick and circumcision sites.
Laboratory evaluation revealed an elevated activated partial
thromboplastin time (aPTT) of 99.7 seconds (21-32 sec), hemoglobin
concentration of 16.0 g/dL (11.0-14.5 g/dL), and factor VIII activity
\textless{}1\%. Genetic testing was obtained due to no family history of
hemophilia that showed an F8 gene variant c.5816C\textgreater{}A
(p.Ala1939Glu). He was prescribed recombinant factor VIII (rFVIII)
concentrate (ADVATE, Takeda, Tokyo, Japan) 60 IU/kg on day two of life
as well as red blood cell transfusion for a decreased hemoglobin
concentration of 6.9 g/dL. Bleeding was controlled with further ADVATE
60 IU/kg every 8 hours for 2 days, then every 12 hours for 2 days
without bleeding recurrence.

At six months of age, the patient was prescribed prophylaxis with once
weekly PEGylated rFVIII (ADYNOVATE, Takeda, Tokyo, Japan), due to
requiring multiple on-demand doses for spontaneous and traumatic soft
tissue bleeding. His parents desired to avoid implantation of a CVAD due
to the associated known risks. His mother was successfully trained on
peripheral venous access and infusion of FVIII concentrates. As he
became more mobile, his parents noticed an increase in spontaneous
ecchymosis despite 1-2 times weekly ADYNOVATE prophylaxis and became
concerned for potentially more severe bleeding events. After multiple
discussions regarding treatment options, the parents chose to remain on
FVIII prophylaxis with ALTUVIIIO (Sanofi Pharma, Paris, France) while
avoiding CVAD placement.

At 19-months of age, the patient received his first \textasciitilde{}50
IU/kg prophylactic dose of ALTUVIIIO (actual 56 IU/kg, 3 -- 220 IU
vials). His weight at the time of initial infusion was 11.9kg. The
ALTUVIIIO package insert recommends infusion rate at no faster than 6
minutes per vial if body weight is \textless{}20 kg (Table
2)\textsuperscript{4}. This is reportedly due to 5\% sucrose in the
final formulation of ALTUVIIIO, which is in accordance with the maximum
infusion rate for intravenous immunoglobulin (IVIG) containing sucrose
per the European Medicine Agency (EMA) guideance\textsuperscript{4}.
This resulted in a peripheral infusion time of 18 minutes, which was
challenging due to patient age and venous access. The patient's FVIII
activity was obtained prior to and 30 minutes post infusion using the
same one-stage FVIII activity assay used in the clinical trials (Table
1)6. \selectlanguage{english}The patient's parents chose to have subsequent weekly infusions in
the clinic setting due to concern over the long infusion time and
potential for infusion failure and product wastage with home
administration. He tolerated all infusions well with no adverse events.

\textbf{Discussion:}

Our patient's trough FVIII activity was \textgreater{}10\% at seven
days, and higher than reported in XTEND-Kids trial\textsuperscript{5}.
He has experienced zero-breakthrough bleeding episodes to date, which is
consistent with XTEND-Kids data that demonstrated 64\% of patients with
zero bleeding episodes, 82\% with zero joint bleeds, and 88\% with zero
spontaneous bleeds\textsuperscript{5}.

The challenge with initiation of ALTUVIIIO prophylaxis in a
\textless{}20kg child remains the recommended prolonged infusion rate
reportedly due to sucrose contained in the final
formulation.\textsuperscript{4} Per the manufacturer's recommendations,
children \textless{}20 kg require each vial to be infused over six
minutes compared to 2-3 minutes per vial if [?]20 kg. This presents a
unique challenge for prophylactic administration for home use without a
CVAD. Our case should encourage production of expanded vial size
availability of ALTUVIIIO to allow for a single vial infusion over 6
minutes in \textless{}20 kg children. Consideration may also be made for
the package insert to allow peripheral infusion rate as tolerated by the
patient, if this is determined safe through appropriate study.

\textbf{Conflict of Interest}

MGE: HEMA biologics: Consultancy; Octapharma: Consultancy

MDT: Biomarin: Consultancy; Genentech: Consultancy; Novartis:
Consultancy; Octapharma: Consultancy, Other: Clinical trial
investigator; Principia: Consultancy; Takeda: Other: Clinical trial
investigator, Research Funding; Spark: Other: Clinical trial
investigator; Amgen: Consultancy.

JCR: Genentech: Consultancy; Novo Nordisk: Honoraria; Takeda: Honoraria,
Other: Consulting; Sanofi: Honoraria, Other: Consulting; HEMA Biologics:
Other: Consulting; Novartis: Other: Consulting; Pfizer: Honoraria; F.
Hoffmann-La Roche AG: Other: Consulting; CSL Behring: Consulting.

JNM, DCC, and MDJ: declare no conflicts of interest

\textbf{Acknowledgements}

The authors would like to thank the patient and his parents for allowing
the report of his clinical management. JNM and JCR wrote the initial
manuscript. All authors critically reviewed, edited, and approved the
final version of the manuscript for submission, and were involved in the
clinical management of the patient.

\textbf{Funding Information}

The authors acknowledge funding support from the Dills Family Foundation
Center for Research at BCDI

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Matuk-Villazon O, Roberts JC, Corrales-Medina FF, Hemophilia: The
  Past, the Present, and the Future, Pediatr Rev. 2021 Dec
  1;42(12):672-683.
\item
  Srivastava A, Santagostino E, Dougall A, et al. WFH guidelines for the
  management of hemophilia, 3rd edition.
  \emph{Haemophilia.}2020;26(Suppl 6):1--158.
\item
  Konkle BA, Shapiro AD, Quon DV, et al. BIVV001 fusion protein as
  factor VIII replacement therapy for hemophilia A. N Engl J Med
  2020;383:1018-1027.
\item
  Bioverativ Therapeutics Inc. Efanesoctocog alfa {[}antihemophilic
  factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl{]}: US
  prescribing information. 2023.
\item
  Malec L, Peyvandi F, Chan AKC, et al; for the XTEND-Kids Trial Group.
  Efanesoctocog alfa prophylaxis for previously treated patients
  \textless{}12 years of age with severe hemophilia A. ISTH 2023
  Congress; June 24-28, 2023. Abstract LB01.1.
\item
  Pipe S, Sadeghi-Khomami A, Konkle BA, Kitchen S, Negrier C, Liu M,
  Santagostino E, Willemze A, Abad-Franch L, Knobe K, Seth Chhabra E. A
  global comparative field study to evaluate the factor VIII activity of
  efanesoctocog alfa by one-stage clotting and chromogenic substrate
  assays at clinical haemostasis laboratories. Haemophilia. 2023 Oct
  30.~doi: 10.1111/hae.14831.~Online ahead of print.
\end{enumerate}

\textbf{Table Legend}

TABLE 1: FVIII activity levels pre- and post- ALTUVIIIO infusions 1-3.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Factor VIII activity (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Factor VIII activity (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Factor VIII activity (\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Infusion number\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Pre-infusion\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
30 min post infusion\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 days post infusion\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
85\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
28\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
14 (7-day trough)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
87\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
21 (7-day trough)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

TABLE 2: Weight-based vial and injection rate recommendations for
Efanesoctocog alfa4.

\selectlanguage{english}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Participant weight & Minimum injection duration per vial\tabularnewline
10 - \textless{}20 kg & 6 minutes per vial\tabularnewline
20 - \textless{}30 kg & 3 minutes per vial\tabularnewline
[?]30 kg & 2 minutes per vial\tabularnewline
\bottomrule
\end{longtable}

\selectlanguage{english}
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